Biopharmaceutics and Pharmacokinetics
1ST SEMESTER – PRELIM
TOPIC 1: Introduction to Biopharmaceutics
and Pharmacokinetics
BIOPHARMACEUTICS
 It is the science that examines the
interrelationship of the physicochemical
properties of the drug, the dosage form in
which the drug is given, and the route of
administration on the rate and extent of
systemic drug absorption.
 It is the study of the chemical and physical
properties of drugs, their components, and
their activities in living organisms.
 Rate and extent of systematic drug
absorption – also referred to as the
<Bioavailability=
 Bioavailability – measure of the rate and
extent of systemic drug absorption; how much
and how fast a drug is being absorbed by our
body.
 3 major factors that affect the rate and extent
of drug absorption/ drug’s bioavailability – (1)
physicochemical properties of a drug, (2)
dosage form/ physical form of the drug
containing both inactive and active
ingredients
Pharmacokinetics
 It is the study of the time course of drug
movement in the body during absorption,
distribution, and elimination.
 Movement of drugs inside our body
 Derived from the Greek words <Pharmakon= =
drug; <kinetikos= = moving/movement
 A branch of pharmacology
 Pharmacology – general study of drugs and its
property
 Pharmacodynamics – study of the
biochemical and physiologic effects of
drugs; what the drug does to the body
 Pharmacokinetics – study of the time
course of drug movement in the body
during the absorption, distribution, and
elimination; what the body does to the
drug
LADMER SYSTEM
 Series of processes which effectively describes
the journey or the movement of the drug
inside our body.
 LIBERATION
 ABSORPTION
Pharmacokinetics
 DISTRIBUTION
Processes
 METABOLISM
 EXCRETION
 RESPONSE – Pharmacodynamics Process
ø Drug Disposition – Distribution, Metabolism,
and Excretion
ø Drug Elimination – Metabolism and Excretion
Liberation
 It is delivery of the active ingredient from a
dosage form into solution.
 Drug release process
 Liberate means <to free=
 In order to be able a drug to be absorbed by
our body, it should be in a form of solution.
2 COMPONENTS OF LIBERATION
 Disintegration - A state in which any residue
of the tablet, except fragments of insoluble
coating, remaining on the screen of the test
apparatus in the soft mass have no
palpably firm core. The process where in the
large and solid particles are broken down to
smaller or finer particles.
 Dissolution - A process by which a chemical or
drug becomes dissolved in a solvent. Also
considered to be the rate-limiting step for
absorption.
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ø Rate-limiting step  The is because of the: First pass effect

- It is the slowest step in a series of kinetic  First pass effect (or Presystemic
processes. metabolism) - a phenomenon in which a
drug gets metabolized at a specific
Dosage forms in which Liberation is altered:
location in the body that results in a
 Parenteral (Intravenous (IV), Intramuscular reduced concentration of the active drug
(IM), Intradermal (ID), Subcutaneous (SC)) upon reaching its site of action or the
– bypass the liberation process because it systemic circulation
is already in a form of solutions already
Example: 100 mg Morphine  F = 0.25 or 25% -
 Per oral – no longer undergo disintegration means that 25 mg lang ang maabsorbed ng
ø sublingual tablets – intended to be
body natin at makakaabot sa ating bloodstream
dissolved under the tongue
or systemic circulation dahil nag undergo sa first
ø buccal tablets – intended to be
pass effect.
dissolved inside the cheek pouch
Distribution
Absorption
 It is the transfer of the drug from the blood to
 It is the process of uptake of the compound
extravascular fluids and tissues
from the site of administration into the
 The amount of blood perfusion in an area of
systemic circulation.
the body also affects the rate at which the
 Transfer of drug from the site of administration drug could be distributed there.
into the systemic circulation.
 Blood – main organ or principle organ for
 It is also the movement of the drug from the
distribution; responsible for the transport of
site of application to the bloodstream.
different substances all throughout our
 Main organ for drug absorption: small intestine
body and responsible for transporting our
 Dosage forms that bypass absorption:
drug molecules to the different tissues of
 Intracardiac Injection – the drugs are
our body, more specifically to transport our
directly injected to the heart or heart
drug molecules to its specific target tissue
muscle
or target site.
 Intravascular Injection – the drugs are
directly injected to the blood vessels Metabolism
ø 2 types of intravascular injection:
 Also known as Detoxification/Biotransformation
- Intravenous Injection – drug
 Refers to the process in which the drug
injected in veins
undergoes a chemical reaction in order to
- Intra-arterial Injection – drug
become more readily excretable.
injected into the arteries
 Simply the conversion of a drug molecule to
Bioavailability (F) its inactive form or more readily excretable
form (polar form).
 Bioavailability - A measurement of the rate
 Liver – main organ or principle organ for
and extent of systemic absorption of
drug metabolism
therapeutically active drug
 An Enzymatic or Biochemical transformation
 F = 1 or 100% - means that the drugs is
of the drug substance to (usually less toxic)
completely absorbed.
metabolic products, which may be
 Oral drugs - F < 1 (less than 1), hindi
eliminated more readily from the body
naaabsorbed completely or 100% of dose
 Metabolic products – metabolite
pag oral drugs
 Xenobiotics – foreign chemicals present in
our body

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Excretion
 Final loss of the drug substance or its
metabolites from the body
 Kidneys – major organ for excretion
 polar metabolites through the kidney –
Renal Excretion; excreted via kidney, urine
 non-polar drugs through the bile – Biliary
Excretion; excreted through the bile, feces
 Renal Excretion – more common type of
excretion process; prerequisite = the
metabolize drug product should be polar in
nature;
 Biliary Excretion
 Bile - digestive fluid produced and
secreted by the liver; that digestive fluid is
used in order to break down fats; excreted
through feces
 Biliary recycling –reabsorption of bile in the
small intestine
Response
 Refers to the therapeutic effect,
subtherapeutic effect, side effect and toxic
effect of a drug.
 Refers to the direct measure of the
pharmacologic effect of a drug.
 Therapeutic effect – means the drug is able to
produce a beneficial or favorable effect in
which the expected therapeutic outcome is
achieved.
 Subtherapeutic effect – means the physiologic
effect of the drug is not enough to achieve
the desired therapeutic outcome
 Side effect – refers to the other secondary
effects of the drug other than the desired or
intended effect
 Finasteride – drug used for the treatment
of Benign prostatic hyperplasia (BPH)
 Beneficial side effect: promote hair growth
 Benign prostatic hyperplasia (BPH) –
condition that is very common in older
man wherein there is abnormal growth or
increase in size of prostate
 Alopecia – hair loss
 Toxic effect – refers to the harmful effects
produce by a drug, especially if the dose
administered is too high or too excessive.
Clinical Pharmacokinetics
 Application of pharmacokinetic methods to
drug therapy.
 The study of the relationships between drug
dosage regimens and concentration–time
profiles
 Dosage regimen – how much and how
frequent, often a drug is administered or
taken
 Dosage regimens 2 components: dose
and dose frequency
 Dose – how much of the drug is
administered
 Dose frequency – how frequent the drugs
is take or administered
 Concentration-time profiles – graph that
shows the amount of drug present in the
blood in a specific period of time.
Three fundamental parameters:
a. Clearance
- volume of fluid completely cleared of drug
per unit time
- unit: mL/min
- indicator of drug elimination
b. Volume of distribution
- apparent volume into which the drug has
distributed to produce the measured
concentration
- Hypothetical amount/volume of fluid or
plasma that is necessary to dissolve a
certain dose or amount of drug in order to
achieve or produce a certain plasma
concentration.
- unit: L
- used to quantify and describe the drug
distribution process
c. Elimination half life
- time taken for 50% of the drug to be
eliminated
- denoted as: t½
- amount of time required to reduce/
eliminate the concentration of a drug by
50% or ½ of the dose of the drug
- Ex. Paracetamol -> half-life = 2 hrs. (200 mg
 after 2 hrs  100 mg.. and so on until ma
eliminate ang drug from our body)
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TDM (Therapeutic Drug Monitoring)
 Employed for very potent drug to optimize
efficacy and to prevent any adverse toxicity
 Branch of clinical pharmacology that
specializes in the measurement of medication
levels in blood
CPKS (Clinical Pharmacokinetic Service)
 Provides pharmacokinetic and drug analysis
services for safe drug monitoring
 Referred to the different clinical services that
deal with pharmacokinetic and drug analysis
services for safe drug monitoring.
Therapeutic range
Drug mg/L
Digoxin (drug used to
0.5 - 2.1
treat heart failure)
Amiodarone 1.0 - 2.5
Salicylate 150 - 300
Theophylline 10 - 20
Phenytoin 10 - 20
Carbamazepine 5.0 - 12
ø Potent drug – able to elicit or produce a
strong physiologic and therapeutic effect
even at small doses.
ø Therapeutic range – difference between the
minimum effective concentration (MEC) and
the minimum toxic concentration (MTC) or
maximum safe concentration.
Population Pharmacokinetics
 Study of pharmacokinetics differences of
drugs in various populations.
Experimental Pharmacokinetics
 Development of biologic sampling
techniques, analytical methods for the
measurement of drugs and metabolites and
procedure that facilitates data collection and
manipulation.
 Main goal is to established a pharmacokinetic
profile of a drug product
 Pharmacokinetic profile – comprehensive
description of the absorption, distribution,
metabolism, and excretion characteristics of
a drug.
 Pharmacokinetics experiments:
 In vivo – involves human subjects/
laboratory animals; in Latin, means <within
the living=
 In vitro – employs test apparatus and
equipment without involving human
subjects/ laboratory animals; in Latin,
means <in glass=
- Dissolution testing
Theoretical Pharmacokinetics
 Development of pharmacokinetics models
that predict drug disposition after
administration
 Branch of pharmacokinetics that focuses in
the prediction and calculation of plasma drug
concentration after administration
 Drug disposition – collective term for
distribution and elimination
 Drug elimination – Metabolism and Excretion
PHARMACOKINETICS: MODEL
Model – a hypothesis using mathematical terms
to describe quantitative relationship concisely.
ø Quantitative relationship between the
plasma concentration and time
a. Empirical – a model in which the plasma
concentration and time data are given an
equation is derived from the given data
b. Physiological – describes drug movement in
the body based or organ blood flow and
organ spaces penetrated by the drug
c. Compartmentally based – a model in which
organs with the same blood flow and drug
affinity are grouped together
Compartment Models - Hypothetical space
bound by an unspecified membrane across
which drugs are transferred
ø Refer to the hypothetical group of organs or
tissues which have the same blood flow, drug
affinity and drug distribution.
ø Used to describe drug distribution
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3 COMPARTMENT MODELS  Central compartment – group of tissues or

organs which have very high blood flow,
 Mamillary Model – One or more peripheral
blood perfusion and drug distribution.
compartments connected to a central
 Blood
compartment
 Brain
 Most common model used in clinical
 Liver
pharmacokinetics
 Central compartment: Represent plasma Catenary Model
and HIGHLY perfused tissues which
RAPIDLY equilibrate with the drug
 Catenary Model – Consists of compartments
joined to one another like the compartments
of a train
 Physiologic Pharmacokinetic Model (Flow
Model) – Considers that BLOOD FLOW is  Arranged in a series and follow a certain
responsible for distributing drugs to various sequence.
parts of the body  We do not use this in pharmacokinetic
Mamillary Model computation because it does not give an
accurate description of the actual drug
distribution in our body.

Physiologic Pharmacokinetic Model (Flow Model)

 Most comprehensive model

 Peripheral compartment – groups of tissues or
organs with similar blood flow, blood perfusion
and drug distribution. However, the blood
flow, blood perfusion and drug distribution
here is lesser compared to the central
compartment.
 Rapidly equilibrating compartment –
composed of tissues and organs where
there is a high blood flow, high blood
perfusion and high rate of drug distribution.
However it has lower values compared to
central compartment
- Muscles
- Visceral tissues
 Slowly equilibrating compartment – group
of tissues and organs where there is a slow
blood flow, blood perfusion and slow rate
of drug distribution.
- Fats
- Bones
 Each organ or tissue are treated as a
separate compartment
 Blood flow limited – mas kokonti and supply
ng blood
 Arterial blood – our drug molecules are
distributed to the different tissues via our
arterial blood.
- Blood that is present in the arteries; it is
usually oxygenated blood.
 Venous blood - drug molecules will dissociate
and leave the tissue through the venous
blood
- Blood present in the veins that are usually
unoxygenated blood.

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Pharmacodynamics Importance of measuring plasma

 The study of the relation of the drug
concentration or amount at the site of action
and its pharmacologic response.
Clinical Toxicology
 The study of the adverse effects of drugs and
toxic substances in the body
 <All things are poison and nothing is without
poison; only the dose makes a thing not a
poison.= Stated by Paracelsus
drug concentration
 Adjustment of the drug dosage in order to
individualize and optimize therapeutic drug
regimen
 Provides guide to the progress of disease state
 Enable to modify the drug dosage
accordingly
Relationship between the drug, the drug product,
and the pharmacologic effect

Measurement of Drug Concentrations

 Sampling of biologic specimen

 Invasive Method
 Requires surgical/ parenteral intervention
 Sampling of blood, spinal fluid, synovial
fluid, tissue biopsy
 Non- invasive method
 Summary of LADMER process
 Without surgical/ parenteral intervention
 Feces, Urine, saliva Plasma Conc. Vs Time Curve

Blood
 Highly specialized tissue composed of many
different kinds of components
 Good indicator for drug absorption and drug
elimination
 Serum – no longer contain the clotting
proteins; does not contain fibrinogen.
 Plasma – anticoagulant: heparin
 Whole blood → clot → centrifuge →
supernatant → SERUM
 Whole blood → (+) heparin → centrifuge
→ supernatant → PLASMA  graph that shows the concentration of a drug
in the plasma after administration or over a
specific period of time
 x-axis: independent variable, time
 y-axis: dependent variable, plasma
concentration
 MEC (Minimum effective concentration)
- Needed to produce the desired
pharmacologic effect
- Minimum concentration needed to
produce the desired therapeutic or
pharmacologic effect, wherein if the drug
is below MEC, it only produces a
subtherapeutic effect.

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 MTC (Minimum Toxic concentration) or
Maximum Safe Concentration
- Needed to just barely produce toxic
effects
- Minimum blood level at which our drug
starts to produce minimal toxic effect.
Above MTC: significant toxic effect
 Therapeutic range
- Difference between MTC and MEC, use as
index of safety, safe and effective (gaano
ka-safe ang product).
 Narrow therapeutic range: smaller
difference, hazardous drug product,
high probability of toxicity
 High therapeutic range: safe drugs, low
level chance to induce toxic or harmful
effect
 Onset time/ Onset of time
- Time required to reach MEC
- Needed for the plasma concentration of
the drug to reach MEC
- indicator of onset of action
 Peak time
- time of Maximum drug concentration in
the plasma and a rough marker of
average rate of drug absorption
 Peak Concentration
- Maximum drug concentration
 Duration of action
- Difference between the onset of time and
time for the drug to decline back to MEC
 AUC (Area Under the Curve)
- Amount of drug absorbed systematically
- Total area found under the plasma
concentration vs time curve from the initial
dose to final elimination of the drug from
the body
BIOPHARMACEUTICS
 Biopharmaceutics: science which studies the
different factors that affect the drugs rate and
extent of absorption.
Involves factors that influence:
a. Design of drug product
b. Stability of drug within the drug product
c. Release of the drug from the drug product
d. Rate of dissolution/ release of the drug
from at the absorption site
e. Delivery of drug to the site of action
Biopharmaceutic Considerations in
Drug Product Design
 Therapeutic objective
 Drug (API)
 Route of administration
 Drug dosage and dosage regimen
 Type of drug product
 Excipients
 Method of manufacture
 Drug Disposition – It is the description of drug
distribution and elimination.
PHYSICOCHEMICAL PROPERTIES
a. Drug Dissolution
b. Drug Solubility
c. Particle Size and Surface Area
d. Partition Coefficient and Extent of Ionization
e. Salt Formation
f. Polymorphism
g. Chirality
h. Hydrates
i. Complex Formation
A. Drug Dissolution
 The rate at which the solid drug enters into
solution is often the rate limiting step in
bioavailability.
 The Noyes-Whitney equation describes the
diffusion controlled rate of drug dissolution
 The type and amount of excipients of drugs
can affect its solubility and dissolution rate.
 Binders
 Lubricant: decreases the friction between
tablets/powders and metal surface;
common excipients in tablets
- very nonpolar and lipophilic
- Ex. Magnesium stearate
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D. Partition Coefficient and Extent of Ionization
 The partition coefficient of a drug is the ratio
 Disintegrant: promotes the rapid
breakdown of solid dosage forms
B. Drug Solubility
 In a saturated solution is a static (equilibrium)
property. The dissolution rate of a drug is a
dynamic property related to the rate of
absorption.
 maximum concentration of a substance that
can be completely dissolve in a given solvent
at a certain temperature and pressure
 "Like dissolves like"
 High polarity = high solubility in GIT = high
dissolution rate = low absorption (high polarity)
 Extent of Ionization
 Need both polar enough and nonpolar
enough
C. Particle Size and Surface Area
 inversely related
 As solid drug particle size decreases, particle
surface area increases.
 Low Particle Size = High Surface Area= High
Dissolution Rate (faster absorption)
 The powders have high dissolution rate than
the tablets
 The pharmaceutical solutions have high
dissolution rate than the powders
of the solubility of the drug, at equilibrium, in a
non-aqueous solvent

 the ratio of the solubility of the drug, at
equilibrium, in an aqueous solvent
 Determinant of lipophilicity or liposolubility
- If Partition Coefficient > 1, drug is
lipophilic (hydrophobic, non-polar)
- If Partition Coefficient < 1, drug is
hydrophilic (water-soluble, polar,
lipophobic)
 Increase in the number of carbon = non-
polar = lipophilic = high partition
coefficient
 Decrease water solubility = High partition
coefficient = high absorption
Figure 1
Water: aqueous layer, polar
Octanol: non-aqueous layer, non-polar
 Drugs that are weak electrolytes (acids or
bases) exist in both an ionized form and a
non-ionized form in solution.
 The extent of ionization depends on the
pKa of the weak electrolyte and the pH of
the solution.
- pKa: negative logarithm of the acidity
dissociation constant, indicator or
measure of acidity of a substance
 The ionized form is POLAR , and therefore
more Water soluble, than the non-ionized
form
- Ionized form: polar, water soluble,
hydrophilic, lipophobic
- Non-ionized form: non-polar,
liposoluble, lipophilic, hydrophobic
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- HIPE: Hydrophobic, Ionized, Polar,

WEAKLY ACIDIC DRUGS WEAKLY BASIC DRUGS
Excreted
- LUNA: Lipophilic, Un-ionized, Non-polar,  Hydrochloride
Absorbed (Diphenhydramine HCl)
 Sulfate (morphine
 Potassium (Losartan K)
sulfate)
 The Henderson-Hasselbalch Equation  Sodium salts
 Citrate
describes the relation between the ionized (Phenytoin Na, Na
 Gluconate salts
and the non-ionized forms of a drug as a Ascorbate)
 Estolate
function of pH and pKa  Napsylate
 pH = pKa →50% ionized and 50% unionized  Stearate salts

E. Salt Formation F. Polymorphism

 The choice of salt form for a drug depends on
the desired physical, chemical, or
pharmacologic proper ties.
 Example: Chloramphenicol
 Primary purpose: to increase the drug's water
solubility, increase absorption rate
 Drugs: weak acid + base = salt
 Drugs: weak base + acid = salt
 Weakly acidic drugs: potassium and sodium
salts
 Losartan Potassium
 Phenytoin Sodium
 Sodium Ascorbate: sodium salt of ascorbic
acid
 Weakly basic drugs: hydrochloride, sulfate,
citrate, gluconate salts, estolate, napsylate,
and stearate salts
 Diphenhydramine hydrochloric acid (HCl)
 Morphine sulfate
 Dextromethorphan hydrobromic acid (HBr)
 Note: salts of long chain organic / fatty acids
are non-polar (estolate, stearate, palmitate)
 Example: Chloramphenicol palmitate:
antibacterial agent (see Figure 1)
o palmitate -> oral salt form
o succinate -> more water-soluble salt
(administered via IV)
 Palmitic acid: 16 carbon carboxylic acid
The ability of a drug to exist in more than
one crystalline form
 Amorphous, or non-crystalline, forms of a
drug have faster dissolution rates than do
crystalline forms.
 Amorphous/ non-crystalline solid:
irregular shape
 Crystalline solid: definite structure and
shape, particles are arranged in a
pattern
Polymorphs
- Same chemical structure
- Different physical properties: solubility, melting
point, x-ray diffraction (ability of a crystal to
scatter x-ray)
 Example: cocoa butter, used as a
suppository base
- Alpha: melting point 22°C
- Beta prime: 28°C
- Beta stable: 34.5°C, used as a
suppository base
- Gamma: 18°C
G. Chirality
 the ability of a drug to exist as optically active
stereoisomers or enantiomers
 Enantiomers: non-superimposable mirror
images of a compound. Same chemical
structure but different in orientation in 3
dimensional space
 can express as "S" or "R", "levo" or "dextro"
 Individual enantiomers may not have the
same pharmacokinetic and
pharmacodynamic activity.

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 For example, ibuprofen (anti- inflammatory
drug) exists as the R- and S-enantiomers; only
the S-enantiomer is pharmacologically active.
 For example: Warfarin: anticoagulant R-
warfarin: longer half-life (t½), less distributed,
less potent (weak); S-warfarin: shorter t½,
more distributed, more potent
 For example: The chelate of tetracycline
with calcium is less water soluble and is
poorly absorbed.
- Tetracycline: broad spectrum
antibiotic. It is capable of forming
complex or chelate with calcium.

H. Hydrates

 Drugs may exist in a hydrated, or solvated,

form or as an anhydrous molecule
 Dissolution rates differ for hydrated and
anhydrous forms.
 Note: Anhydrous form is more soluble than
hydrated form
 Example:
- CuSO4: anhydrous form
- CuSO4•5H2O: hydrated form

I. Complex Formation

 A complex is a species formed by the

reversible or irreversible association of two or
more interacting molecules or ions.
 Chelates are complexes that typically involve
a ring-like structure formed by the interaction
between a partial ring of atoms and a metal
 complex in which a central metal ion binds to
a polydentate ligand
 Example: hemoglobin, insulin,
cyanocobalamin
 Complex formation usually alters the physical
and chemical characteristics of the drug.
 Large drug complexes, such as drug-protein
complexes, do not cross cell membranes
easily.

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TOPIC 2: Absorption and Distribution  Drugs with

ABSORPTION poor lipid
solubility
 The process of uptake of the compound from and
irritating
the site of administration into the systemic drugs
circulation. Easier to
 Covers a drug’s progress from the time it’s Intramuscular Rapid (aqueous inject than IV
administered, through its passage to the (IM) solution) Larger
Irritating drugs
Slow (non - volume may
tissues, until it becomes available for use by may be painful
aqueous be used
the body. solution) compared to
SC solution
Common Routes of Drug Administration Prompt from
Depends on
Subcutaneous aqueous solution
 Parenteral – involves the injection of the drug For insulin blood
(SC) Slow absorption
from repository injection flow and
directly to the body by passing the skin and injection volume
mucous membranes formulation
 Enteral – involves the absorption of the drug ENTERAL
via the gastrointestinal tract Not for most
Rapid abs from
 Transdermal – the drug product is topically Buccal or
lipid soluble
No < First drugs with
Sublingual Pass Effect= higher
applied on the skin wherein the drug drugs doses
penetrates the layers of the skin in order to Abs may vary > Some may
reach the systemic circulation Oral (PO) Slower Safest and have erratic abs
 Inhalation and Intranasal – the drug enters the absorption easiest route > First pass
oral or nasal cavity in order to reach the lungs compared to IV effect
> Supp may
and from the lungs the drug can also reach Rectal
For patient
migrate to
the systemic circulation. Abs may vary who cannot
different position
swallow
 Note: there are routes of administration in discomfort
which the absorption process is bypassed: OTHER
ø Bioavailability of Intracardiac, intravenous, > Easy to use
and intra-arterial routes = 1 or 100% Transdermal > Slow abs > Used for
> Irritation
 Intracardiac route – drug is directly > Inc abs with lipid-soluble
> Permeability
occlusive drugs with
injected to the heart (F=1) vary
dressing low dose and
 Intravenous route – drug is injected into the low MW
blood vessels (F=1) > Part. Size
 Intra-arterial route – drug is injected into Inhalation and determines
intranasal For local or anatomic
the artery (F=1)
Rapid abs systemic placement in
effects respiratory tract
Route Bioavailability Advantages Disadvantages
> Stimulate
PARENTERAL cough reflex

Intravenous Inc. chance of NOTES:

Immediate
bolus 100% Adverse
(IV bolus) effect
reaction  Intravenous bolus – refers to the single fast
 Plasma administration or rapid injection of medication
Intravenous drug levels Requires skill of into the veins.
infusion precisely insertion
(IV infusion) ø Administered at an angle of 25°
100 % controlled Tissue damage
 May inject at the site of ø Advantage: Capable of producing an
large fluid injection immediate therapeutic or physiologic
volumes effect

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ø Most of the emergency drugs are
formulated as intravenous bolus injection
ø Ex. Naloxone – antidote for opioid toxicity
or poisoning; used in life threatening
situations
ø Disadvantage: increase probability of
increase risk of toxicity
 Intravenous infusion – refers to the gradual
administration of a drug into the veins in which
the drugs is usually administered at a
controlled and constant rate. Mas malaking
amount of fluid ang inaadminister dito.
ø Administered at an angle of 25°
ø Ex. Parenteral nutrition, Electrolytes, anti-
cancer drugs
ø Advantage: It is easier to adjust the plasma
concentration of the drug
ø Preferred intravenous route if the drug is
irritating.
ø Disadvantage: can cause phlebitis
ø Phlebitis – <inflammation of the veins=
 Intramuscular injections – the drug is directly
injected to the muscles
ø Administered at an angle of 90°
ø Ex. Vaccines and Hormones
ø Common sites of injection:
- Deltoid muscle
- Gluteus muscle
- Thigh muscles
ø Bioavailability
- Aqueous solution – rapid absorption
process
- Non-aqueous solution – slow
absorption process
ø Easier to administer than intravenous
injections
ø It allows the administration of larger
volumes of drug solution compared to
subcutaneous injections
ø Maximum amount of drug solution that
can be administered = 5 mL
ø Disadvantage: painful
 Subcutaneous injections – the drug is being
injected into the hypodermis (the fatty layer
beneath the skin wherein it is mainly
composed of adipose tissue)
ø Maximum amount of drug solution that
can be administered = 1.5 mL – 2 mL
ø Administered at an angle of 45°
ø Ex of drugs administered via SC: Insulin,
Heparin
ø Bioavailability is the same with IM injection
ø Advantage: the fatty tissue; adipose tissue;
subcutaneous tissue can actually store
lipophilic drugs wherein they can act as
storage depot or drug reservoir for the
lipophilic drugs which are administered via
subcutaneous injection. These tissues can
store the lipophilic drugs wherein they can
release it in a gradual and constant
manner. That can increase the duration of
action of the drug.
ø Disadvantage: only few drug solutions can
be administered. Only few blood supplies
received. Lesser blood supply  low rate
of absorption
 Intradermal injection – one of the most
common parenteral route of administration;
the drugs is being injected into the dermis or
inner layer of the skin
ø Administered at an angle of 10° - 15°
ø Usually used for allergy testing
 Enteral routes of administration – the drugs are
intended to be absorbed inside the
alimentary canal or gastrointestinal tract.
 Sublingual – intended to be dissolved under
the tongue
 Ex. Nitroglycerin – vasodilator that is used in
the treatment of angina (a heart condition
that is characterized by an extreme pain
because of decrease blood flow/supply in
heart)
 Buccal – intended to be dissolved inside the
cheek pouch
 Oral route - the most common and most
preferred route of administration; also
considered to be the safest, most convenient,
and easiest route of administration.
ø Disadvantage: undergo first pass effect
 Rectal route – suitable route of administration
for patients who cannot swallow.
ø Preferred route if the drug is being
degraded by the gastric acid or intestinal
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enzymes; if the drug is sensitive to the
gastric acid or intestinal enzymes of our
GIT.
 Transdermal route – active ingredients are
delivered across the skin for systemic
distribution
ø Transdermal patch – drugs which are
delivered via the transdermal route
 Ex. Nicotine patch – used by individual
who wants to quit smoking; reduce the
craving for cigarettes.
ø Transdermal drugs have a very slow rate of
absorption, at the same time, their
absorption process can be increased by
the use of the occlusive dressing (medical
dressing in which it can prevent the
escape of moisture from the skin)
ø Suitable route of administration for lipid
soluble or lipophilic drugs with low dose
and low molecular weight
 Inhalation and Intranasal – drug enters the
body via the nasal or oral cavity and the drug
moves through the respiratory tract until it
reaches the lungs.
ø Ex. anti-asthma drugs
ø Bioavailability: Very rapid absorption
process
ø Local effects – physiologic or therapeutic
effect of drugs is only contained in a
specific area
ø Systemic effects – scattered; drugs are
distributed to different tissues in the body
ø High dose of intranasal or inhalation drug =
produce a systemic effect
ø Drugs absorption is limited by the particle
size of the drug
PHARMACEUTIC FACTORS AFFECTING DRUG
BIOVAILABILITY
 the type of drug product (eg, solution,
suspension, suppository)
 the nature of the excipients in the drug
product
 the physicochemical properties of the drug
molecule
The nature of the excipients
 Binder
 Disintegrant
 Lubricants – non-polar in nature
Physical and chemical nature of the active drug
 Particle size – faster dissolution process =
faster absorption process
 Polymorphism – ability of a solid to exist in
more than one crystalline form
 Solvates – hydrated or anhydrous form of a
drug
 Ionization – ration of the ionized and non-
ionized form of a drug
SYSTEMIC ABSORPTION OF
DRUG IS DEPENDENT ON:
 Physicochemical properties of the drug
 Surface area, solubility, Partition coefficient
 Nature of the drug
 Anatomy and physiology of the drug
absorption
Types of Absorption
 Transcellular - Process of drug movement
across the cell
 Paracellular - Process of drug movement that
goes through gaps or tight junction between
cell
 Drug absorption requires the drugs to be
transported across various cell membranes
 Drug should be small and non-polar
CELL MEMBRANE
 Also known as plasmalemma or plasma
membrane
 The outermost layer of a cell
 A semipermeable structure composed
primarily of lipids and proteins
 Basic structural unit is phospholipid
 Generally thin, approximately 70 to 100 A in
thickness.
ø 1 angstrom = 10-10 m or 0.1 nm
 Molecules easily permeate or cross cell
membrane: small non-polar molecules
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 Primarily composed of:
 Lipid
 Protein
 Major functions:
 Hold together the aqueous cell contents
(structure)
 Separate cellular contents from the
aqueous external fluid (barrier)
 Control transport of substances in and out
of the cell (regulation)
Theories of Cell membrane
Lipid bilayer or unit membrane theory
 composed of two layers of phospholipids
between two surface layers of proteins
 cell membranes have 2 phospholipid layers
and 2 protein layers
Fluid mosaic model
 consists of globular protein embedded in a
dynamic fluid, lipid bilayer matrix
 Proteins embedded in a phospholipid bilayer.
 Called as fluid model because in this
biological model the molecules are
constantly moving
 Called mosaic because the cell membrane
is composed of many and different kinds of
small molecules
 Consists of globular protein embedded in a
dynamic fluid, lipid bilayer matrix
Important components
ø Phospholipid bilayer – composed of 2 layers
of phospholipid and many phospholipid
molecules. Phospholipid molecules are
composed of single polar head and 2 non-
polar tails. Only allow the passage of non-
polar or lipophilic molecules, and non-ionized
or hydrophobic molecules
ø Cholesterol – determines the rigidity or fluidity
of cell membrane
- More cholesterol = more rigid and stiff ang
cell membrane
- Less cholesterol = more fluid cell membrane
ø Proteins
a. Integral protein – embedded within the
phospholipid bilayer.
Ex. protein channels
b. Peripheral protein – embedded on the
surface of the phospholipid bilayer.
Ex. receptors, cell surface markers
Parts of Cell Membrane
 Phospholipid
ø 1 polar head and 2 non-polar tails
- Polar head attract water: hydrophilic
 3 components: phosphate, choline,
glycerol
- Non-polar tails repel water: hydrophobic
 Made up of fatty acids or long carbon
chain carboxylic acids
 Bilayer
ø 2 layers of phospholipids
- The polar heads stay on the outside and
the tails stay on the inside
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Cell Surface Proteins
a. Channel proteins - transport food and other
molecules into the cell and transport wastes out
of the cells.
ø Allows transport of hydrophilic substance and
small ions
ø Considered as an Integral protein
ø Ex. Na+ channel, K+ channel
ø Ion channel protein – allow the passage of ion
across the cell membrane
b. Receptor proteins - gather information about
the cell’s surroundings
ø Considered as peripheral proteins
c. Cell surface markers - identify the type of cell,
important for cell recognition
ø Considered as peripheral proteins
Permeability of the Cell Membrane
1. Semi permeable/selectively permeable
 Only certain substances can pass across the
membrane.
2. Factors that determine whether a molecule
can pass through a membrane or not:
a. size – small molecular size/weight
b. type (polar, non-polar) – can easily cross
cell membrane
PASSAGE OF DRUGS ACROSS CELL MEMBRANE
Absorption mechanism/ Transport mechanism
 Absorption mechanism/ Transport mechanism
ø Describes the process of how a drug
molecule moves in and out of a cell.
 Passive transport
 Carrier Mediated Transport
o Active transport
o Facilitated transport
 Convective transport
 Ion Pair transport
 Vesicular transport
o Endocytosis
o Pinocytosis
o Phagocytosis
TRANSPORT MECHANISM
 Transport Mechanisms – moving material in
and out of the cell
ø Active transport – utilize ATP; using/
requires energy
ø Passive transport – do not utilize ATP; not
use/ require energy
 Concentration gradient – the difference in
the amount of a substance inside and
outside of the cell
1. Going <with the gradient= – high to low
concentration; passive
2. Going <against the gradient= – low
concentration to high concentration;
active
3. Equilibrium exists when the concentration
of molecules is the same throughout a
space (inside and outside the cell)
Passive Diffusion
 process by which molecules spontaneously
diffuse from a region of higher concentration
to a region of lower concentration
 Major transmembrane process for most drugs.
 Major transport mechanism for small and non-
polar molecules
ø Ex. Osmosis – passive diffusion of water
across a permeable membrane.
 The passage of molecules through a
membrane which behaves inertly.
 along the concentration gradient
 Fick’s first law - states that the rate of
diffusion is proportional to the difference
in drug concentration on both sides of
the membrane
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1. D = diffusion coefficient of the drug through
the membrane (area/time)
a. Inversely proportional to molecule size; the
larger the molecular size, the lower the
diffusion coefficient which indicates a
slower rate of diffusion
b. Constant that measures the diffusivity
which is the ability of a molecule to
diffuse through membranes
2. A = surface area of the membrane through
which drug diffusion is taking place (area)
a. Surface area of the cell membrane is
directly proportional to the rate of diffusion
b. Larger surface area, faster rate of diffusion
3. Km/w = partition coefficient of the drug
between the lipoidal membrane and the
GI-fluids
a. Partition coefficient – determinant of
liposolubility that is also directly
proportional to the rate of diffusion
b. Higher partition coefficient, the more
lipophilic molecule
c. More lipophilic, more non-polar, more
non-ionized, higher partition coefficient
and faster rate of diffusion
4. h = thickness of cell membrane
a. Inversely proportional to the rate of
diffusion
b. Thicker, slow rate of diffusion
c. Thinner, fast rate of diffusion
5. Concentration gradient b/w GIT and
plasma – directly proportional to the rate of
diffusion
a. Higher difference in drug concentration
between GIT and plasma, faster rate of
diffusion
b. To have a faster rate of diffusion, the
concentration of drug in the GIT must
be higher compared to the drug of
plasma
ø High rate of diffusion = High rate of absorption
Examples
 Weak organic acids
 Weak organic bases
 Organic nonelectrolytes
ø Alcohol
ø Amidopyrine – analgesic
ø Urea – waste product of protein
 Cardiac glycosides – drugs that increases the
force of contraction of heart (ex. Digoxin)
Carrier Mediated Transport
 Uses carrier/transport proteins
 Usually for polar and large molecules
Characteristics of carrier mediated transport:
1. Saturation – a limited number of carrier
binding sites are available.
2. Selectivity – each carrier transports a specific
substance or a few closely related
compounds
3. Competition – several closely related
compounds may compete for transport on
the same carrier.
ø Compounds with similar structures may
compete for the same carrier protein
Carrier mediated: Active Transport
Characteristics
 carrier-mediated transmembrane process
 across the concentration gradient
 from regions of low drug concentrations to
regions of high concentrations
 an energy-consuming system; uses ATP
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 Fast process, faster than passive diffusion Carrier mediated: Facilitated Diffusion
 Plays an important role in the renal and biliary Characteristics
secretion of many drugs and metabolites.
 carrier-mediated transport system
 along concentration gradient
 moves from a region of high drug
concentration to a region of a low drug
concentration
 does not require energy
 saturable and structurally selective
 shows competition kinetics for drugs of a
similar structure

ø Na, K, I, hexoses, monosaccharides, amino

acids, strong organic acids and bases,
cardiac glycosides, pyrimidine bases,
testosterone, estradiol, 5-FU(5 fluorouracil), Fe,
Ca (Polar or large molecules/substances)
 Polar substances – Na, Ka, I, Fe, Ca
 Hexoses/Monosaccharides – glucose
 Amino acids – building block of proteins ;
polar functional groups
 Very similar to passive diffusion, they only differ
 Strong organic acids and bases
in the use of transport protein
 Cardiac glycosides – digoxin; can be
 Example: Vitamin B12 or cyanobalamin,
transported on either via passive
uptake of glucose by muscle and fat cells
diffusion or active transport mechanism
 Pyrimidine bases – organic bases present Notes
in genetic materials, nucleic acids, RNA or  Active Transport mechanism – absorption
DNA such as Cytosine ( present in DNA of glucose form the GIT
and RNA), Uracil (present in RNA),  Facilitated Diffusion – uptake of glucose by
Thymine (present in DNA) muscle and fat cells
 Testosterone/Estradiol – sex hormones;
non-polar but have large molecule size, Convective (Pore) Transport
therefore, they cannot easily cross the  Also known as paracellular transport
cell membrane via passive diffusion and  Movement of a compound across
their major transport mechanism would be membranes by way of passages between the
via active transport cells
 5-FU (5 fluorouracil) – polar anti-cancer;  Drug molecules dissolved in aqueous medium
structure is very similar to the structure of at the absorption site move along the solvent
pyrimidine base (Uracil) through the pore.
 Very small molecules and ions

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 Transport protein
ø may form an open channel across the lipid
membrane of the cell
 Drug transport across tight (narrow) junctions
between cells or transendothelial channels of
cells
 <Solvent drag= – the solvent or aqueous
medium which carries the dissolved molecules
into the pores or narrow junctions between
the cells
 Inner lining of pores may possess charges in
ø Example: Propanol (+) + Oleic acid (-) =
which if they have charges, they can attract
will form a neutral complex (non-polar
ions with opposite charges
molecule; can easily cross the cell
 Can also allow the transport of small ions membrane if non-polar)
especially if the ion has an opposite charge to
ø Examples
the charge of pore lining
 Quaternary ammonium compounds – R4N+
ø Examples
 Sulfonic acids – RSO3H
 Inorganic and organic electrolytes up to
150 to 400MW Vesicular Transport
 Ions of opposite charge of pore lining
 The process of engulfing particles or dissolved
 Ionized sulfonamides – a type of synthetic
materials by the cell.
antimicrobial agent
 Types of bulk transport which is a types of
transport in which it involves the transport of
large amount of substances or molecules.
 Transport of molecules in and out of the
cell by forming or using vesicles
ø Vesicles – cell organelles which are
described as tiny sacs that transports
material within or outside the cell

2 types of vesicular transport

ø Exocytosis – movement of molecules from

ø Endocytosis – movement of molecules or
Ion Pair Transport
 The absorption of some highly ionized
compounds at physiological pH cannot be
explained by simple or passive diffusion or any
other existing hypothesis of absorption
 Strong electrolytes drugs are highly ionized or
charged molecules, penetrate membranes
poorly
within the cell to the external environment
or extracellular fluid
substances are from the external environment
or extracellular fluid into the cell
- When it comes to drug absorption, we
are more concerned with the endocytosis
- The process of engulfing particles or
dissolved materials by the cell
 Pinocytosis – <cell drinking=; ingestion or
engulfment of liquids by the cell

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 Phagocytosis – <cell eating=; ingestion Good for absorption

or engulfment of large solid particles by Not good as an absorption site - because intestines have a large
- because of shorter surface surface area because of the
the cell
area presence of finger hair-like
ø Endocytosis: projections.
ONLY transport mechanism that DOES NOT
ø Stomach is essential to absorption of a weakly
REQUIRE the drug to be in a solution
acidic drugs, theoretically weakly acidic
ø Examples: Endocytosis/Pinocytosis drugs they are better absorb in the stomach
 Fats, glycerin, starch while the weak basic drugs they are better
 Parasite eggs absorb in the small intestine.
 Vitamins A, D, E and K
 Plastic particles, hairs and yeast cells Review: How to know if a drug is a weak acid or
 Ferritin and insulin weak base given the salt form of the drug.
 Sabin polio vaccine
ø Weak acid – if the salt form ay meron sodium
- Sabin – oral or potassium or group 1 cation.
- Salk – administered via injection ø Weak base – kapag meron acid or meron
anion of acid in a salt form of drug. Ends with -
-amine or -ine.

1. Phenytoin Na – Weak acid

2. Phenobarbital Na – Weak acid
3. Digoxin K – weak acid
4. Naproxen Na – weak acid
5. Losartan K – weak acid
6. Dextromethorphan Hbr – Weak base
7. Cetirizine HCl – weak base
Anatomic and Physiologic 8. Quinine HCl – weak base
Considerations of drug absorption 9. Chlorpheniramine maleate- weak base
Comparison of the features of the stomach and
ø Maleate - an anion form of malic acid.
intestine in relation to drug absorption
 1,2,3,4 - best absorb in the stomach
 5,6,7,8- best absorb in small intestine
Stomach Intestine
 Basic - better absorb in small intestine
Essential for absorption of Essential organ for weakly basic  Acid - better absorb in stomach
weakly acidic drugs drugs
Basic (pH 6-8); depending on REMEMBER THIS!
Highly acidic Part (because of the excretion of
(pH 1.5-2) (pH 2-6) pancreatic juice which contain  Acidic drug + acidic environment = non-
bicarbonate ions) ionized
Covered with thick mucus layer Has villi, large surface area  Non-ionized or nonpolar- non-polar from
- (can act as physical barrier for - (villi – this are tiny hair, finger- of drug is considered to be more
absorption) like projections that line inside
- (kapag mas makapal mucus the small intestine) absorbable or readily absorbable form.
layer, mas bumabagal ang - (because of the presence of  Acidic drug + basic environment= ionized
formation or penetration drug in this villi, it increases the surface  Polar or ionized- less absorbable form
our GIT, mas mabagal na area ng ating small intestine.  Basic drug + basic environment= non-
rreach ang systemic circulation)
ionized
Short surface area Long  Basic drug + acidic environment= ionized

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LEARNING CHECK:
What will happen to the absorption of aspirin
(acetylsalicylic acid- weakly acidic drug) if it is
administered w/ NaHCO3 (antacid- makes
gastric basic)?
 Acidic drug + basic environment = ionized
form= decrease absorption of the aspirin
 Overdose or toxicity of aspirin- antidote is
sodium bicarbonate injection
 Antacid- they can impair the absorption of
weakly acidic drugs.
 Ionized form of the drug - readily excretable
form
 HIPE- hydrophilic drug or ionized drug or
polar drug that would be the excretable
form of drugs
 LUNA- lipophilic or unionized or non-ionized
and at the same time nonpolar that would
be the absorbable form of drug.
 Polar – more excretable
 Non-polar- more absorbable
The major physiologic processes that occur in the
gastrointestinal system:
Secretion
 The transport of substances into the lumen of
the gastro intestinal tract
 includes the transport of fluid, electrolytes,
peptides, and proteins into the lumen of the
alimentary canal.
Digestion
 Breakdown of food particles into the smaller
and simpler molecules.
 is the breakdown of food constituents into
smaller structures in preparation for
absorption.
Absorption
 Movement of substances form the
gastrointestinal tract to the bloodstream
 is the entry of constituents from the lumen of
the gut into the body. May be considered as
the net results of both lumen-to-blood and
blood-to-lumen transport movements.
 The most important site for drug absorption is
the small intestine.
COMPONENTS OF TOTAL TRANSIT TIME
(0.4 to 5 days)
 gastric emptying- 1.5 hours to 2hrs. Transport
of food and other substance from the
stomach into small intestine.
 small intestinal transit (3 to 4 hours; 7 hours)-
passage of food and other substances inside
our small intestines until to large intestines.
 colonic transit- passage of food and other
substances inside the large intestines until to
rectum. 30-40 hours.
4 – 8 hours  fasting state (S and SI)
8 – 12 hours  fed state (S and SI)
Acidic drugs- advisable with meal because
irritating to stomach
Certain drugs usually take without meal to fast
absorption.
Fed state
 marami laman GIT. Increases transit time. Slow
movement of absorption
Fasting state
 empty GIT. Decreases the transit time. Fast
movement of absorption
Transit time
 the time it takes for food to pass through your
entire digestive tract
Digestive tract
 also known as the gaseous intestinal tract.
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Notes
 Stomach- food particle are digested or
broken down into simpler molecules
 Small intestines- undergo further digestion.
Considered as major absorption site for both
drug and foo particles.
 Large intestines - undigested and unabsorbed
substances they passed through LI until to
reach rectum and they will be excreted to the
rectum as diseases.
 Total transit time- time the food enters the
cavity until the time in which the unabsorbed
and undigested foods reach the rectum it is
called total transit time.
 Average total transit time 0.4 to 5 days.
Different parts of GIT:
Oral Cavity
 Saliva
 main secretion; pH 7
 1500 ml/day
 Enzyme in stomach (Ptyalin) – also known
as salivary amylase which digests starches
into simpler sugar molecules
 Enzyme in stomach (Mucin) – acts as
lubricant. It is glycoprotein present in both
saliva and the mucus membrane of our
oral cavity.
Esophagus
 connects the pharynx and the cardiac orifice
of the stomach
 pH 5 – 6
ø esophageal sphincter
 which prevents acid reflux from the
stomach
 lower esophageal sphincter – valve
between esophagus and stomach in
which prevents the stomach content
from going back up to esophagus. If not
function properly it can cause reflux of
gastric acid going to esophagus that
can feel of burning sensation in chest
called heart burn.
 Very little drug dissolution occurs in the
esophagus
 Tablets and capsule that lodge in this area
causing irritation
Stomach
 innervated by the vagus nerve also known as
cranial 10
 Fasting state - pH 2 to 6
 Fed state – pH 1.5 to 2
 Contains gastric acid, which is made up of
HCl, gastric acid secretion that is stimulated
by two hormones: Stomach acid secretion is
stimulated by gastrin and histamine
- Histamine- naturally present in our body.
Responsible for producing symptoms of
allergic reaction. Antihistamine drugs:
diphenhydramine, cetirizine. Histamine
stimulates gastric acid secretion. Ex: for
hyperacidity- class of drug that can give is
histamine 2 blockers or h2 blockers. H2
blockers are drug that ends with <-tidine=
such as cimetidine, ranitidine, famotidine,
etc. H2 blockers they antagonized the
action of histamine they prevent histamine
form stimulating gastric acid secretion.
- Primary purpose: to grind food and mix it
with acidic gastric acid
- Antral milling- process of breaking down
large food particles by the stomach and
passing them into small intestine
- Empty stomach (fasting): 100 mL of gastric
fluid
- (fed) - >100 mL
- average capacity: about 1.1 to 1.2 L max.
4L
3 types of glands
 Mucous glands- secrete gastric mucus.
Gastric mucus has 2 functions first is for the
lubrication of the stomach in order to
facilitate the movement of food. Second it
forms protective layer over the lining
epithelium of the stomach cavity.
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 Chief (zymogenic cells) - secrete inactive
enzyme pepsinogen. Pepsinogen is an
inactive enzyme that activate with the
presence of acid or low pH environment. Low
pH can activate pepsinogen converts it to
active enzyme which is pepsin. Pepsin
enzyme that is responsible for the breakdown
or digestion of proteins in the stomach.
 Parietal cell- secretion of HCl.
Stomach (additional notes)
 Gastrin release is regulated by stomach
distension and the presence of peptides and
amino acids
 Stomach emptying influenced by the food
content and osmolality.
 High food content mas increase ang
osmolality ng gastric fluid = increase of
gastric emptying time.
Small intestine
 Longer than to large intestine (1.5 meters)
 6 meters in length
 pH 6 to 6.5
 Bicarbonate
 neutralizes the acidic chyme emptied
from the stomach
 Chyme - mixture of partially digested
food and juices.
 ester prodrugs are hydrolyzed
 they undergo metabolism they
converted to their pharmacologically
active form by the process of hydrolysis
 Presence of villi increase surface are
 Large SA
 Prodrugs – inactive drug that must undergo
chemical conversion/metabolism to become
pharmacologically active.
Parts of small intestine
 Duodenum - most proximal part that
connected to the stomach.
 Jejunum - It is the middle portion
 Ileum - distal part. Terminal portion.
Duodenum
 Shortest portion of small intestines
 presence of proteolytic enzymes
 Amylase- carbohydrates
 Pancreatic lipase
 Bile secretion (liver to duodenum): 250 – 1000
mL/day
 Pancreatic juice: 300 – 500 mL/day
 Digestive enzymes present in PJ such as
amylase that responsible for breakdown
carbohydrates into simple sugar and also
lipase that responsible for the breakdown
or digestion of lipids into fatty acids and
also trypsin responsible for breakdown of
proteins to peptide and from peptides to
amino acids
JEJUNUM
 Middle part of small intestine
 Preferred IN VIVO drug absorption studies
(uses laboratory animals)
 Intestinal fluid: 3000 mL/day (average volume
that is secreted into the jejunum
** why Jejunum when it comes to IN VIVO drug
absorption studies? Why not Duodenum?
- Because Duodenum is short
** between Jejunum and Ileum, why Jejunum?
- Because Jejunum has better absorption
site/characteristics compared to Ileum
PHBP221 22
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ILEUM  Doesn’t need to pass through hepatic

 terminal part of the small intestine portal vein and liver
 Longest part of the small intestine  No first pass effect
 has fewer contractions than the duodenum.  High bioavailability of drug
 pH 7, with the distal part as high as 8
 Ileocecal valve – separates Small Intestine 3. Distal Rectum
from Large Intestine Vein present: Inferior Rectal Vein – it also drains
directly into the inferior vena cava
COLON
 lacks microvilli / does not contain villi or  Doesn’t need to pass through hepatic
microvilli portal vein and liver
 refers to large intestine  No first pass effect
 not good absorption site  High bioavailability of drug
 has lower surface area
 very limited in drug absorption due to the
more viscous and semisolid nature of the
lumen contents
 lined with mucin (lubricant and protectant)
 pH 5.5 to 7
 Drugs that are absorbed well in this region are
good candidates for an oral sustained-
release dosage form (gradual release of
active ingredients from the dosage form)
 The colon contains both aerobic and
anaerobic microorganisms that may
metabolize some drugs.

RECTUM
 15 cm, ending the anus
 Distal part of Large Intestine
 Drug absorption is variable/erratic
 The drug absorption in Rectum is highly
dependent on the positioning or placement
of the drug within the rectum
(3) THREE DIVISIONS OF RECTUM
1. Upper Rectum
Vein present: Superior Rectal Vein – it drains into
the hepatic portal vein
 Drug passes through the liver, thus it
undergoes first pass effect, resulting the
lower bioavailability of a drug
2. Middle Rectum
Vein present: Middle Rectal Vein – it drains
directly into the inferior vena cava
Drug absorption in the Gastrointestinal Tract
 The most common transport mechanism
for the absorption of drugs would be
passive diffusion
 Drugs may be absorbed by passive
diffusion from all parts of the alimentary
canal including sublingual, buccal, GI, and
rectal absorption.
 For most drugs, the optimum site for drug
absorption after oral administration is the
upper portion of the small intestine or
duodenum region.
Gastrointestinal Motility
 GI motility tends to move the drug through the
alimentary canal so that it may not stay at the
absorption site.
 Refers to the contraction of the smooth
muscles of the Gastrointestinal tract

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 This is also a major factor that can affect the  Directly proportional to Absorption Rate (ú
rate and extent of absorption of a drug GER, úABSORPTION) then (ùGER,
ùABSORPTION)
The transit time of the drug in the GI tract
depends upon: ùGET, ú GER, ú ABS úGET, ùGER, ùABS
Fatty meal Cold foods
ø Pharmacologic properties of the drug Hot meal Mild exercise
ø Type of dosage form Stress Motility
ø Various physiologic factors Lying on the left Lying on the right
Side Side
 Physiologic movement of the drug within the Heavy exercise Standing position
Anti-motility
GI tract depends upon whether the
alimentary canal contains recently ingested
food or is in fasted or inter-digestive state.  Anti-motility drugs – drugs that decrease the
 fast GIT motility, fast movement of passage gastrointestinal motility by decreasing the
of drug in gastrointestinal tract contraction of the smooth muscles in GIT
 if may laman yung GIT, it results to slower
Examples of drugs that can decrease GIT Motility
GIT motility
and Rate and resulting slower Absorption Process
Gastric Emptying Time (GET)
Antidiarrheal drugs
 The time it takes the stomach to empty its - Diphenoxylate + Atropine (Lomotil)
contents - Loperamide (diatabs, Imodium)
 Major factor that affects the rate of Anticholinergics
absorption - Hyoscine butylbromide (buscopan)
 Duodenum --- has the greatest capacity Opiates
for the absorption of drugs from the GI - Morphine + Codeine
tract
 a delay in the gastric emptying time for *** HINDI PWEDENG PAGSABAYIN INUMIN YUNG
the drug to reach the duodenum will slow MGA DRUG NA YAN galet na qu emz
the rate and possibly the extent of drug Examples of drugs that can increase GER, reduce
absorption, hereby prolonging the onset GET and resulting Fast Absorption
time for the drugs.
(Motility enhancing drugs)
*** the longer it takes for the drug to reach the
duodenum, that would result to a slower rate of Antiemetic drugs
absorption of the drug - Metoclopramide
- Domperidone (Motilium)
*** If there is a delay in Gastric Emptying time,
that would also result to a delay in the drug Metoclopramide + Domperidone + other drugs =
absorption process increase rate of absorption of the other drugs

Gastric Emptying Rate (GER) Factors Affecting Gastric Emptying Rate

 refers to the rate at which the stomach 1. Volume of the stomach

transfers its contents into the duodenum or
small intestine
 inversely proportional to Gastric Emptying
Time. (úGER, ùGET,)
- ùVolume of the stomach, ù GER, úGET
2. Type of meal – basta may food sa
stomach, it decreases GER and prolongs
GET
 Fatty acids – greatly decreases GER

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1ST SEMESTER – PRELIM

 Triglycerides – greatly decreases

GER
 Carbohydrates
 Amino acids
3. Osmotic Pressure
- amounts of solutes dissolved in gastric
fluid
- Decrease GER
- ùOsmotic pressure, úGER
4. Physical State of gastric content
- úParticle Size, ùGER, ùABSORPTION
5. Chemicals
- Acids - úGER (ùGET)
- Alkali (NaHCO3)
(ú conc. = ù GER, ùconc. = úGER)
6. Drugs
Anticholinergics úGER, ùGET, úABS
Narcotic analgesics
úGER, ùGET, úABS
(Opioids – morphine)
Metoclopramide
ùGER, úGET, ùABS
(Anti-emetic)
Ethanol úGER, ùGET, ùABS Intestinal Motility
7. Miscellaneous  Normal peristaltic movements mix the
Body Position contents of the duodenum, bringing the drug
- Standing Position = ùGER particles into intimate contact with the
- Lying right side = ùGER intestinal mucosal cells.
- Lying left side = úGER  The drugs must have a sufficient time at the
absorption site for the optimum absorption.
ø Viscosity = ùViscosity, úGER  For modified-release or controlled dosage
ø Emotional State = ex, stress úGER forms, which slowly release the drug over an
ø Bile salts = úGER extended period of time, the dosage form
ø Disease States = úGER must stay within a certain segment of the
ø Exercise = mild  ùGER, heavy  úGER intestinal tract so that the drug contents are
ø Gastric surgery = ex. Gastrectomy = ùGER released and absorbed prior to loss of the
<dumping syndrome= dosage form in the feces.
Example of Modified-Release Dosage Form
ø Diamicron XR (Gliclazide – antidiabetic)

** Modified-Release Drugs should not be

administered with motility enhancing drugs

ø Peristaltic movement/Peristalsis – refers to the

series of wave-like muscle contractions of the
smooth muscle of the gastrointestinal tract

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Effect of food on Gastrointestinal Drug Absorption

 The presence of food in the GI tract can
affect the bioavailability of the drug
 Digested food contains amino acids, fatty
acids, and many nutrients that may affect
intestinal pH and solubility of drugs.
 The absorption of some antibiotics is
decreased with food
 Griseofulvin – antifungal (better absorbed
when given with food containing a high fat
content)
 Mebendazole (anthelmintic)
 Fasted state = ùGER, ùABSORPTION
Perfusion of the Gastrointestinal Tract
 Enteric-coated tablets – Protects drug from
1. The Splanchnic circulation receives about 28% acidic pH, release in small intestine
of the cardiac output and is increased after Examples:
meals.  Bisacodyl (Laxative)
- irritating to the stomach
Splanchnic circulation – describes the blood flow
- should NOT BE taken with antacids –
to the abdominal gastrointestinal organs such as
premature release = gastric irritation
stomach, liver, spleen, pancreas, small and large
intestine

Mesenteric vessels supply.

2. The Lymphatic circulation in drug absorption is

well absorbed. Drugs are absorbed through the
lacteal or lymphatic vessels under the microvilli

 Bypasses the first-pass effect

 Important in the absorption of dietary lipids
 partially responsible for the absorption for
some lipophilic drugs
 INCREASED BIOAVAILABILITY

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Double-peak Phenomenon
 The double-peak phenomenon is generally
observed after the administration of a single
dose to fasted patients
 Food can also affect the integrity of the
dosage form causing an alteration in the
release rate of the drug
 The rationale for the double-peak
phenomenon has been attributed to
variability in stomach emptying, intestinal
motility, presence of food, enterohepatic
recycling, or failure of a tablet dosage form.
 Usually observed after the administration of a
single dose to a fasted patient

Examples of Drugs in Double-peek phenomenon:

Cimetidine + Ranitidine

Effect of Disease States on Drug Absorption:

ø Intestinal blood flow

ø Gastrointestinal motility
ø Changes in stomach emptying time
ø Gastric pH that affects drug solubility
ø Intestinal pH that affects the extent of
ionization
ø The permeability of the gut wall
ø Bile secretion
ø Digestive enzyme secretion
ø Alteration of normal GI flora

Drugs that Affect Absorption of Other Drugs

Anticholinergic Drugs ú rate of absorption

Metoclopramide (motility ù rate of absorption
enhancing drug) úextent of abs. of modified-
release drug
Antacids ú rate of absorption of acidic
drugs
Cholestyramine ú rate of absorption
Vitamin D ù absorption of calcium
Cholestyramine

 bile acid sequestrant. (promote

elimination/excretion of bile acids)
 Used as cholesterol lowering drug.
 Forms large complex with several drugs:
Thyroxine (thyroid hormone) and Digoxin
 Cholestyramine decreases the absorption of
thyroxine and digoxin

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TOPIC 3: Drug Elimination ANATOMY AND PHYSIOLOGY OF THE LIVER

Metabolism – Principles and Factors

 Also known as biotransformation

 The enzymatic or biochemical transformation
of the drug substance to (usually less toxic)
metabolic products, which may be
eliminated more readily from the body
 Enzyme – protein that catalyzes a chemical
reaction.
 Drug metabolism refers solely to the chemical
biotransformation of a drug by the biological
environment.
 In biochemistry, total amount of the
biochemical reactions involved in maintaining Liver
the living condition of the cells in an organism.
 Principal site of metabolism
Metabolism serves three principal purposes: - Hepatocytes – liver cells; contain
1. to supply energy for body functions and metabolizing enzymes
 Both synthesizing and eliminating organ
maintenance; Ex. glycolysis (metabolic
reaction)  Substances synthesized:
2. to break down ingested (foreign) compounds  Bile – produce in liver; greenish yellow fluid
and biosynthesis of more complex molecules; responsible for breaking down fats
Ex. ingested proteins (broken into simpler  Albumin – protein
molecules = amino acids, via metabolic  Cholesterol
reaction, they will be converted into more 1. Liver lobule - Basic unit of the liver
complex protein molecule)
3. To make compounds more polar water a. Larger right lobe
soluble; Ex. drug metabolism goal – convert b. Smaller left lobe
the drug molecule into a more excretable 2. Hepatic artery
form; (excretable from = more polar water
soluble form) a. Perfused blood in the liver
4. To inactivate the drug; inactivated drug – b. Carries oxygen in the liver
cannot cause of produce toxic effect
5. Detoxify harmful substances ø different from hepatic vein
6. To activate some drugs; there are drugs ø Hepatic vein – carries blood from the liver to
required chemical the heart
transformation/reaction/metabolism
3. Hepatic portal vein
ø Xenobiotics – foreign chemicals
a. Collects blood from the various segments
ø Drug metabolism is a preparatory process for
of the GIT that perfuse in the liver
excretion.
b. Carries nutrient to the liver
ø Prodrug – require initial metabolism before
being pharmacologically active 4. Sinusoids

a. Large vascular capillaries

b. Facilitates drug and nutrient removal
before the blood enters the general
circulation

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1ST SEMESTER – PRELIM
Metabolizing enzymes
 Present in hepatocytes or liver cells
 occur in the soluble, the mitochondrial, or
the microsomal fractions
 mitochondria – contain energy
metabolizing enzymes
 microsome – contain drug
metabolizing enzymes
 metabolism can also take place in the
bloodstream to some extent because
some enzymes produced by the cell spill
over into the extracellular fluid
2 types of metabolism
 Hepatic metabolism – metabolic process
or reaction occurs inside the liver
 Extrahepatic metabolism – metabolic
process or reaction occurs outside the liver
Metabolism
Metabolites – product of metabolic reaction
ø Inactive metabolites
ø Metabolites that retain similar activity
ø Metabolites with altered activity
ø Bioactivated metabolite
ø Reactive metabolite
1. INACTIVE METABOLITES
 They are no longer pharmacologically
active, no longer capable of producing a
physiologic or therapeutic effect.
Examples:
Procaine (local anesthetic) → p-aminobenzoic acid
6-mercaptopurine (immunosupressant) → 6-mercaptopuric acid
amphetamine (CNS stimulant)→ phenylacetone
phenobarbital (anticonvulsant)→ hydroxyphenobarbital
2. METABOLITES THAT RETAIN SIMILAR ACTIVITY
 Retain the therapeutic or pharmacologic
activity of parent compound
 Imipramine – also used for enuresis (bed-
wetting)
Examples:
Imipramine (Anti-depressant) → desipramine
acetohexamide (antidiabetic) → L-hydroxyhexamide
Codeine (analgesic,antitussive) → Morphine
Procainamide (antiarryhtmic) → N-acetyl procainamide
phenylbutazone (anti-inflammatory) → oxyphenbutazone
3. METABOLITES WITH ALTERED ACTIVITY
 There pharmacologic or therapeutic
activity is different from the original
drug/parent compound
 Isotretinoin – Teratogenic drug (means
toxic to the fetus; cannot be taken by
pregnant)
Examples:
Iproniazid (Anti-depressant) → isoniazid (anti-TB molecule)
Retinoic acid (Vitamin A derivative) → Isotretinoin (anti-acne)
4. BIOACTIVATED METABOLITE
 Metabolites of Prodrug
 Prontosil – a red organic dye; first prodrug
discovered by Gerhard Domagk
Examples:
Enalapril → Enalaprilat (anti-hypertensive)
Sulindac → active sulfide (anti-inflammatory)
Levodopa → dopamine (anti-Parkinson drug)
Prontosil → sulphanilamide (antibacterial drug)
Hetacillin → ampicillin (antibacterial)
Sulfasalazine → sulfapyridine {byproduct of the
aminosalicylic} + aminosalicylic acid {pharmacologically
active} (ulcerative colitis)
5. REACTIVE METABOLITE
 Toxic metabolites
 NAPQI – N-acetyl-p-benzoquinone imine
 Hepatotoxic metabolite
 Benzopyrene – aromatic hydrocarbon; Ex.
charcoal grilled food and cigarette
 Malathion – an organophospahate
insecticide
Examples:
Acetaminophen → NAPQI
Benzopyrene → Reactive epoxide metabolite (binds to DNA;
produced mutation that could develop cancer cells
Malathion → parathion
 Mostly, drug metabolites are more ionized
than their parent structures and are, therefore
in the form of water-soluble salts which have
reduced lipid solubility.
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Three major components of a drug  Monooxygenase/mixed function oxidase

biotransformation enzyme – enzyme that introduce an oxygen
atom into a molecule
1. Reactant (drug or xenobiotics)
 Most common and most important class of
2. Product (metabolite)
enzymes for phase 1 metabolism
3. Reaction catalyst (enzymes)
 responsible for REDOX rxn
 Located primarily in the endoplasmic
reticulum of hepatocytes

PATHWAYS TO DRUG METABOLISM

Phase I Reaction

 Also known as functionalization phase or

unmasking phase
 Polar functional group: OH (alcohol func. grp),
SH (thiol func. grp), NH2 (amino func. grp)
 Non-synthetic
 Which small chemical changes occur in one
or more functional groups of drug
 3 types: Oxidation, reduction and hydrolysis
 CYP450 most important isoenzymes
a. Oxidation
responsible for liver metabolism.
b. Reduction
 CYP450 – 50+ types/variants of isoforms
c. Hydrolysis
 CYP3A4 – most common isoform
Phase II Reaction  Different type of cyp enzymes = different type
of drug being metabolized
 AKA Synthetic phase or conjugation phase
 A molecule provided by the body is added to Proportion of Drug Metabolized by P459 Enzymes
the drug
 Glucoronidation, sulfation, amino acid
conjugation, acetylation, glutathione
conjugation, methylation
a. Glucoronidation
b. Sulfate Conjugation
c. Methylation
d. Acetylation
e. Glutathione Conjugation
f. Amino Acid Conjugation

Phase 1 Metabolism

 Cytochrome P450 – class or family of enzymes

which are responsible for the phase 1
metabolism of drugs; most important enzyme
in phase 1 metabolism.

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Acetaminophen, Diazepam, Fluvoxamine,

CYP1A2 A. Ester hydrolysis (Procaine)
Theophylline, Methadone, Propranolol C. Hydrolysis Addition of H2O
B. Amide Hydrolysis (Lidocaine)
CYP2B1 Chlorpheniramine
CYP2B6 Bupropion, Cyclophosphamide
CYP2C8 Diclofenac, Omeprazole, Paclitaxel NOTES
CYP2C9 S-warfarin, Tolbutamide, Ibuprofen
S-mephenytoin, Cimetidine (hyper-acidity), A. Oxidation
CYP2C19  Most common oxidation reaction –
Fluoxetine
Antidepressants, Beta blockers (-olol) – hydroxylation reaction (insert –OH group or
CYP2D6
antihypertensive drugs, Captopril alcohol functional group)
Ethanol, Felbamate, GA (general  Deamination – removal of amino group;
CYP2E1
anesthetics), INH, ondansetron
product is a less polar metabolite
Acetaminophen, BZD (-zepam), Busulfan,
CYP3A4  Dealkylation – removal of an alkyl group
Amitriptylline, Amiodarone, Azole antifungals
(non-polar)
 Removal of non-polar mol.  less non-
FUNCTIONALIZATION PHASE polar metabolite (too produce a more
PHASE 1 ASYNTHETIC PHASE ADDING OR polar metabolite
UNMASKING FUNCTIONAL GROUP  Codeine – alkylation reaction it undergo is
 Aromatic hydroxylation O-demethylation (produce morphine)
(Phenytoin)  N-oxidation - paracetamol
 Aliphatic hydroxylation
(Phenobarbital) (acetaminophen) converted into NAPQI
 Olefenic hydroxylation  S-oxidation - sulfide functional group 
(Carbamazepine) sulfoxide (more polar functional group)
 Benzylic hydroxylation
 Desulfuration – thiono compound 
(Tolbutamide, Imipramine)
 Allylic hydroxylation carbonyl group (more polar)
(Pentazocine, Hexobarbital)  Dehalogenation – removal of halogen;
 Hydroxylation N-Alpha to a used to inactivate the drug
carbonyl (Diazepam,
Most dominant Dopamine)  Ethanol – 2 pathways: non CYP-450
phase 1  Oxidative Deamination mediated pathway (major pathway; using
A. Oxidation + O2 (increase) (Amphetamine) – inactivate special enzymes: alcohol dehydrogenase
- most common - H (decrease) drug and aldehyde dehydrogenase) and CYP-
reaction LEORA  N-dealkylation (Morphine,
Ephedrine) 450 mediated pathway (minor pathway;
 N-oxidation (Acetaminophen) phase 1 reaction/oxidation {CYP2E1})
 O-dealkylation (Codeine,  Acetaldehyde – toxic metabolite
Papaverine)
 S-dealkylation (6 –  Acetic acid – excretable metabolite
methylmercaptopurine)  Ethanoic acid; acetic acid – Carboxylic
 S-oxidation (Chlorpromazine) acids (one of the most functional group)
 Desulfuration (Thiopental)  Ethanol  acetaldehyde  acetic acid
 Dehalogenation (Halothane,
Chloramphenicol)
 Aldehyde dehydrogenase – affect alcohol
 Oxidation of alcohols (Ethanol, tolerance
Estradiol) B. Reduction
 Oxidation of aldehyde  Reduction – characterized by the
(Acetaldehyde, PGE2
A. Carbonyl reduction decreased in valence and gain of
+H (Acetohexamide) electrons; addition/increase of hydrogen
B. Reduction - O2 B. Azoreduction (Sulfasalazine) atom and removal/decrease of oxygen
GEROA C. Nitroreduction atoms
(Chloramphenicol)
 Oxidizing agents – substances that
undergo reduction

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 Carbonyl reduction – C=O
 Type of compounds with carbonyl =
ketone (RC=OR) and aldehydes (RC=OH)
 undergo reduction, converted and
transform into an alcohol (more polar
compared to carbonyl containing
compounds)
 Ex. Acetohexamide – anti-diabetic drug
 Azoreduction – refer to the reduction
reaction of Azo compound (RN=NR)
 RN=NR  RNH2(amine) + RNH2(amine)
 Nitroreduction – chemical reaction in
which the nitro functional group (RNO2) is
being reduced or converted to an amine
 RNO2  RNH2(amine)
C. Hydrolysis
 Hydrolysis – reaction in which there is a
breaking of chemical bond via the
addition of water; common metabolic
pathway for local anesthetics
 Local anesthetics: Procaine and Lidocaine
 Ester hydrolysis
 Ester (RC=OOR) + H2O  Carboxylic
acid (RC=OOH) + alcohol (ROH){more
polar products/substances}
 Ester local anesthetics (1i)
 Procaine
 Tetracaine
 Chlorprocaine
 Amide hydrolysis
 Amide local anesthetics like lidocaine
usually are secondary amide
(RC=ONHR)
 Secondary amide (RC=ONHR) + H2O 
Carboxylic acid (RC=OOH) + amine
(RNH2)
 Amide local anesthetics (2i)
 Lidocaine
 Bupivacaine
 Ropivacaine
 2 enzymes involved in hydrolysis:
 Esterases – enzymes responsible for
catalyzing ester hydrolysis reaction;
found in the blood and other tissues of
the body (more abundant); reason
why ester local anesthetic have faster
elimination rate or shorter t ½
 The faster elimination  decrease
of duration of action/ therapeutic
effect
 Amidases - enzymes responsible for
catalyzing amide hydrolysis reaction
(found only in the liver)
Red Blood Cell (RBC) in metabolism
 Primary role is to transport or carry oxygen
molecules into the liver in which the oxygen
molecules are necessary for phase 1 reaction,
more specifically for redox reaction.
 to exchange oxygen for carbon dioxide at
the tissue level
 equipped with numerous enzyme systems
(energy supply for the cell protection of
hemoglobin and cell membrane from
oxidation)
 has no nucleus, no mitochondria, no
ribosomes or m-RNA, it cannot synthesize
protein
 no cytochrome P-450
PHASE 2 Reactions
 AKA conjugation or synthetic reactions
 Conjugation or addition of a molecule from
an endogenous substance to the parent
compound
 Enzyme: Transferase – a type of enzyme that
catalyze the transfer of group of atom from
one molecule to another
 Cofactor – pertain to the substances that are
needed by certain enzymes to carry out
catalysis of a particular chemical reaction.
 Source of molecule that is to be
transferred to the parent compound or
drug
GLUCURONIC ACID CONJUGATION
 Most common phase 2 reaction
 AKA : Glucuronidation (major metabolic
pathway for adults)
 is a condensation of the drug or its primary
metabolite with d-glucuronic acid.
 The reaction requires activation of glucoronic
acid by synthesis of UDPGA (uridine
diphosphate glucoronic acid)  cofactor.
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 Enzyme: Glucuronyl transferase or Glucuronides

Glucuronosyl transferase
 are more water-soluble than the parent
 UDPGA is formed from UDP-glucose by a
structures due to the large hydrophilic
dehydrogenase found in the supernatant
carbohydrate moiety; very polar
fraction of the liver.
 more acidic than the parent molecule
 The reaction between UDPGA and the drug is
hence are more ionized
catalyzed by glucuronyl transferase, a
 less easily permeate through membranes
solubilized microsomal enzyme found in the
and are poorly reabsorbed by the kidney
liver, kidney, GI tract and skin.
tubule
 Example of drugs: Acetaminophen
 Excreted in tubular secretion via kidneys,
(paracetamol), Morphine (narcotic
bile(minor)
analgesic), Diazepam (sedative hypnotic),
Chloramphenicol (antimicrobial agent)
 Microsomal drug inducers increase the
activity of glucuronyl transferase, whereas
microsomal enzyme inhibitors and some drugs
reduce or inhibit glucuronyl transferase
activity
 Enzyme inducers – stimulate or increase the
activity of metabolizing enzyme such as the
glucuronyl transferase = faster rate of
elimination of the drug
 Enzyme inhibitors – inhibit or decrease the
activity of enzyme such as glucuronyl
transferase = decrease rate of elimination of
drug

Condition wherein Glucuronidation is altered

ø During pregnancy
 glucoronidation is reduced probably due
to increase progesterone and
pregnanediol levels
 progesterone and pregnanediol levels –
considered as inhibitors of glucuronyl
transferase
 ú rate of elimination = ù plasma
concentration = ù risk of toxicity
ø Newborns
 very low glucuronyl transferase activity
 Gray baby syndrome
 kernicterus
 Glucuronide – metabolite or product of a
glucuronidation reaction Gray Baby Syndrome and Kernicterus
 Alcohols and phenols  ether type
glucuronides
 aromatic and aliphatic carboxylic acids 
ester type glucuronides

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 Gray baby syndrome – toxicity cause by
chloramphenicol; having an Ashen gray skin
 Kernicterus – neurological disorder caused by
hyperbilirubinemia; occurs when the
glucuronyl transferase is reduced or inhibited.
 Hyperbilirubinemia – refers to a condition
wherein there is an excessive levels of
bilirubin in the blood
 Bilirubin – waste product of hemoglobin
metabolism eliminated by our body via
glucuronidation; can cause brain
damage.
 Drugs that compete for glucuronidation or
reduce the already low glucuronyl transferase
activity can precipitate Kernicterus.
 Treatment: Administration of Phenobarbital to
the newborn or the mother before delivery
 Phenobarbital – enzyme inducer; stimulate or
increase the activity of glucuronyl transferase
= increase of rate of metabolism/ elimination
chloramphenicol that cause gray baby
syndrome and rate of elimination of bilirubin
that cause kernicterus
Sulfate conjugation
 Addition of a sulfate molecule to a parent
compound/ drug
 PAPS – cofactor
 Most common metabolic pathway for
newborns
 Example of drugs undergo sulfation:
Acetaminophen (analgesic), Methyldopa
(antihypertensive), Estrone (hormone)
 Enzyme: sulfotransferase or sulfokinase
 found in the liver, kidney and GI tract
 limited and easily depleted
 with increasing drug doses sulfate
conjugation becomes easily saturated
Methylation
 addition of methyl group (non-polar) to a
parent compound or drug molecule
 minor pathway of metabolism
 of importance for many endogenous
substances (substances that are naturally
occurring inside our body like
cathecolamines: Dopamine (chemical that
mediates the sensation of pleasure in the
brain; happy hormone) , Epinephrine and
Norepinephrine (major neurotransmitters of
sympathetic nervous system; responsible for
fight response); Histamine (substance
responsible for producing the symptoms of
allergic reactions)
 Enzyme: methyl transferase
 S-adenosylmethionine (cofactor) is formed
which reacts with the drug in the presence of
a methyl transferase
 occur in different tissues, such as liver, brain,
kidney, skin, blood cells, glands, nerve fibers
and lung
 metabolite formed is less polar
 main purpose is to inactivate the drug
Acetylation
 does not make the drug polar
 main purpose is to inactivate the drug
 metabolic pathway for amines, amides, N-
containing compounds
 addition of an acetyl group to a parent
compound
 Acetyl – C=OCH3 (non-polar molecule) = less
polar metabolite
 Conjugation of aromatic primary amines,
aliphatic amines, amino acids, hydrazines,
hydrazides and sulfonamides
 minor pathway of metabolism except for
isoniazid and sulfonamides
 Enzyme: N-acetyl transferase
 Cofactor – Acetyl CoA
 Important drug examples: (HIPS) – drugs
caused drug induced Systemic Lupus
Erythematasus (SLE) – auto immune disorder in
which the immune system attacks the
different tissues of our body causing wide
spread inflammation and tissue damage.
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 Hydralazine (vasodilator)  Example of substances that are metabolized

 Isoniazid (anti-tubercular drug) via GSH conjugation: Naphthalene,
 Procainamide (local anesthetic and anti- Ethacrynic acid (diuretic drug), NAPQI (toxic
arrhythmic agent) metabolite)
 Sulfonamide (antimicrobial) ø A peptide of glutamyl- cysteine-glycine which
is important in the detoxification of reactive
 Expression of acetyl transferase is subject to
oxygen and is the main intracellular molecule
genetic polymorphism (variation in the
for protection of cell against electrophilic
expression of genes between populations)
compounds
 slow acetylators and fast acetylators
 Slow acetylators
 Ex. races: Egyptian, Caucasians,
African-American
 ú enzyme (N-acetyl transferase)  ú
rate of elimination (longer t ½)  ù
plasma concentration  ù risk of
toxicity
 High change of developed of drug
induced Systemic Lupus Erythematasus
after taking the HIPS
 Fast acetylators
 Ex. races: Asians, Eskimos
 ù enzyme (N-acetyl transferase)  ù
rate of elimination (shorter t ½)  ú
plasma concentration  ú effect
Metabolism of acetaminophen in Adults
 Genes – portions of DNA that codes for the
production of protein such as enzyme; gives ø Glucuronidation – major metabolic pathway
instruction to produce protein in the body for paracetamol or acetaminophen
 Newborns are not capable ø Via glucuronidation, it is being converted into
glucuronide metabolite (non-toxic, readily
Glutathione conjugation excretable)
 Addition of glutathione molecule to parent ø Sulfation – secondary metabolic pathway for
compound or drug molecule paracetamol acetaminophen
 Responsible for detoxification of free radical ø When paracetamol will undergo N-oxidation
or reactive oxygen species in Phase 1, it will produce toxic metabolite
 Glutathione – a peptide containing which is the NAPQI
glutamine, cysteine and glycine; very potent ø Glutathione – can neutralize NAPQI, can
reducing agent; thus, it can donate electron convert it to a non-toxic glutathione
to free radicals metabolite
 Free radicals – molecules that have an ø Maximum daily dose of paracetamol: 4g (8
unpaired electron; highly reactive 500 mg paracetamol tablets)
 Reactive oxygen – example: hydroxyl radical
Metabolism of acetaminophen in
 Enzyme: Glutathione S transferase Infants/Newborns
 Cofactor: Glutathione
 Has a synergistic effect with vitamin C ø Sulfation – major metabolic pathway for
 + vitamin C – also a reducing paracetamol in pregnant woman and
agent/antioxidant newborns

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1ST SEMESTER – PRELIM

Amino acid conjugation Glutamine conjugation

 Addition of amino acid molecule to a parent  for conjugation with organic acids such as
compound or drug molecule phenylacetic and related acids
 Important metabolic pathway for organic  Enzyme: N- Acyltransferase
acids such as salicylic acid and nicotinic acid  Cofactor: Coenzyme A (Acyl CoA)
 Enzyme: N- Acyltransferase
Maturation of Metabolic Processes in infant
 Cofactor: Acyl CoA
ø Glycine conjugation – amino acid added AGE Metabolism Capacity Developed
or transfer to parent molecule is glycine Birth Sulfation
ø Glutamine conjugation – amino acid 1st week Reduction, Oxidation
added or transfer to parent molecule is 1 month Acetylation
glutamine 2 months Glucuronidation
Glycine conjugation
Glutathione conjugation
3 months
Cysteine conjugation
+ N-Acyltransferase is developed

Enzyme Induction

 Drug or chemical-stimulated increase in

enzyme activity
 Alteration in the enzyme activity in liver
microsomes resulting in a faster rate of
metabolism
 not a disease; it is an adaptation of the body
to exogenous material
 ù enzymes ù metabolism ú effect
 ù activity of enzymes = ù rate of
Glycine conjugation metabolism/elimination (shorter half-life) = ú
plasma concentration = ú intensity and
 Most common endogenous amine for
duration of pharmacologic effect
conjugation with organic acids (aromatic
 Nababawasan ang effectiveness ng drug
heterocyclic carboxylic acid drugs and
dahil naeeliminate agad
aliphatic acids)
 Bile acids are conjugated with glycine Auto-induction
 Limited
 Enzyme: N- Acyltransferase  A drug that stimulates its own metabolism
 Cofactor: Coenzyme A (Acyl CoA)  EX. Phenobarbital is given repeatedly its
 Reduced in liver damage metabolism is increased
 Reduced in newborn and aged Foreign-induction
 Benzoic acid  hippuric acid
 one enzyme inducer stimulate the rate of
metabolism of another drug
 EX. If a dose of hexobarbital is then given its
metabolism is also increased
 Hexobarbital induces the metabolism of
phenobarbital

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Enzyme Inducers grapefruit juice; chemical that has anti-

oxidant and anti-inflammatory properties
 Increase the rate of metabolism of other drug
= decrease plasma concentration = decrease  Decrease the efficacy of prodrugs – efficiency
effect is increase by enzyme inducers.

ø P- Phenytoin First pass effect

ø P- Phenobarbital
 Aka: PRESYSTEMIC METABOLISM
ø R- Rifampicin
 initial BIOTRANSFORMATION of an active drug
ø C- Carbamazepine (auto-induction) –
BEFORE reaching the systemic circulation
example of a drug that shows extensive
 reduces the systemic availability of the drug
auto-induction
 IV and PO
ø C- Cigarette smoking – contain polycyclic
 eg. Propranolol (anti-hypertensive drug), NTG
aromatic hydrocarbons (substances that
- nitroglycerin (vasodilator), Morphine
acts as enzyme inducers)
(narcotic analgesics), Pentazocine (narcotic
ø C – Chronic alcoholism – refers to alcohol
analgesics), meperidine (narcotic analgesics),
consumption for a long period of time;
Verapamil (anti-arrhythmic drug)
enzyme induction; Acute alcoholism –
 NTG: Oral BA: <1; If sublingual, increase BA
enzyme inhibition.
Learning Check!
Enzyme Inhibition
1. Ms. Danvers takes Phenytoin as a
 May be due to substrate competition o due
maintenance drug for her epilepsy. She was
to direct inhibition of drug metabolizing
recently diagnosed with tuberculosis and she
enzyme
was prescribed with Isoniazid. After several
 ú enzymes ú metabolism ù effect
days of taking Isoniazid, she had experienced
 decrease enzyme activity = decrease rate of
ataxia and slurred speech which is neurotoxic
elimination (increase half-life (t ½)) = increase
effects of Phenytoin. How can you explain this
plasma concentration = increase
phenomenon?
pharmacologic effect = increase risk of
toxicity ø Isoniazid is an enzyme inhibitor
ø Isoniazid inhibited the metabolism or
Enzyme Inhibitors
elimination of phenytoin and thus, resulting to
 decreases the rate of elimination of other an increase in the plasma concentration on
drugs. phenytoin.
 Because of decreased elimination,
ø M- Metronidazole (anti-microbial)
phenytoin plasma level might have
ø E- Erythromycin (anti-bacterial)
exceeded the minimum toxic
ø D- Disulfiram (used to treat alcoholism)
concentration and thus, had toxic effects
ø I- Isoniazid (anti-TB drug)
like ataxia and allured speech.
ø C- Cimetidine (histamine antagonist used in
the treatment of hyperacidity); very potent 2. Katya is sexually active woman who takes oral
enzyme inhibitor; not to be used with other contraceptives on a daily basis. She was
drugs) diagnosed with epilepsy and was prescribed
ø K- Ketoconazole (anti-fungal drug) with Phenobarbital. After 2 months, she had a
ø V- Valproic acid (used to treat seizures) positive result for pregnancy test. She was
ø A- Acute alcoholism confused about thus as she never missed a
ø G- Grapefruit juice (Naringin) – compound dose of her oral contraceptive drug. How can
with enzyme inhibitory action present: you explain this case?
furocoumarins; Naringin – component of

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ø Phenobarbital is an enzyme inducer.

ø Phenobarbital induced the metabolism/
elimination of the oral contraceptive drug,
resulting to a decreased plasma
concentration of the oral contraceptive.
ø ú plasma concentration of oral
contraceptive = ú effectiveness

Excretion

 the final LOSS of the drug substance or its

metabolites from the body such as through
the kidney (urine), intestines (feces), skin
(sweat), saliva, and/or milk.
Drug Elimination
 Irreversible removal of drug from the body by
all routes of elimination.
 Collective term for metabolism and excretion
Nonvolatile drugs
 are excreted mainly by renal excretion, into
the urine
Regulation of Renal Blood flow
ø Blood flow to an organ is directly proportional
to the arteriovenous pressure difference
(perfusion pressure) across the vascular bed
and indirectly proportional to the vascular
resistance.
Nephrons / malphigian bodies
ø responsible for the removal of metabolic
waste and the maintenance of water and
electrolyte balance

Volatile drugs Parts

 gaseous anesthetics, or drugs with high  Capillary part

volatility, are excreted via the lungs into  Glomerulus
expired air  Bowman’s capsule

Clearance Tubular part

 the process of drug elimination from the body  PCT

or from a single organ without identifying the  LOH
individual processes involved.  DCT
 the volume of fluid cleared of drug from the  CD
body per unit of time  Ureter
 mL/min or L/hr.

Kidney

 Located in the peritoneal cavity

 most important organ for excretion
 maintain normal fluid volume
 maintain salt and water balance
 with 2 endocrine fxn
 secretion of renin(regulates BP)
 secretion of erythropoetin(RBC production)

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3 kidney processes  Diet rich in:

1. Glomerular filtration
2. Active tubular secretion
3. Tubular reabsorption
Glomerular Filtration
 filtration of LMW molecules (MW<500)
 normal GFR:125mL/min (180 L/day)
 GFR - tells how healthy the kidney is
 ave urine: 1-1.5 L(99% are reabsorbed)
 depends on pressure
 100 mmHg - pressure of artery
 45-65 mmHg - pressure on glomerulus
Active renal secretion
 Occurs in proximal Convuluted tubule
 Reabsorption of water and active secretion of
some weak electrolyte ( weak acids)
 Requires carrier and energy ( against conc
gradient)
 reflects the effective renal plasma flow (ERPF)
- 425 to 650 mL/min
 Drugs used to measure active tubular
secretion
 P-amino hippuric acid (PAH) and
iodopyracet (Diodrast)
 These substances are both filtered by the
glomeruli and secreted by the tubular cells
Tubular reabsorption
 Carbohydrate  higher urinary pH
 protein  lower urinary pH
 Drugs (ascorbic acid and antacids)
 alter urinary pH when administered in large
quantity
 Intravenous fluids (solutions of bicarbonate or
ammonium chloride)
 change urinary pH and alter drug
reabsorption
Drug Clearance
 pharmacokinetic term for describing drug
elimination from the body without identifying
the mechanism of the process
 described in terms of volume of fluid clear of
drug per time unit
 fixed volume of fluid (containing the drug)
cleared of drug per unit of time
 units : volume/time (eg, mL/min, L/hr)
Organ clearance
1. Renal clearance - voL of plasma that is
cleared of drug per unit time through the
KIDNEY
2. Hepatic clearance - voL of plasma that is
cleared of drug per unit time through the
LIVER
3. Creatine clearance - ratio of creatine in the
urine and creatinine in the plasma

 occurs in Distal convoluted Tubule

 If a drug completely reabsorbed (eg.
Response
Glucose), then the values for the clearance of
the drug is approximately zero.  refers to the therapeutic effect, sub-
 For drugs that are partially reabsorbed, therapeutic effect, side effect and toxic
clearance values will be less than the GFR of effect
125 to 130 mL/min
 Reabsorption of water and passive excretion
of lipid soluble drugs
 Depends on urine pH
 Based of Henderson-Hasselbalch equation

 Acidic Urine + Acidic Drug = Reabsorb

 Acidic urine + Basic Drug = Excreted
 Basic urine + Acidic drug = Excreted
 Basic urine + Basic drug = Reabsorb

PHBP221 39