POLYMORPHISM

AFFECTING DRUG
METABOLISM
1 Presented by :
Jayesh Patil
Dept : Pharmacology
CONTENT:
 Introduction
 Drug metabolism

 Polymorphism

 Variations in phase I metabolism

 Variation in phase II metabolism

 Reference

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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 :

i. Polymorphisms can cause differences in drug

responses among individuals.
ii. This can make it challenging to predict how a person
will react to a specific medication, leading to
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variations on therapeutic outcomes.
 Adverse effects :
i. Genetic polymorphism can increase the risk of adverse
drug reactions, as some individuals may be more
susceptible to side effects due to altered drug
metabolism.

 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.

 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 individuals among the members of a
single species. 5
INTRODUCTION:
 Genetic polymorphism and drug metabolism:

inetics by Leon Shargel, 5th edition.

Applied Biopharmaceutics and Pharmacok
 These enzymes give rise to distinct subgroups in the
population that differ in their ability to perform certain
drug biotransformation reactions.

 polymorphism are generated by mutation in the genes for

these enzymes, which cause decreased, increased, or
absent enzyme expression or the activity by multiple
molecular mechanism.
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DRUG METABOLISM:
 It is the process of conversion of drugs into more
hydrophilic metabolites for easier elimination.

inetics by Leon Shargel, 5th edition.

Applied Biopharmaceutics and Pharmacok
 This process also helps to terminate the biological and
pharmacological activity of the drug.
 Drugs metabolism or biotransformation reaction are
classified as either phaseI reactions or phaseII
biosynthetic (conjugation reactions).
 The prime site for metabolism is LIVER.

 These ractions are carried out by CYPs (Cytochrome

P450 isoform) and by a variety of transferases.
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 Pathways of drug metabolism are classified as either:
1. Phase I reactions: oxidation, reduction, hydrolysis.
2. Phase II reaction: acetylation, glucuronidation,
sulfation, methylation.

inetics by Leon Shargel, 5th edition.

Applied Biopharmaceutics and Pharmacok
o Both types of reactions convert relatively lipid soluble
drugs into relatively inactive and hydrophilic
metabolites facilitating efficient systemic elimination.

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Applied Biopharmaceutics and Pharmacok
inetics by Leon Shargel, 5th edition.
9
METABOLIZERS:

 Metabolizers are the substances that increase the ability

of the body to metabolise a specific class of compounds.

inetics by Leon Shargel, 5th Edition.

Applied Biopharmaceutics and Pharmacok
 Based on their action they classified as:
1. Poor metabolizers
2. Normal metabolizers
3. Intermediate metabolizers
4. Ultra-rapid metabolizers

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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.

 Differences in enzyme activity occurs at a different rates

according to racial group.

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 Applied Biopharmaceutics and pharmacok
13

inetics by Leon Shargel, 5th edition.

TYPES OF POLYMORPHISMS:
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 SINGLE NUCLEOTIDE
POLYMORPHISM (SNP)
 Single changes in one allele of a gene responsible for a
variety of metabolic processes including enzymatic
metabolism.

inetics by Leon Shargel, 5th edition.

Applied Biopharmaceutics and pharmacok
 EXAMPLE:

 The overall function of the enzyme is the phenotype of 15

enzyme function.
 Advantages of SNP :
1. In disease diagnosis
2. In drug discovery
3. Investigation of migration patterns.

 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.

 Insulin production is inadequate

o Ressecively inherited
chronic hemolytic anemia

o Nucleotide substitution in b
globin gene in chromosome
11
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 VARIATION IN PHASE I METABOLISM:

1. Cytochrome P450 2D6: This heme-containing enzyme

is responsible for the metabolism of about 25-30% of
prescription drugs including tricyclic antidepressant,

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SSRI’s, antiarrhythmic drugs, antipsychotic drugs & α-
blockers.

 This enzyme also plays a role in metabolising

drugs such as ‘Sparteine’ & Debrisoquine’.

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Important allelic & phenotypic variants of this
are as follows:

Sr. No. Phenotypes Allelic variants

01. Poor metabolizer CYPD6*3, CYP2D6*8, CYP2D6*36

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02. Intermediate CYP2D6*9, CYP2D6*10, CYP2D6*17,
metabolizer CYP2D6*29, CYP2D6*41

03. Ultra-rapid metabolizer CYP2D6*1, CYP2D6*2, CYP2D6*35

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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.

B. Intermediate Metabolizers Phenotype:

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• These variants have intermediate metabolising activity & these
include CYP2D6*9, CYP2D6*10, CYP2D6*17, CYP2D6*29,
CYP2D6*41.

C. Extensive or Ultra-rapid Metabolizer Phenotype:

• These variants have very rapid metabolising activity & these
include CYP2D6*1, CYP2D6*2, CYP2D6*35.
NOTE: distribution of these variants are as follows
• CYP2D6*10 is more common in East Asians (38%--50%).
•CYP2D6*17 is exclusively found in African populations (21%). 20
•CYP2D6*2 is present in Caucasians (25%) & African (31%).
INTERACTIONS CAUSED BY VARIANTS:
I. Tamoxifen in Breast Cancer:
• Tamoxifen is metabolised into endoxifen by the
enzymes.

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• These is more potent estrogen receptor blocker.
• Patients with poor metabolizer phenotype of CYP2D6
have lower levels of endoxifen & there more chances of
relapse of cancer in these patients.

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2. Cytochrome P450 2C19 (CYP2C19) :

• The genes of these enzyme are located on the

chromosome 10q24.

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• These enzymes metabolise Diazepam, omeprazole, S-
mephenytoin, biguanides.

• About 30 allelic variants of CYP2C19 have been

identified.

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 Important allelic & phenotypic variants of this are as
follows:

Sr. No. Phenotype Allelic variants

01. Poor Metabolizers CYP2C19*2, CYP2C19*3, CYP2C19*4,

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CYP2C19*6, CYP2C19*7.

02. Intermediate Metabolizers CYP2C19*5, CYP2C19*8.

03. Ultra-rapid Metabolizers CYP2C10*17

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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.

B. Intermediate Metabolizers Phenotype :

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Cellular and Molecular Pharmacology by
• These variants have reduced metabolising activity and these include
CYP2C19*5, CYP2C19*8.

C. Extensive or Ultra-rapid Metabolizers Phenotype:

• These variants have very rapid metabolising activity and these
include CYP2C19*17.

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

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Cellular and Molecular Pharmacology by
metabolite by CYP2C19.
• Due to variants of this enzyme, there is difference in
therapeutic response of omeprazole and its reduced
effectiveness is found in poor metabolizers.

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3. CYTOCHROME P450 2C9 (CYP2C9)
 This enzyme is responsible for the metabolism of drugs
with narrow therapeutic index such as phenytoin and
warfarin.

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Cellular and Molecular Pharmacology by
 The coding of CYP2C9 is located on chromosome
10q24.2.

 CYP2C9*1 is normal or wild type allele with normal

enzymatic activity.

 CYP2C9*2 & CYP2C9*3 represent variants with highly

reduced enzymatic activities (poor metabolizers). 26
INTERACTION CAUSED BY VARIANTS :

1. Phenytoin as antiepileptic drug:

• CYP2C9 is a an important to metabolism of pheytoin.
• This drug has a narrow therapeutic index, so decrease in
CYP2C9 activityt may increase the levels of phenytoin to

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.

 However the metabolism of S-warfarin is impaired in

patients possessing CYP2C9*2 &CYP2C9*3. Thus these
patients are more prone to bleeding in response to

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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Cellular and Molecular Pharmacology by
antibiotics, opium, calcium channel blockers and statins.
 There are different other variants of this enzymes such
as:
I. CYP3A4*2 & CYP3A4*3
 This variants are observed in Caucasians population.
 CYP3A4*18 variant is present in Chinese people.

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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,

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Cellular and Molecular Pharmacology by
which are incorporated in DNA strands to produce DNA
damage.
 These thioguinin nucleotides are metabolised in blood
cells by the enzyme TPMT.
 Patients with low TPMT activity have higher levels of
thioguinin nucleotides in blood cells, leading to adverse
effects like drug induced neutropenia.
 And patients with higher TPMT activity lead to
decreased anticancer activity of purine. 31
 UDP Glucuronyltransferases (UGTs) :
 Patients with absence of UGT activity tend to develop
Gilberts Syndrome, characterised by development of mild
hyperbilirubinemia.
 These variants also devlope severe hematologic and

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Cellular and Molecular Pharmacology by
gastrointestinal side effects in response to treatment with
antineoplastic agents, irinotecan.

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 APPLICATION:

1. Enzymes variants lead to reduced or increased

enzymatic activity as compared to the wild type alleles
have been identified.

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.

3. Possible applications od genotyping is discussed for

depression, cardiovascular diseases and
thromboembolic disorders, gastric ulcer, malignant
diseases and tuberculosis.
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REFERENCES :
 Applied Biopharmaceutics and Pharmacokinetics by
Leon Shargel, 5th edition.
 Cellular and molecular pharmacology by Amteshwar
Singh Jaggi.
 Goodman & Gilman’s, The pharmacological basis of
therapeutics, 12th edition.
 https://www.researchgate.net/figure/Advantages-and-
Disadvantages-of-Forensic-Biomarkers_tbl1_261799306

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