TOPIC 1 - INTRODUCTION TOPHYSICAL PHARMACY AND PRINCIPLES OF

BIOPHARMACEUTICS

I. Physical Pharmacy
1. Definition
2. Importance
II. Biopharmaceutics
1. Definition
2. Background Principles
a. Drug Targets
b. Dosage Forms
c. Routes of Administration
d. Bioavailability
3. Drug Disposition
a. LADME
b. Plasma Conc – Time Profile
c. Physicochemical Factors Related to the Fate of the Drug in the Body
III. Pharmacokinetics
1. Liberation
2. Absorption
a. Oral Administration
b. Transporters
c. Enterohepatic Circulation
d. Rate-Limiting Step in Absorption
e. First-Pass Metabolism
3. Distribution
i. Plasma Protein Binding
ii. Tissue Binding
iii. Apparent Volume of Distribution
4. Metabolism
i. Phase 1
ii. Phase 2
5. Excretion
i. Renal Excretion
ii. Clearance
iii. Elimination Half-life

----- HIGLIGHTED WORDS – TOPICS/subtopics (indicator/guide only) ----

----- BOLD WORDS/Diagram – TERMS OR QUESTIONS -----
I. Physical Pharmacy

Physical Pharmacy
- the study of the physical and chemical properties of drugs and their dosage forms.

- It explains how a drug, usually in the form of a crystal, is transformed into a usable product that is
administered to patient to reach its pharmacological target, and then leaves the body.

- It provides a physicochemical basis for rational formulation, manufacturing, compounding, drug

delivery, product selection, and product usage.

Relationship of Concepts

BIOPHARMACEUTICS

Biopharmaceutics

- the study of the physical and chemical properties of drugs and their proper dosage as related to the
onset, duration, and intensity of drug action.

- the study of effects of physicochemical properties of the drug and the drug product, in vitro, on the
bioavailability of the drug, in vivo, to produce a desired therapeutic effect.

- the relationship between the physicochemical properties of the drug, the drug’s biological fate in the
body after its administration, and the resulting pharmacological action of the drug.

DRUG TARGETS

Drug Targets – are molecules or structures that are linked to a particular disease.

Protein targets dominate and include the following – enzymes, ion channels, nuclear hormone
receptors, structural proteins, membrane transport proteins, and G protein-coupled receptors.
True or False: The targets are found in various areas of the body, and they may be outside
cells, embedded in cell membranes, or outside of cells in various body fluids. (Answer: False,
*inside cells*)

Systemic circulation - In most cases, drug targets are reached by the drug after it enters here and
distributes to the specific areas or cells that contain them.

Size, charge, and lipophilicity - Drug entry and distribution are also under the influence of these
physiochemical properties of the drug

DOSAGE FORMS

 A formulation of the drug with various excipients. – Dosage forms

 These are used in improving stability, dissolution, manufacturing speed and quality, and
flavoring. – Excipients
 What are the two most common physical forms of drugs? – Crystals and molecules
 Crystals in a compressed powder – Tablet
 Crystals in a non-compressed powder - Capsules, powder – filled
 Capsules, liquid – filled - Molecules or crystals in vegetable oil
 Crystals in waxy, water-miscible or water-immiscible base – Suppository
 Solution - Molecules
 Suspension - Crystals in an aqueous or non-aqueous liquid
 Crystals or molecules in a semisolid oleaginous base – Ointment
 Crystals or molecules in water-miscible or immiscible semisolid cream base – Cream
 Crystals or molecules in water-miscible semi-solid gel base – Gel
 Aerosol - Crystals or molecules in a gas, liquid, or semisolid

ROUTES OF ADMINISTRATION

o ROUTE: Oral
o ADMINISTRATION SITE: Mouth (swallowed)

o ROUTE: Sublingual
o ADMINISTRATION SITE: Under the tongue

o ROUTE: Buccal
o ADMINISTRATION SITE: Between the cheek and
o gums
o ROUTE: Rectal
o ADMINISTRATION SITE: Rectum

o ROUTE: Vaginal
o ADMINISTRATION SITE: Vagina

o ROUTE: Intranasal
o ADMINISTRATION SITE: Nasal cavity

o ROUTE: Pulmonary
o ADMINISTRATION SITE: Mouth (inhaled)

o ROUTE: Ophthalmic
o ADMINISTRATION SITE: Eye surface

o ROUTE: Topical
o ADMINISTRATION SITE: Epidermal surface

o ROUTE: Transdermal
o ADMINISTRATION SITE: Epidermal surface

o ROUTE: Intravenous injection or infusion

o ADMINISTRATION SITE: Veins

o ROUTE: Intramuscular injection

o ADMINISTRATION SITE: Striated muscles (e.g.deltoid, thigh, buttocks)

o ROUTE: Subcutaneous injection

o ADMINISTRATION SITE: Subcutaneous fat

o ROUTE: Intraperitoneal
o ADMINISTRATION SITE: Peritoneal cavity

o ROUTE: Intrathecal injection or infusion

o ADMINISTRATION SITE: Spinal cord (into the cerebrospinal fluid)
o ROUTE: Epidural injection or infusion
o ADMINISTRATION SITE: matter of the spinal cord

o ROUTE: Intrasynovial injection

o ADMINISTRATION SITE: Synovial space of joints

o ROUTE: Intraosseous injection or infusion

o ADMINISTRATION SITE: Bone marrow (e.g. of the tibia)

o ROUTE: Intravitreal injection

o ADMINISTRATION SITE: Vitreous humor of the Eyeball

1. Drug is given by mouth and absorbed through the stomach or intestine: oral administration
2. Drug is administered under the tongue: sublingual administration
3. Drug that administer via suppository or fluid into the anus: rectal administration
4. Drug is applied locally on skin or mucous membrane: topical application
5. Drug is administered via vapor or gas into the nose or mouth: inhalation

BIOAVAILABILITY

Bioavailability

 the proportion (percent or fraction) of an administered dose of unchanged drug that

reaches the systemic circulation.
 the rate and extent to which a drug is absorbed and becomes available at the site of action.
 a fundamental component of drug product performance that is assessed in the drug
development process

100% bioavailable - An intravenous drug is administered directly into the systemic circulation.

Bioavailability can be decreased by

- incomplete dissolution, incomplete absorption through epithelia, and presystemic

metabolism.

DRUG DISPOSITION

Drug Disposition- the fate of the drug in the body.

LADME
 LADME- liberation, absorption, distribution, metabolism, elimination

Liberation - the release of the drug from its dosage form.

Absorption - the movement of drugs into the bloodstream.

Distribution - the passage of drugs from the bloodstream to various parts of the body (tissues
and organs).

Metabolism - the change of drug to compounds that are easier to eliminate by enzymes.

-the chemical conversion or transformation of drugs into compounds which are easier to
eliminate.

Excretion - the elimination of drugs from the body through the kidneys or other routes.

PLASMA CONCENTRATION – TIME PROFILE

FILL IN THE BOX

Answers:
1. Onset of action
2. Peak plasma concentration (Cmax)
3. Intensity of action
4. Duration of action
5. Onset time
6. Time of peak concentration (Tmax)
7. Therapeutic range
 8. Maximum safe concentration
9. Minimum effective concentration

Peak plasma concentration (Cmax) - at point in which the maximum concentration of drug in plasma.

Time of peak concentration (Tmax) - the time of the drug to reach peak concentration of plasma.

Area under curve - the total integrated area under the plasma level time profile and express the total
amount of drug that comes into systemic circulation after its administration.

Minimum effective concentration (MEC) - minimum amount of drug in the plasma require to have
therapeutic effect.

Maximum safe concentration (MSC) - concentration of plasma above which adverse or unwanted
effects are precipitated.

Onset time - time required to start producing pharmacological response

Onset of action - the beginning of pharmacologic response

Duration of action - the time period which the plasma concentration of the drug remains above MEC
level.

Therapeutic range - the drug concentration between MEC and MSC

Subtherapeutic level - a dosage less than the amount required for a therapeutic effect.

PHARMACOKINETICS

Pharmacokinetics
 The science of the kinetics of drug absorption, distribution and elimination
 Mathematically relates the ADME processes to parameters that are used to calculate and
adjust dosing regimens for patients
LIBERATION
Liberation – is the first step in the process by which medication enters the body and liberates the
active ingredient that has been administered. It also describes the way that a drug is released from its
administered form.

Immediate (release types) – the medicine is formulated to release the medicinal drug without delay

Delayed (release types) – the medicine is formulated to release medicinal drug sometime after it is
taken (usually orally)

Extended (release types) – the medicine is formulated to make the drug available over an extended
period, allowing a reduction in dosing frequency compared with immediate or delayed-release
medicines.

ABSORPTION
Absorption
– depends on the route of a drug product’s administration
- once the drug is dissolved in the fluid of the route, it faces different membrane barriers on its
transfer into the fluid (blood) that will either contain the target or transport it to the target location
- is the process by which drug molecules gain access to the bloodstream from the site of drug
administration.
- The speed of this process (the rate of drug absorption) and its completeness (the extent of drug
absorption) depend on the route of administration.

Routes of administration can be considered in two categories: Enteral and Parental

Enteral - Drugs given by mouth are normally swallowed before being absorbed in the stomach or
small bowel, after which they enter the portal venous system and pass through the liver before
gaining access to the systemic circulation. 
- Some drugs introduced into the alimentary tract are absorbed directly into the systemic circulation
without passing through the liver (e.g. via the buccal, sublingual or rectal routes), thereby avoiding the
potential hazards of gastric acid, binding to food, and metabolism by gut wall or liver enzymes (first-
pass metabolism).

Parenteral - This includes any route that avoids absorption via the gastrointestinal tract such as
administration by injection, inhalation or by application to the skin.

 Absorption after an oral dose - is a lengthy process, during which drug molecules may be
damaged (e.g. denatured by gastric acid), sequestered (e.g. bound to food preventing absorption) or
modified by first-pass metabolism.
- As a consequence of all these hazards, it is not surprising that absorption is frequently incomplete
following oral administration.

Bioavailability of the drug - The proportion of a dose that reaches the systemic circulation
unscathed.
Surface area of the GI tract, stomach-emptying rate, GI mobility, and blood flow to the
absorption site –factors that affect the rate and the extent of drug absorption for oral dosing

In pharmacokinetics, the overall rate of drug absorption may be described as either a - first-
order or zero-order input process.

ORAL Administration

• Administration Site: Mouth (swallowed)

• Primary Absorption Site: Epithelia of the upper small intestine, stomach
• Purpose: For systemic effect
• Common Dosage Forms: tablet, capsule, solution, suspension, emulsion
• Common Mechanism: Passive Diffusion

Effect of pH on Absorption
- The less polar, nonionized form the drug is the form that can most readily traverse the
enterocyte lipid bilayer.

TRANSPORTERS
Transporters - Dictates how the drug will be distributed all throughout the body, how will it go the
specific organs, muscles or fats.

Diffusion: spontaneous movement of a membrane permeable substance across the membrane

Facilitated transport: the movement of a membrane impermeable substance across the membrane
via transporters

P-glycoprotein – move xenobiotics back into the lumen to maximize the exposure of xenobiotics to
metabolic cell enzymes.

ENTEROHEPATIC CIRCULATION

Enterohepatic Circulation - refers to the process whereby a drug or a metastable metabolite thereof
in the liver is secreted into the bile, stored in the gallbladder, and subsequently released into the small
intestine, where the drug can be reabsorbed back into circulation and subsequently returned to the
liver.

- Can prolong the time that a drug is in the body: ↑ duration

Bile duct – digests the fats, it is the organ involved in enterohepatic circulation, bile passes through
the gut

RATE- LIMITING STEP IN DRUG ABSORPTION

RATE- LIMITING STEP IN DRUG ABSORPTION

 The slowest rate that dictate how quickly a drug will enter the bloodstream.
 Usually it will be the rate of dissolution or rate of absorption that will be rate limiting.
 Dissolution of the solid drug particles in gastrointestinal fluids

FIRST PASS METABOLISM

FIRST PASS METABOLISM - It can significantly limit the amount of active drug that enters the
systemic circulation and therefore can significantly limit an oral drug’s bioavailability.

- Metabolism of drug before it reaches to systemic circulation

A major type of metabolism of first pass metabolism - hepatic first-pass

It is also called first-pass metabolism because it occurs on the first pass of the drug from the
intestinal lumen and through the liver, before it enters the systemic circulation. (answer: pre-
systemic metabolism)

Administration pathways that don’t undergo first-pass metabolism (answer: sublingual,

intramuscularly)

What does a greater first pass effect do? (answer: lower the bioavailability of the drug ( the rate
and extent of the drug reaching systemic circulation)

DISTRIBUTION
Distribution - Generally fastest to well-perfused organs, such as the liver, kidney and brain

- Slower to other tissues such as the muscle, fat and skin

PLASMA PROTEIN BINDING

Plasma Protein Binding
- Only the free drug can leave the systemic circulation.
- The binding of drugs to plasma proteins is reversible, so when free drug leaves the plasma during
distribution to tissues or by excretion, protein-bound drug dissociates to maintain the equilibrium.

TISSUE BINDING
- Upon reaching the tissues, drugs can also bind to tissue components, such as cell membrane
phospholipids and proteins, which, along with active transport processes, can lead to tissue
accumulation of the drug.
- This tissue bound drug can act as a drug reservoir that can slowly release the drug and prolong its
action, but it can also lead to adverse effects if the drug is toxic to the particular tissue.

Apparent Volume of Distribution (Vd)

Apparent Volume of Distribution (Vd)

- is a key pharmacokinetic parameter that enables that calculation.

- the volume of distribution is a proportionality factor that relates the total amount of drug in the body
to the plasma or blood level.

- Vd = Dose/Cpₒ, where Cpₒ is the initial plasma concentration achieved after an intravenous dose.

- is a hypothetical rather than an actual physiological volume, thus the term “apparent” is used.

- can be used to rationalize the distribution behavior of the drug, based on its physicochemical
properties.

- A drug that is highly protein-bound may exhibit a low volume of distribution, approximating the
plasma volume, because of the inability of the protein to pass into the interstitial fluid.

- A drug that has high interstitial tissue binding will have a relatively low plasma concentration, and
therefore the calculated Vd can even exceed the total body water volume.

- Drugs with low protein and tissue binding and good ability to penetrate cell membranes will have an
intermediate Vd closer to total body water, a reflection of their ability to distribute to total body water.

METABOLISM

Metabolism

- The primary function of metabolism, of which the liver is the primary location, is to transform these
compounds into more hydrophilic, and therefore more extractable metabolites.

- Most drugs are too lipophilic to be excreted unchanged in the urine.

Two Main Types of Enzymatic Pathways - Phase 1 and Phase 2

PHASE 1

Phase 1 reactions - also called functionalization reactions

The most well-known and most important enzyme family for phase 1 reactions is the-
cytochrome P450(CYP) superfamily of enzymes

Other possible reactive pathways in phase 1 reactions includes- hydrolysis and reduction

The product of phase 1 reactions - may be excreted with the newly created or exposed polar
functional group, but in many ways they may not be.

PHASE 2

Phase 2 reactions - also called conjugation reactions

 - involve the covalent conjugation of a polar functional group on the parent compound or on phase
1 metabolite, with endogenous polar compounds such as glucuronic acid, sulfuric acid, acetic
acid, or amino acid.

Conjugation with glucuronic acid to form a glucuronide - is the most common phase 2 reaction.

The resulting conjugate in phase 2 reactions - is usually hydrophilic enough to be rapidly

excreted.

EXCRETION

Excretion involves three major processes: Glomerular filtration, Secretion & Reabsorption.

 Kidney – major excretory pathway

 Biliary secretion of drugs – can be aided by efflux transporters and the process favors larger
molecules.
 Enterohepatic recycling – process where drugs/metabolites are secreted into the biliary
canaliculi and ultimately reach the intestines, some will be eliminated in the feces and some
may be reabsorbed back into the body through the intestines.
 Saliva, sweat, tears, breath, breast milk- other route of drug excretion.

FILTRATION –

Retained: Protein-bound drugs

Excreted: Polar or Ionized Compounds

SECRETION –

Excreted: Drugs transported by OATs and OCTs

REABSORPTION –

Retained:

 Nonpolar and relatively lipophilic

 Acidic drugs (acidic urine)
 Basic drugs (basic urine)
 Drugs by uptake transporters in the PCT

Excreted:
 Acidic drugs (basic urine)
 Basic drugs (acidic urine)
CLEARANCE

Clearance - a Primary pharmacokinetic parameter that is used as a measure of drug elimination from
the body.

- the volume of plasma that is completely cleared of drug per unit time (e.g., mL/min)

- The relationship between the rate of drug elimination from the plasma and its plasma concentration.

Total body clearance/ systematic clearance – is a composite of the contributing elimination

processes (CLren, CLhep and CLother)

Drug clearance – calculation of the dose rate required to maintain a target steady state plasma
concentration.

ELIMINIATION HALF-LIFE

Elimination Half-life – Time required for the plasma concentration to decrease by 50%

• Useful for estimating appropriate dosing intervals and for estimating the time to reach steady
state with multiple dosing which requires about four to five half-lives

V ss
t 1/ 2= .
CL

Half-life – is dependent on the drug’s clearance and volume of distribution at steady state.