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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.

17. THANK YOU