Basic Principles of

Pharmacokinetics
DR B. A. AFRANE
Introduction to PK

 Pharmacokinetics:
 Defined as the study of the time course and extent of
absorption, distribution, metabolism, and excretion
 Clinical Pharmacokinetics
 Deals with the application of PK principles to safe and
effective therapeutic management of drugs in an
individual patient
PHARMACOKINETICS
“WHAT THE BODY DOES TO THE DRUG”
 Pharmacokinetics (PK)

 The study of the disposition of a drug

 The disposition of a drug includes the
processes of ADME
 Absorption

 Distribution
 Metabolism Elimination
 Excretion
ADME
 DRUG R&D

 Drug discovery and development

• 10-15 years to develop a new medicine
• Likelihood of success: 10%
• Cost $800 million – 1 billion dollars (US)

Drug discovery and development

•10-15 years to develop a new medicine
•Likelihood of success: 10%
•Cost $800 million – 1 billion dollars (US)
Why drugs fail
 Importance of PK studies

 Patients may suffer:

 Toxic drugs may accumulate

 Useful drugs may have no benefit because doses are

too small to establish therapy

 A drug can be rapidly metabolized.

 Routes Of Administration

Routes Of Drug
Administration

Parenteral Enteral

Injection Topical Respiratory Rectal Oral

 Absorption

 The process by which drug proceeds from the

site of administration to the site of
measurement (blood stream) within the body.

 Necessary for the production of a therapeutic

effect.

 Most drugs undergo gastrointestinal

absorption. This is extent to which drug is
absorbed from gut lumen into portal circulation
 Exception: IV drug administration
 IV vs Oral

I.V Drug Oral Drug

Immediately Delayed

completely incomplete
 The Process

 Absorption relies on
 Passage through membranes to reach the blood
 passive diffusion of lipid soluble species.
 The Rule of Five - formulation

Poor absorption or permeation are

more likely when:

 There are more than 5 H-bond donors.

 The molecular weight is over 500.
 The LogP is over 5.
 There are more than 10 H-bond acceptors.
Absorption & Ionization
Non-ionised drug

More lipid soluble drug

Diffuse across cell

membranes more
easily
 First Pass Metabolism

Destroyed Not Destroyed Destroyed

in gut absorbed by gut wall by liver

to
Dose systemic
circulation

 Bioavailability: the fraction of the administered dose reaching

the systemic circulation
 Determination of bioavailability

 A drug given by the intravenous

route will have an absolute
bioavailability of 1 (F=1 or 100%
bioavavailable)

 While drugs given by other routes

usually have an absolute
bioavailability of less than one.

.
 The absolute bioavailability is the
area under curve (AUC) non-
intravenous divided by AUC
intravenous
 Toxicity
 The therapeutic index
is the degree of
separation between
toxic and therapeutic
doses.

 Relationship Between
Dose, Therapeutic
Effect and Toxic Effect.
The Therapeutic Index
is Narrow for Most 100× 10×
Cancer Drugs
 Distribution

 The movement of drug from the blood

to and from the tissues
 DISTRIBUTION

 Determined by:
 • partitioning across various membranes

 •binding to tissue components

 •binding to blood components (RBC,

plasma protein)

 •physiological volumes
 DISTRIBUTION

 All of the fluid in the body (referred to as the total

body water), in which a drug can be dissolved, can
be roughly divided into three compartments:

 intravascular (blood plasma found within blood

vessels)
 interstitial/tissue (fluid surrounding cells)
 intracellular (fluid within cells, i.e. cytosol)

 The distribution of a drug into these compartments

is dictated by it's physical and chemical properties
 Distribution

 Apparent volume of distribution (Vd) =

Amt of drug in body/plasma drug conc

 VOLUME OF DISTRIBUTION FOR SOME DRUGS

DRUG Vd (L)
cocaine 140
clonazepam 210
amitriptyline 1050
amiodarone ~5000
 Factors affecting drugs Vd

 Blood flow: rate varies widely as function of tissue

Muscle = slow
Organs = fast

 Capillary structure:
•Most capillaries are “leaky” and do not impede diffusion of drugs
•Blood-brain barrier formed by high level of tight junctions between
cells
•BBB is impermeable to most water-soluble drugs
 Blood Brain Barrier

•Disruption by osmotic
means
•Use of endogenous
transport systems
•Blocking of active efflux
transporters
• Intracerebral implantation
•Etc
 Plasma Protein Binding

 Many drugs bind to plasma proteins in the

blood steam

 Plasma protein binding limits distribution.

A drug that binds plasma protein diffuses

less efficiently, than a drug that doesn’t.
 Physiochemical properties-
Po/w

 The Partition coefficient (Po/w) and can be

used to determine where a drug likes to go in
the body
 Any drug with a Po/w greater than 1(diffuse
through cell membranes easily) is likely be
found throughout all three fluid compartments
 Drugs with low Po/w values (meaning that
they are fairly water-soluble) are often unable
to cross and require more time to distribute
throughout the rest of the body
 Physiochemical Properties
Size of Drug
•The size of a drug also dictates where it can go in the body.

•Most drugs : 250 and 450 Da MW

•Tiny drugs (150-200 Da) with low Po/w values like caffeine can passively
diffuse through cell membranes

•Antibodies and other drugs range into the thousands of daltons

•Drugs >200 Da with low Po/w values cannot passively cross membranes-
require specialized protein-based transmembrane transport systems- slower
distribution

•Drugs < thousand daltons with high Po/w values-simply diffuse between the
lipid molecules that make up membranes, while anything larger requires
specialized transport.
 Elimination

 The irreversible removal of the parent drugs from the body

Elimination

Excretion Drug Metabolism

(Biotransformation)
 Drug Metabolism

 The chemical modification of drugs with the

overall goal of getting rid of the drug
 Enzymes are typically involved in metabolism

Metabolism Excretion
More polar
Drug
(water soluble)
Drug
 METABOLISM
•From 1898 through to 1910 heroin was marketed as a non-addictive
morphine substitute and cough medicine for children. Bayer
marketed heroin as a cure for morphine addiction
•Heroin is converted to morphine when metabolized in the liver
 Phases of Drug Metabolism

 Phase I Reactions

 Convert parent compound into a more polar

(=hydrophilic) metabolite by adding or unmasking
functional groups (-OH, -SH, -NH2, -COOH, etc.) eg.
oxidation

 Often these metabolites are inactive

 May be sufficiently polar to be excreted readily

 Phases of metabolism

 Phase II Reactions

 Conjugation with endogenous

substrate to further increase aqueous
solubility

 Conjugation with glucoronide, sulfate,

acetate, amino acid
Mostly occurs in the liver
because all of the blood
in the body passes
through the liver
 The Most Important Enzymes
 Microsomal cytochrome P450 monooxygenase
family of enzymes, which oxidize drugs

 Act on structurally unrelated drugs

 Metabolize the widest range of drugs.

 CYP family of enzymes

• Found in liver, small intestine, lungs, kidneys, placenta

• Consists of > 50 isoforms (57 IDed based on}

• Major source of catalytic activity for drug oxidation

• It’s been estimated that 90% or more of human drug oxidation can
be attributed to 9 main enzymes:
• CYP1A2 • CYP2D6 CYP2B6
• CYP2C9 • CYP2E1
• CYP2C19 • CYP3A4
 CYP8B1 CYP3A7
In different people and different populations, activity of CYP
oxidases differs.
Inhibitors and inducers of microsomal
enzymes

Inhibitors:
cimetidine prolongs action of drugs or inhibits action of those
biotransformed to active agents (pro-drugs)

Inducers: barbiturates, carbamazepine shorten action of drugs or increase

effects of those biotransformed to active agents

Blockers: acting on non-microsomal enzymes (MAOI, anticholinesterase

drugs)
 Phase II

 Mainfunction of phase I reactions is to

prepare chemicals for phase II metabolism
and subsequent excretion

 Phase
II is the true “detoxification” step in the
metabolism process.
 Phase II reactions

 Conjugation reactions
 Glucuronidation (on -OH, -COOH, -NH2, -SH groups)

 Sulfation (on -NH2, -SO2NH2, -OH groups)

 Acetylation (on -NH2, -SO2NH2, -OH groups)

 Amino acid conjugation (on -COOH groups)

 Glutathione conjugation (to epoxides or organic halides)

 Fatty acid conjugation (on -OH groups)

 Condensation reactions
 Glucuronidation

 Conjugation to a-d-glucuronic acid

 Quantitatively the most important phase II

pathway for drugs and endogenous compounds

 Products are often excreted in the bile

 Phase I and II - Summary

 Products are generally more water soluble

 These reactions products are ready for (renal) excretion

 There are many complementary, sequential and competing

pathways

 Phase I and Phase II metabolism are a coupled interactive system

interfacing with endogenous metabolic pathways
 Excretion

 The main process that body eliminates

"unwanted" substances.

 Most common route - biliary or renal

 Other routes - lung (through exhalation), skin

(through perspiration) etc.

 Lipophilic drugs may require several metabolism

steps before they are excreted
ADME - Summary