PHA6120: BIOPHARMACEUTICS & PHARMACOKINETICS

Unit 1:
Introduction to Biopharmaceutics
and Pharmacokinetics

Prepared by:
PHA6120 Cluster (A.Y. 2022-2023)
OUTLINE OF DISCUSSION:
A. Definition of terms and basic concepts
B. LADMER System
C. Routes of administration and drug disposition
 DRUG
DRUG VS PRODUCT
 Biopharmaceutics
• Interrelationship of the physicochemical properties of the drug,
the dosage form (drug product) in which the drug is given, and
the route of administration on the rate and extent of systemic
drug absorption.
 Biopharmaceutics
• Relation of the physical and chemical properties of the drug to:

1. BIOAVAILABILITY - rate & extent (amount) of systemic

absorption of the therapeutically active drug
 Bioavailability
• A measure of systemic availability of a drug

Factors: If Drug is:

• Nature of drug molecule • Therapeutically
• Route of Delivery effective
• Formulation of dosage • Toxic
form • No Apparent effect
 Biopharmaceutics
• Relation of the physical and chemical properties of the drug to:

2. PHARMACOKINETICS - the time course of drug movement in

the body during absorption, distribution, metabolism, & excretion
(ADME)
 Pharmacokinetics
• the time course of drug movement in the body during absorption,
distribution, metabolism, & excretion (ADME)

Pharmakon Kinesis Pharmacokinetics

 Pharmacokinetics
Distribution Metabolism

Absorption Excretion

Pharmacokinetics
Goal of Application of Pharmacokinetics

“Assure maintenance of therapeutic drug concentration

in the body while preventing danger of toxicity.”
 Biopharmaceutics
• Relation of the physical and chemical properties of the drug to:

3. PHARMACODYNAMICS - relation of the drug concentration or

amount at the site of action (receptor) & its pharmacologic
response

4. TOXICOLOGIC EFFECTS - harmful or undesirable effects

 Pharmacodynamics

• Relationship between the drug concentration at

the site of action (receptor) and pharmacologic
response
• Includes biochemical and physiologic effects that
influence the interaction of drug with the receptor
 Pharmacodynamics

• Receptor – component of a cell or organism that

interacts with a drug and initiates the chain of
events leading to the drug’s observed effects
Pharmacodynamics
Drug Exposure Drug Response
• Refers to dose and • Refers to direct measure of
various measures of the pharmacologic effect of
acute or integrated drug the drug
concentrations in plasma • Includes endpoints or
and other biological fluid biomarkers from: remote,
presumed mechanistic effect
to a potential or accepted
surrogate and to a full range
short/long term clinical effect
 Biopharmaceutics
Involves factors that influence:
1. Design of drug product
2. Stability of the drug within the drug product
3. Manufacture of drug product
4. Release of drug from drug product
5. Rate of dissolution/release of drug from absorption site
6. Delivery of drug to the site of action
SCOPE OF BIOPHARMACEUTICS
1. All possible effects observed following the administration of
the drug in its various dosage forms
• therapeutic effect, adverse effect, drug-drug interaction
SCOPE OF BIOPHARMACEUTICS
2. All possible effects of various dosage forms on biological
response
• onset of action, duration of action
 Plasma Drug Concentration-Time Curve

• MEC (minimum effective

concentration) reflects
the minimum concentration
of drug needed at the
receptors to produce the
desired pharmacologic effect
• MTC (minimum toxic
concentration) represents
the drug concentration
needed to just barely
produce a toxic effect
Plasma Drug Concentration-Time Curve

• Therapeutic window - the

concentration between MTC
and MEC
• Therapeutic index – ratio
between toxic and
therapeutic dose

Wide vs Narrow
Therapeutic Index…
Which is safer?
Plasma Drug Concentration-Time Curve
• The onset time corresponds to
the time required for the drug to
reach the MEC
• The intensity of the
pharmacologic effect is
proportional to the number of drug
receptors occupied, which is
reflected in the observation that
higher plasma drug
concentrations produce a greater
pharmacologic response, up to a
maximum
• The duration of drug action is
the difference between the onset
time and the time for the drug to
decline back to the MEC
 Plasma Drug Concentration-Time Curve
• The time of peak plasma level is
the time of maximum drug
concentration in the plasma and is a
rough marker of average rate of drug
absorption
• The peak plasma level or
maximum drug concentration is
related to the dose, the rate constant
for absorption, and the elimination
constant of the drug
• The AUC is related to the amount of
drug absorbed systemically.
SCOPE OF BIOPHARMACEUTICS
3. All possible physiological factors which may affect the drug
contained in the dosage form
• pH of the stomach & intestine, surface area of skin

4. The dosage form of the drug

Processes of Drug Bioavailability
A drug that is bioavailable is most likely to cause an effect in the body
 Processes of Drug Bioavailability

1
Drug in drug
product
Disintegration
release
2
Solid drug
particles
Dissolution

3
Drug in
solution
Absorption

4
Drug in the
body
Dynamic relationship between drug, drug product and pharmacological effect
DRUG PRODUCT
RELEASE, DISSOLUTION
Manufacturing Process/ Drug Product Design

DRUG IN SYSTEMIC CIRCULATION

EXCRETION , METABOLISM

DRUG IN TISSUES
Pharmacologic/ clinical effect

THIS SEQUENCE OF EVENTS IS AFFECTED BY THE DESIGN OF

DOSAGE FORM AND PHYSICOCHEMICAL PROPERTIES OF THE DRUG
• PHARMACOKINETICS – a process of how the body
deals with the drug, “what your body does to your drug”

• PHARMACODYNAMICS – a process of how your drug

deals with the body, “what your drug does to your body”
 Clinical Pharmacokinetics
• Application of pharmacokinetic models to drug therapy
• Factors affecting drug disposition:
– Drug disposition serves as basis of dosing regimens
– Disease
– Age
– Gender
– Genetic and ethnic differences
 Clinical Pharmacokinetics
Therapeutic drug Monitoring (TDM)
• very potent drugs ex. w/ narrow therapeutic range;
optimize efficacy and prevent adverse toxicity
– Monitoring plasma drug conc ( theophylline, chemotherapeutic
drugs, anticonvulsants, aminoglycosides)
– Monitor specific pharmacodynamic endpoint such as
Prothrombin clotting time ( warfarin)
Drug Concentration and Drug Response

TOXIC

CONCENTRATION
DRUG POTENTIALLY TOXIC

THERAPEUTIC

POTENTIALLY SUBTHERAPEUTIC

SUBTHERAPEUTIC

VARIABLE RESPONSES
POTENT DRUGS (Adverse effects can occur at drug conc needed for therapeutic effect)
Pharmaceutic Factors Affecting Drug Bioavailability

• Goal – design a drug product that will deliver active drug in

the most bioavailable form

1. Type of drug product

2. Nature of the excipients in the drug
3. The physicochemical properties of the drug molecule
 Physicochemical Properties
• Measurable characteristics
• Determined by the number, kind, arrangement of atoms
• Preferred expression of the properties that relate to
biological action vs physical or chemical

• Ex. pH, solubility, H-bonding, partition coefficient,

hydrophilicity, lipophilicity, BBB, placental barrier
 Physicochemical Factors that may Alter
Bioavailability
1. Particle size of the drug in solid dosage form
ex. Griseofulvin – not very soluble -> micronized griseofulvin

2. Particle size of dispersed phase in an emulsion

3. Tablet disintegration – Break up of intact dosage form to its

component aggregates
ex. Starch, Explotab®, Avicel®
Physicochemical Factors that may Alter
Bioavailability
• Complete disintegration (USP)
“That 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”

• Solid products exempted from disintegration test: troches,

chewable tabs
• Separate specs for: uncoated, plain coated, enteric, buccal, SL
tabs
Physicochemical Factors that may Alter
Bioavailability
4. Tablet and capsule adjuncts
Excipients – added to form the dosage form; inert, inactive

Roles:
• May affect drug absorption
• May increase solubility
• May increase retention time of drug in GIT
• May act as carrier to increase drug diffusion across the
intestinal wall
Physicochemical Factors that may Alter
Bioavailability
Excipients:
• Suspending agents
– increase viscosity of drug vehicle, resulting to changes in drug
dissolution
• Lubricants, glidants, anti-adherents
– prevent the sticking of fill material to the punches and dies to
produce tablets having a sheen
– Enhance the flow of the tableting material in the tablet dies,
minimize wear of punches and dies
ex. Talc, hydrogenated vegetable oil, magnesium stearate (hydrophobic
lubricant); excessive use will repel water and reduce dissolution
Physicochemical Factors that may Alter
Bioavailability
• Diluent/Filler
– Increase bulk or mass of the dosage form
– Excess use will retard dissolution
ex. Lactose, dibasic calcium phosphate, starch, microcrystalline cellulose

• Binder
– Makes diluent adhere to the tablet to form a compact mass
– Excessive use will retard disintegration and dissolution
ex. Acacia
Physicochemical Factors that may Alter
Bioavailability
5. Tablet coating
– Thickness will affect drug release
– Uneven release or not released at all

• Enteric coated – protection against gastric acid

ex. cellulose acetate phthalate
• Film coated – protection against light, moisture & air during storage
ex. hydroxypropylmethyl cellulose
• Sugar coated – to conceal or mask bitter taste
ex. sucrose, glucose
Physicochemical Factors that may Alter
Bioavailability
6. Crystalline drug properties
– More rigid and more thermodynamically stable than amorphous
form
– Slower dissolution rate than amorphous
– Hydrates (crystal) – drug + water
• Different solubility than anhydrous
Ex. Erythromycin dihydrate – faster dissolution than monohydrate or
anhydrous in phosphate buffer
Anhydrous ampicillin – has faster dissolution than ampicillin trihydrate
 Physicochemical Factors that may Alter
Bioavailability
• Polymorphs – different crystal forms, same chemical
structure, different physical properties (e.g. solubility, density,
hardness, compression characteristics)

• Polymorphism – arrangement of drug in various crystal forms

Ex. Chloramphenicol – several polymorphs, ß polymorph is used for suspension
(more soluble and better absorbed)
Physicochemical properties of drug
product

Pharmacologic/clinical effect
 Prerequisites for a Drug to Exert
Biological Effect
1. Soluble in body fluids
2. Transported by body fluids
– Indiscriminate distribution to all parts of the body:
a) Site where it has no action
b) Storage site
c) Site of action
 Prerequisites for a Drug to Exert
Biological Effect
3. Pass membrane barriers
– More lipid soluble -> transverse cell membrane easily
– Ionized drug -> more water soluble
– Non-ionized drug -> more lipid soluble
– Low molecular weight
– BBB, placental barrier
 Prerequisites for a Drug to Exert
Biological Effect
4. Escape excessive distribution to inert body depots
e.g. fats, muscle tissues
5. Endure metabolic attack
– Stomach enzymes that catalyze drug degradation
Ex. Erythromycin
• pH dependent stability profile
• Decomposition in acidic medium
• Relatively stable in neutral and alkaline medium
• Erythromycin are enteric coated
 Prerequisites for a Drug to Exert
Biological Effect
6. Penetrate to its site of action
– Blood perfusion in tissue or organ
7. Act so as to alter a particular function
ex. High blood pressure
• Action
– Bioresponse to drug; consequence of drug-living system
interaction
– Cause changes in biological state that was present before
drug administration
 AIM:
To deliver the right amount of drug that is EFFECTIVE
and SAFE at the right place (site of action) and at the
right time (oral, SL or IV/ fast or slow-release)
Routes of Administration and
Drug Disposition
 Drug Disposition

• Drug disposition refers to the distribution, metabolism

and excretion of the drug in the body
– serves as basis of dosing regimens for individual or group of
patients

• Drug elimination refers to the metabolism and excretion

of the drug in the body
Tablet (oral)

A. In stomach, drug is released

• Tablet à disintegration à granules à dissolution à
solution

• must be in a form of a solution for it to be absorbed

Factors that affect the dissolution of a drug

1. Particle size
2. Water/lipid solubility
3. pka
• Water solubility, ionized form of a drug favors
dissolution
Tablet (oral)

B. The drug (in the form of a solution) will be absorbed

in the small intestines.
• passage of a drug through a semipermeable membrane
(diffusion)
• Lipid solubility, unionized form of a drug favors absorption
• pka = - log ka
• Ka = [H][A]/ [HA]
Factors that affect the absorption of a drug
1. Particle/molecular size of the drug
2. Molecular weight of the drug
3. Water/lipid solubility of a drug
4. pKa
5. Surface area of the absorbing surface (villi & microvilli increases
the surface area of the small intestines)
6. Blood supply or perfusion of the absorbing surface
7. Thickness of the membrane of the absorbing surface
8. Type of transport system
(e.g. passive diffusion, active transport, facilitated diffusion)
Tablet (oral)

C. After absorption, it will

pass by the liver via the
portal vein

• First-pass effect/first-pass
metabolism/pre-systemic
elimination
– drug undergoes metabolism
before it reaches the
systemic circulation
Effects of metabolism on the drug
1. Deactivation

2. Activation (Prodrugs)

3. Active drugs with active metabolites

4. Active drugs with toxic metabolites

• PRODRUGS
• Pharmacologically inactive compounds designed to maximize the
amount of the active species that reaches its site
• ACTIVE DRUGS WITH ACTIVE METABOLITES
• ACTIVE DRUGS WITH TOXIC METABOLITES
Tablet (oral)

D. Once the drug reaches the systemic circulation, it

will undergo distribution to the peripheral tissues
and plasma proteins.

• Plasma proteins are located in the systemic

circulation/bloodstream.
• Drug A
– 40% peripheral tissues, 60% systemic circulation
(20% protein bound, 40% unbound)
• Drug B
– 40% peripheral tissues, 60% systemic circulation
(45% protein bound, 15% unbound)
• Drug C
– 70% peripheral tissues, 30% systemic circulation
(10% protein bound, 20% unbound)
Distribution of a drug to the peripheral tissues and plasma
protein depends on:

1. affinity of a drug for the tissues

2. availability of the tissues or storage sites
(e.g. dose is decreased in the elderly because of less
muscle mass)
• Plasma protein-binding is not specific and reversible
• A drug in the peripheral tissues or bound to plasma
proteins à cannot elicit an effect and cannot be eliminated
• free (unbound) à effect and can be eliminated
• A drug can be displaced from its plasma protein-binding site if:

1. Free drug has ↓ due to elimination

2. Another drug which has a higher affinity for the plasma protein
• Most drugs cannot penetrate the BBB because:
1. Presence of astrocytes
2. Presence of the MDR (multiple drug resistant) protein, a
transport protein that carries the drug back to the bloodstream
3. Protein content in the bloodstream is ↑ than the protein in the
brain = ↑ in oncotic pressure in blood
• Unlike BBB, the blood-placenta barrier usually allows the drug
to pass through the barrier.
Tablet (oral)

E. The free drug will bind to a receptor eliciting a

response
• The intensity of clinical effect depends on the amount of
drug molecule at the site of action (receptor site) and the
potency of the drug.
• Notice that doses of potent drugs are in “mcg”
(e.g. thyroxine, lanoxin).
Tablet (oral)

F. The drug will reach the liver for

metabolism /biotransformation.

• Conversion of a drug to a water-soluble/polar form

• Sites of metabolism:
1. Liver
2. Intestinal wall
3. Normal flora of the intestine
• Enterohepatic recycling/enterohepatic recirculation
– drug that is biliary-excreted is
converted by the intestinal
flora to a reabsorbable form =
reabsorbed in the small
intestines
Tablet (oral)
G. Once the drug is polar, it will be excreted by the kidneys.

• Sites of excretion:
1. Kidneys
2. Biliary ducts
3. Sweat glands, lacrimal glands
4. Mammary glands
Factors affecting absorption of drugs via oral administration:

1. Contents of GIT affect dissolution rate of the drug

(change in pH, viscosity)
2. GI motility = may affect absorption rate (gastric
emptying rate, intestinal motility)
Release of drug from other oral dosage forms
Other routes of administration:
Intravenous route (IV)

• 100% bioavailability
• Rapid onset of action
• IV bolus – the whole amount of drug is
given instantaneously
• IV infusion – the drug reaches the
circulation by increments (slow infusion)
• Dose given cannot be reversed, an excess
can be a potential for drug toxicity
• No FPE
Other routes of administration:
Sublingual route (SL)

• usually a tablet (e.g. Isosorbide

dinitrate SL tab) or a solution
• tablet à liberation
• absorption in the mucosa of the tongue
(lingual vein)
• drug directly reaches the systemic
circulation, no FPE
• Rapid onset of action
Other routes of administration:
Buccal route

• usually a solution (e.g. Nitroglycerin

buccal spray)
• absorption in the mucosa of the buccal
cavity
• No FPE
• Rapid onset of action
Other routes of administration:
Rectal route

• suppository à liberation
• absorption through the rectal mucosa
• FPE à upper region
• No FPE à lower region
Other routes of administration:

Intramuscular route (IM)

• Parenteral drug à deltoid, gluteal

region, lateral thigh with the needle
at 90 °angle
• Drug à muscle layer to reach the
bloodstream
• Drug is slowly absorbed from the
site of administration
• Slow or gradual onset of action
• No FPE
Other routes of administration:

Subcutaneous route (SQ)

• Parenteral drug à deltoid and lateral

thigh with the needle at 45 ° angle
• Drug à subcutaneous tissue and
muscle layer to reach the
bloodstream
• Drug is slowly absorbed from the
site of administration
• Slow or gradual onset of action
• No FPE
Other routes of administration:

Transdermal route (TD)

• Differs from a topical because the drug is intended to be absorbed through the skin to
reach the systemic circulation
• usually a patch, drug is slowly liberated prolonging the duration of action
• Drug à all the layers (skin, subcutaneous tissue and muscles) to reach the
bloodstream
• rate of absorption is directly proportional to the hydration & perfusion of the skin
and lipophilicity of the drug
• No FPE
Other routes of administration:
Intrathecal/spinal route

• Drug (e.g. local anesthetics) reaches

the cerebrospinal fluid then goes to the
bloodstream via the choroid plexus
• No FPE
Other routes of administration:
Inhalational route

• Drug à airways to reach the alveoli

where it will be absorbed to reach the
systemic circulation
• rate of absorption depends on the
pressure and perfusion in the alveoli/air
sacs
• No FPE
• immediate effect (e.g. salbutamol
metered-dose inhalers, isoflurane gas)
Other routes of administration:
Intraosseous route (IO)

• Drug à bone marrow for it to reach the

systemic circulation
• accessed if the IV route is difficult to
achieve
 Other routes of administration:
Intrasynovial route

• Drug à synovial fluid and it will

eventually go back to the systemic
circulation
• Drugs given by this route are intended
to reach the site of action immediately
(e.g. an anti-inflammatory drug
injected in the joints to treat arthritis)
END OF DISCUSSION