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Polymorphism Affecting Drug Metabolism
Polymorphism Affecting Drug Metabolism
AFFECTING DRUG
METABOLISM
1 Presented by :
Jayesh Patil
Dept : Pharmacology
CONTENT:
Introduction
Drug metabolism
Polymorphism
Reference
2
OUTCOME:
Altered drug efficacy :
i. Genetic variations can result in changes to the
metabolism of drugs.
ii. Some individuals may metabolize drugs too quickly,
leading to reduced effectiveness, while others may
metabolize them too slowly, increasing the risk of
toxicity.
Variables Drug Response :
Personal medicine :
i. Polymorphism can also provide opportunities for
personalized medicine.
ii. Tailoring drug doses and regimens to an individuals
genetic profile can optimize treatment outcomes while
minimizing side effects.
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WHAT IS GENETIC POLYMORPHISM?
TERMENOLOGY
Polymorphism Poly=many Morph=shapes
ion
al Basis of Therapeutics, Chpt 7, 12th Edit
Goodman & Gilman's The pharmacologic
Ability to appear in different shapes.
8
Applied Biopharmaceutics and Pharmacok
inetics by Leon Shargel, 5th edition.
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METABOLIZERS:
10
https/genesight.com
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POLYMORPHISM:
Genetic differences in drug metabolism are the result of
genetically based variation in alleles for genes.
ion
al Basis of Therapeutics, Chpt 7, 12th Edit
Goodman & Gilman's The pharmacologic
In polymorphisms, the genes contain abnormal pairs or
abnormal alleles leading to altered enzyme function.
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Applied Biopharmaceutics and pharmacok
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Disadvantages of SNP :
1. Less alleles
each marker is less informative.
2. A wide range of disease occurred by SNP in humans.
i. Sickle cell anemia
ii. B thalassemia
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iii. Diabetes
High blood glucose levels.
o Ressecively inherited
chronic hemolytic anemia
o Nucleotide substitution in b
globin gene in chromosome
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VARIATION IN PHASE I METABOLISM:
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Important allelic & phenotypic variants of this
are as follows:
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A. Poor Metabolizers Phenotype:
• These variants have poor metabolising activity & no functional
activity.
• These include CYP2D6*3,CYP2D6*8, CYP2D6*36.
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2. Cytochrome P450 2C19 (CYP2C19) :
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Important allelic & phenotypic variants of this are as
follows:
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A. Poor Metabolizer Phenotype :
• These variants have no functional activity & these include
CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*6,
CYP2C19*7.
NOTE :
• Amongst these variants CYP2C19*2 & CYP2C19*3 are the most
common variants.
• CYP2C19*2 variant is mainly found in South Indians (30%) 24
• CYP2C19*3 is mainly found in the Japanese people.
INTERACTIONS CAUSED BY VARIANTS:
1. Omeprazole in peptic ulcer :
• Omeprazole is also metabolised to form an active
25
3. CYTOCHROME P450 2C9 (CYP2C9)
This enzyme is responsible for the metabolism of drugs
with narrow therapeutic index such as phenytoin and
warfarin.
ion
al Basis of Therapeutics, Chpt 7, 12th Edit
Goodman & Gilman's The pharmacologic
produce toxicity.
2. Warfarin as anticoagulanannt:
• Clinically available warfarin is a racemic mixture of the R
and S enantiomers.
• S-isomer has high therapeutic activity than R-isomer.
• S-isomer is exclusively metabolised byCYP2C9 enzyme.
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Metabolism of warfarin is normal inCYP2C9*1 variants.
ion
al Basis of Therapeutics, Chpt 7, 12th Edit
Goodman & Gilman's The pharmacologic
warfarin therapy.
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4. CYP3A4 & CYP3A5:
CYP3A4 is the most abundant enzyme in the liver and is
responsible for metabolism of more than 50% of
clinically administered drugs such as
immunosuppressant, anticancer drugs, macrolide
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VARIATIONS IN PHASE II METABOLISM :
1. N-Acetyltransferases :
Influence of variations in enzyme activity of
N-Acetyltranserases can be seen on antituberculosis
ion
al Basis of Therapeutics, Chpt 7, 12th Edit
Goodman & Gilman's The pharmacologic
agent, “isoniazid”.
The decrease metabolism of isoniazide in ‘slow
acetylators’ develop peripheral neuritis.
The above side effect cannot be seen in ‘fast
acetylators’.
Slow acetylators are also prone to develop Systemic
Lupus Erythematosus (SLE) in patients taking
hydralazine.
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2. Thiopurine Methyltransferase (TPMT) :
Different purin analogs like 6-mercaptopurine and
azathioprine have been used for the treatment of
hematologic malignancies.
These drugs are converted to thioguanine nucleotides,
32
APPLICATION:
ion
al Basis of Therapeutics, Chpt 7, 12th Edit
Goodman & Gilman's The pharmacologic
2. Genotyping of genetically polymorphic DME might be
beneficial for drug safety or therapeutic outcome.
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