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Presentation polymorphism affecting drug metabolism
1. Polymorphism affecting drug Metabolism
Submitted By
MOHD MUZAHID
M.Pharm (pharmacology) 1st year
Submitted To
Dr. ANURADHA MISHRA
Asst. Professor
INTEGRAL UNIVERSITY
2. What is Genetic Polymorphism ?
The existence together of many forms of DNA sequences at a locus
within the population.
A discontinuous genetic variation that results in different forms or
types of individuals among the members of a single species.
3. Genetic Polymorphism & Drug Metabolism
Inter-individual variation of drug effects
Genetic polymorphisms of drug-metabolizing enzymes
give rise to distinct subgroups in the population that
differ in their ability to perform certain drug
biotransformation reactions.
4. Drug Metabolism
The metabolism of drugs and other xenobiotics into more hydrophilic metabolites is
essential for their elimination from the body, as well as for termination of their
biological and pharmacological activity.
Drug metabolism or biotransformation reactions are classified as either phase I
functionalization reactions or phase II biosynthetic (conjugation reactions).
5. Cont….
The enzyme systems involved in the biotransformation of drugs are localized
primarily in the liver.
Other organs with significant metabolic capacity include the GI tract, kidneys, and
lungs.
These biotransformation reactions are carried out by CYPs (cytochrome CYP450
isoforms) and by a variety of transferases.
6. Cont…
Pathways of drug metabolism are classified as either:Phase I reactions: oxidation,
reduction, hydrolysis
Phase II reactions: acetylation, glucuronidation, sulfation, methylation
Both types of reactions convert relatively lipid soluble drugs into relatively inactive
and more water soluble metabolites, allowing for more efficient systemic
elimination.
7. Polymorphisms
Genetic differences in drug metabolism are the result of genetically based
variation in alleles for genes that code for enzymes responsible for the
metabolism of drugs.
In polymorphisms, the genes contain abnormal pairs or multiples or abnormal
alleles leading to altered enzyme function.
Differences in enzyme activity occur at different rates according to racial group.
8. Single Nucleotide Polymorphisms (SNPs)
Single changes in one allele of a gene responsible for
a variety of metabolic processes including enzymatic
metabolism.
The combination of alleles encoding the gene
determines the activity and effectiveness of the
enzyme.
9. Poor metabolizers
two defective alleles (ex: CYP2D6*4/*5 and CYP2D6*4)
Combination of alleles including one resulting in no enzyme (ex: CYP2D6*5 and CYP2D6*4 deletion)
Intermediate metabolizers
Heterozygous –having only one wild type allele and one defective allele
Normal metabolizers
Carry wild type alleles (ex: CYP2D6*1/*3).
Wild type alleles encode genes for normal enzyme function
10. Extensive metabolizers
Carry one wild type and one amplified gene
ex: CYP2D6*1/*2, CYP2D6*A/*1a, and CYP2D6*1A/*5
Ultra-rapid metabolizers
Carry two or more copies of amplified gene
ex: CYP2D6*2/*3
11. Inhibitors & Inducers
Polymorphisms affect drug interactions by altering the effect of inhibitors and
inducers on the enzyme.
results in an exaggerated effect or minimal effect on the substrate
Inhibitor: An enzyme inhibitor is a molecule, which binds to enzymes and decreases
their activity.
12. Complex Drug Interactions
Can be seen when a substrate is metabolized through more than one enzyme systems where one or
more enzymes are affected by polymorphism.
Substrate is metabolized through a polymorphic enzyme
Substrate becomes active metabolite
This active metabolite acts as an inhibitor or inducer in
second system
13. P450 Enzymes in Drug Metabolism
The polymorphic P450 (CYP) enzyme super family is the most important system involved in the
biotransformation of many endogenous and exogenous substances including drugs, toxins, and
carcinogens.
Genotyping for CYP polymorphisms provides important genetic information that help to
understand the effects of xenobioticson human body.
14. CYTOCHROME P4502CSUBFAMILY
Accounts for approximately 18% of the CYP content in the liver
Catalyzes roughly 20% of the CYP-mediated metabolism of drugs
CYP2C19
Study using mephenytoinas probe drug determined that individuals can be segregated into EMs
and PMs.PM trait is autosomal recessive –present in 3-5% of Caucasians & 12-23% of Asian
populations
15. Diazepam is demethylated by CYP2C19
Plasma diazepam half-life is longer in individuals who are homozygous for the defective CYP2C19*2
allele compared to those who are homozygous for the wild type allele.
Half-life of the desmethyl diazepam metabolite is also longer in CYP2C19 poor metabolizers.
High frequency in Asian population.
Diazepam induced toxicity may occur as a result of slower metabolism –careful dosing in Asian
population.
16. References
Shargel, Leon. Chapter 12 –Pharmacogenetics. Applied Biopharmaceuticsand Pharmacokinetics,
5thedition. E-book.
•Shargel, Leon. Comprehensive Pharmacy Review, 7thEdition. Philadelphia: Lipincott-William
& Wilkins, 2010. Print. Pages 430-433.
•David B. Troy, Paul Beringer. Remington: The Science and Practice of Pharmacy, 21st Edition.
Pages 1230 –1239.
•Brunton, Laurence. Chabner, Bruce. Knollman, Bjorn. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics, 12thedition. Pages 124-130.