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

Excretion

Toxicity

Elimination

ADMET

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)

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
Enteral

Parenteral

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
in gut

Dose

Not
absorbed

Destroyed
by gut wall

Destroyed
by liver

to
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
Cancer Drugs

100

10

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

TOTAL BODY WATER

Vascular

Extravascular

Intracellular

3L

9L

28 L

4% BW

13% BW

41% BW

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 doesnt.

Physiochemical propertiesPo/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 PropertiesSize 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 membranesrequire 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

Drug

More polar
(water soluble)
Drug

Excretion

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

Major source of catalytic activity for drug oxidation

Its been estimated that 90% or more of human drug oxidation

can be attributed to 6 main enzymes:
CYP1A2
CYP2D6
CYP2C9
CYP2E1
CYP2C19
CYP3A4
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

Main function 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