Download drug metabolism

Drug Elimination
 Drug elimination
consists of 2 processes
 Drug Metabolism or
Biotransformation
 Drug Excretion
METABOLISM
Biotransformation,
or drug metabolism, is the
enzyme-catalyzed conversion of drugs to their
metabolites.
Most
liver.
drug biotransformation takes place in the
Clinical sketch
A man with moderately severe
alcoholic liver disease needs flecainide
for a cardiac arrhythmia. The clinical
team consults Appendix of the BNF
and is advised to give reduced doses.
Comments： flecainide accumulates in
patients with chronic liver disease.
WHY IS DRUG BIOTRANSFORMATION
NECESSARY?
The
majority of drugs are lipidsoluble to some extent.
Most
lipid-soluble drugs filtered
through the glomerulus are largely
reabsorbed into the systemic
circulation during passage though
the renal tubules.
lipid-soluble drug
water-soluble drug
WHY IS DRUG BIOTRANSFORMATION NECESSARY?
The end result of metabolism is that the original
drug molecule is altered in ways that make the
drug more polar, hydrophilic, and water soluble
Without metabolism, 99.9% of all drugs filtered at
the glomerulus would be reabsorbed into systemic
circulation.
Role of Drug Biotransformation
The
fundamental role of drug-metabolizing
enzymes is to inactivate and detoxify drugs and
other foreign compounds (xenobiotics).
Drug
metabolites are usually more water
soluble than is the parent molecule.
Role of Drug Biotransformation
No
particular
relationship exists
between
biotransformation and
pharmacologic activity.
Most
conjugated drug
metabolites are inactive,
but a few exceptions exist.
Formation of Active Metabolites
Some agents, known
as prodrugs, are
administered as
inactive compounds
and then
biotransformed to
active metabolites.
Paracetamol poisoning
Toxic metabolites of paracetamol are
detoxified by phase II conjugation joining
with glutathione.
In an overdose situation,
toxic metabolites
accumulate causing toxicity
and can result in hepatitis.
Phases of Drug Biotransformation
General Metabolic Pathways
 Phase I reactions – Functionalization
 Oxidation
 Reduction
 Hydrolytic reactions
 Purpose
 Introduction of polar functional groups in a
molecules
 Hydroxyl groups; Carboxylate groups; Amino
Groups; Thiol Groups
 Increase a molecules polarity
 Does provide a site for phase II metabolism
Phase I reactions
Oxidative Reactions
Oxidative
reactions are catalyzed by enzymes
isolated in the microsomal fraction of liver
homogenates (the fraction derived from the
endoplasmic reticulum) and by cytoplasmic
enzymes.
Cytochrome
P450s are the enzymes that catalyze
phase I reactions.
Cytochrome P450 Monooxygenase System
A family
of enzymes that catalyze the
biotransformation of drugs
Modest
specificity for substrates and catalyze
the metabolism of widely differing chemical
structures
Characterized
by an intense absorption band at
450 nm in the presence of carbon monoxide.
Phase I reactions
family ≥40%
subfamily≥55%
ROLE OF CYP ENZYMES IN HEPATIC
DRUG METABOLISM
RELATIVE HEPATIC CONTENT
OF CYP ENZYMES
CYP2D6
2%
% DRUGS METABOLIZED
BY CYP ENZYMES
CYP2E1
7%
CYP 2C19
11%
CYP 2C9
14%
CYP2D6
23%
CYP 2C
17%
OTHER
36%
CYP 1A2
12%
CYP 3A4-5
26%
CYP 1A2
14%
CYP 3A4-5
33%
CYP2E1
5%
Cytochrome P450
Monooxygenase System
Genetic
polymorphisms exist for these genes
Genetic
variations in these metabolism genes
can have important consequences for patients.
“Poor metabolizers” have a greater risk than the
general population of experiencing adverse drug
reactions.

Hydrolysis of Esters and Amides
Catalyzed
by widely distributed hydrolytic
enzymes
Cholinesterase
and other plasma esterases
Few
CYP enzymes that carry out
hydrolytic reactions
Phase I reactions
Phase I reactions
Reductive Reactions
Less common than are oxidative and
hydrolytic reactions.
Nitroglycerin, a vasodilator, undergoes reductive
hydrolysis catalyzed by glutathione- organic
nitrate reductase.
General Metabolic Pathways
 Phase II reactions – Conjugation
 Purpose
 Introduce highly polar conjugates
 Glucuronic acid; Sulfate; Glycine or other
Amino Acids; Glutathione
 Conjugation enzymes are present in the liver
and other tissues
 Conjugates are readily excreted in the urine
 Usually inactive - notable exception is
morphine 6-glucuronide
Enzyme Induction and Inhibition
Many
drugs alter drug metabolism by
inhibiting or inducing CYP enzymes.
Drug
interactions can occur when these drugs
are administered concurrently with other drugs
that are metabolized by CYP.
Enzyme Induction
 Enzyme induction is the process by which
exposure to certain substrates results in
accelerated biotransformation with a
corresponding reduction in parent drug.
Enzyme inducer stimulates the synthesis of the
enzyme and the metabolic capacity is increased
Consequences of Induction
 Increased
rate of metabolism
 Decrease in drug plasma concentration
 Enhanced oral first pass metabolism
 Reduced bioavailability
 If metabolite is active or reactive,
increased drug effects or toxicity
Clinical sketch
A young woman on the contraceptive
pills is found to have tuberculosis. She
is started on treatment and suffers
contraceptive failure soon after.
Comments： it would be unacceptable
practice to fail to warn the woman that
rifampicin (which induces the liver drugmetabolising enzyme CYP450) is very
likely to cause failure of contraception.
Therapeutic Implications of Induction


Most drugs can exhibit decreased efficacy
due to rapid metabolism
 but drugs with active metabolites can
display increased drug effect and/or
toxicity due to enzyme induction
Dosing rates may need to be increased to
maintain effective plasma concentrations
Induction
Auto-inducer


Some currently used drugs are well known to
induce their own metabolism or the metabolism
of other drugs.
The longer the drug is given, the more rapidly it
is metabolized.
Enzyme Inhibition


Enzyme inhibitor inhibits the synthesis of the
enzyme and the metabolic capacity is
decreased
Cimetidine: CYP2C9 P450 enzyme inhibitor
Grapefruit
+
Statins
Consequences of Inhibition
 Increase
in the plasma concentration of
parent drug
 Exaggerated and prolonged
pharmacological effects
 Increased likelihood of drug-induced
toxicity
Enzyme induction will decrease the duration
and intensity of the drug action.
The opposite is also true.
In cases where an enzyme is responsible for
metabolizing a pro-drug into a drug, enzyme
induction can speed up this conversion and
increase drug levels, potentially causing
toxicity.