The document discusses genetic polymorphism and its impact on drug metabolism, highlighting how variations in DNA sequences can affect enzyme functions responsible for biotransformation of drugs. It explores types of polymorphisms, their causes, and the influence of genetic differences on drug metabolism efficiency across different populations. The document emphasizes the role of cytochrome P450 enzymes and the implications of genetic variations for therapeutic outcomes and adverse drug reactions.

1. Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Polymorphism Affecting Drug Metabolism
Raghavendra Institute of Pharmaceutical Education and Research(RIPER)-
Autonomous
JNT University Anantapur
A Seminar as a part of curricular requirement for I year M . Pharmacy I Semester
Presented by
AGGMI SUMA SHREE
(20L81S0102)
Pharmacology
Under the guidance of
Dr. K. Somasekhar Reddy
Associate Professor and Head of the Department

2. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 2
CONTENTS:
Introduction
Types
Causes
Inducers and inhibitors
Complex drug interactions
References

3. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Introduction:
• Genetic polymorphism: the existence together
of many forms of DNA sequences at a locus
within the population.
• A discontinuous genetic variation that results
different forms of types of indiviuals among
the members of a single species.
3

4. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 4
Polymorphism
Nucleotide repeat
Polymorphism
Insertion and deletion
Polymorphism
Single nucleotide
Polymorphism
(SNPs)

5. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 5
Causes:
Balance between variation created by
new mutations and natural selection
Frequency dependent selection
Multiple niche polymorphism

6. Singal nucleotide
polymorphism:
6
Most common form
Change in a single base
pair(bp)
Affect gene function
Eg:influence the amount
of mRNA produced.

7. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Genetic polymorphism and drug
metabolism:
Inter-individual variation of drug effects.
Polymorphism
Enzyme increase or decrease or absent activity
Genectic polymorphisms of drug-metabolizing enzymes give rise
to distinct subgroups in the population that differ in their ability
to perform certain drug biotransformation reactions.
Variation of drug effects.
7

8. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
• 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 phase1 and
functionalization reactions or phase2
biosynthetic(conjugation reactions).
8

9. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
• 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.
9

10. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
• Pathways of drug metabolism are classified as
either: Phase1 reactions: oxidation, reduction,
hydrolysis.
• Phase2 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.
10

11. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 11
Drug Metabolism
Phase I Reaction
(Functionalization
reaction )
Phase II Reaction
(Conjugation
reaction )
Oxidation
Reduction
Hydrolysis
Acetylation
Methylatio
Sulfation
Glucoronoidation

12. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Polymorphism in drug metabolism:
12
• 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.

13. RIPER
AUTONOMOUS
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NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Types of metabolizers:
13

14. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 14

15. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Inhibitors and inducer:
15

16. RIPER
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Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Complex drug interactions:
Substrate is metabolised through a polymeric
enzyme
Substrate becomes active metabolite
This active metabolite acts as an inhibitor or
inducer in second system
16

17. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Phase I Enzymes:
17

18. RIPER
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Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 18

19. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
P450 in drug metabolism:
• The polymorphic P-450 enzyme superfamily is the most
important system in the biotransformation of many
endogenous and exogenous substances.
• Genotyping for CYP polymorphs provides important genetic
information that helps to understand the effects of xenobiotics
on human body.
• For drug metabolism, the most important polymorphisms are
those of the genes coding for CYP2C9, CYP2C19, CYP2D6,
and CYP3A4/5, which can result in therapeutic failure or
server adverse reactions.
19

20. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
Phase II Enzymes:
20

21. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
N-Acetyltransferases:
 N-acetylation of isoniazid to acetyl isoniazid
 Individuals are slow or raipd acetylators
 NAT2 protein is the specific protein isoform that
acetylates isoniazid
27 unique NAT2 alleles identified
NAT2*4 is the wild type allel
NAT2 alleles containing the G191A, A434C,
T341C, G590A, and/or G857A missense associated
substitutions are associated with slow acetylator
phenotype.
21

22. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721
References:
• Tu, T.(2005). Pharmacogenomics frontiers in
Medicine and Race. The Journal of Young
Investigators,13(5).
• Shargel, Leon. Comprehensive Pharmacy
Review, 7th edition. Philadelphia: Lipincott-
William and Wilkins, 2010. print. Pg.,430-433.
22

23. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 23