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Pharmacokinetics: "What The Body Does To The Drug"
Pharmacokinetics: "What The Body Does To The Drug"
Distribution
Metabolism
Elimination
Excretion
Toxicity
ADMET
DRUG R&D
Routes Of Drug
Administration
Parenteral Enteral
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:
Diffuse across
cell
membranes more
easily
First Pass Metabolism
to
Dose systemic
circulation
.
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 100× 10×
Most Cancer Drugs
Distribution
The movement of drug from the blood
to and from the tissues
DISTRIBUTION
Determined by:
• partitioning across various membranes
•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:
3L 9L 28 L
4% BW 13% BW 41% BW
Distribution
Apparent volume of distribution (Vd) =
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
•Tiny drugs (150-200 Da) with low Po/w values like caffeine can
passively diffuse through cell membranes
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
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
Conjugation reactions
Condensation reactions
Glucuronidation
Conjugation to a-d-glucuronic acid