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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
Parenteral
Injection
Topical
Respiratory
Enteral
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 doesn’t.
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
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
Drug
More polar
(water soluble)
Drug
Excretion
METABOLISM
•From 1898 through to 1910 heroin was marketed as a nonaddictive 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
•
It’s 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