Pharmacokinetics
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Transcript Pharmacokinetics
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