In this slide contains definition, types, causes, inducers and inhibitors, complex drug interactions. Presented by: SUMASHREE AGGIM (Department of pharmacology). RIPER, anantapur

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
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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
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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:
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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
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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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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