The document discusses pharmacogenetics and how genetic polymorphisms can impact individual responses to drug therapies. It provides examples of polymorphisms in drug metabolizing enzymes like CYP450 isozymes and transporters that can result in differences in drug efficacy and safety between patients. Understanding an individual's genetic makeup can help determine the optimal dose and regimen for a drug to maximize benefits and minimize risks. Pharmacogenetics aims to develop personalized medicines by identifying genetic factors that influence drug response.

1. PHARMACOGENETICS
Dr. Ramesh Bhandari
Asst. Professor,
KLE College of Pharmacy, Belagavi

2. Dr.
Ramesh
Bhandari
PERSONALISED MEDICINES
Same symptoms
Same findings Same Drug
Same disease Same Dose
Different Patients
Different Effects

3. Dr.
Ramesh
Bhandari
AT A RECOMMENDED PRESCRIBED
DOSES:
A Drug is efficacious in most
Not efficacious in others Lack
of Efficacy
And harmful in few Side effects

4. Dr.
Ramesh
Bhandari
One Dose Does Not fit all patients
Therapeutic window is only
Generalisation

5. Dr.
Ramesh
Bhandari
WHY DOES DRUG RESPONSE
VARY?
One of the important reason is:
GENTIC POLYMORPHISM

6. Dr.
Ramesh
Bhandari
WHAT IS THE SOLUTION?
PHARMACOGENTICS
Identifying a population subgroup
 More likely or less likely to
respond
 More prone to ADRs
Defining better dose and dosage
regimen

7. Dr.
Ramesh
Bhandari
HUMAN GENOME
30,000 genes
Each gene composed of sequence of
100s - 1000s of DNA
Nucleotides those builds the DNA are:
Adenine (A)
Cytosine (C)
Guanine (G)
Thymine (T)
 They pair each other with specific rules:
A with T
C with G

8. Dr.
Ramesh
Bhandari
HUMAN GENOME.....
Order of these nucleotides
arrangements in DNA
Structure of RNA Intermediate
Protein Product (Enzymes)

9. Dr.
Ramesh
Bhandari
HUMAN GENOME.....
 Every Individual inherits two copies of
most gene, one from each parent.
 Though 99 percent of nucleotides,
constituting human DNA are identical in
any two individuals, millions of variants in
nucleotides sequence still exist as the total
number of nucleotides in a DNA is so large,
approximately about 3 billion.
 Variants that are found in more than one
percent of the population are defined as
“Polymorphisms”.

10. Dr.
Ramesh
Bhandari
COMMONEST TYPES OF
POLYMORPHISMS ARE:
 Single Nucleotide Polymorphism (SNP):
 Insertion
 Deletion
 Tandem Repeats

11. Dr.
Ramesh
Bhandari
PHARMACOGENTICS VS
PHARMACOGENOMICS
Pharmacogenetics: Study of
variability in drug response
determined by single genes.
Pharmacogenomics: Study of
variability in drug response
determined by multiple genes within
the genome.

12. Dr.
Ramesh
Bhandari
PHARMACOGENETICS
Pharmacogenetics
Genetic Polymorphism:
SNPs
Potential Target Genes are those that encode:
PK PD
Drug metabolizing enzymes Receptors
Transporters Ion Channels
Drug Targets Enzymes
Immune Molecules
The study of variations
in genes that determine
an individual’s response
to drug therapy
Common variation
in DNA sequence
(>1% of population)

13. GENETIC
POLYMORPHISM ON
METABOLISM

14. Dr.
Ramesh
Bhandari
CYTOCHROME ENZYMES
NOMENCLATURE
The cytochrome P450 (CYP450) enzymes
are chiefly involved in the phase I
metabolism of a large number of drugs.
These enzymes are constituents of a
superfamily with 57 related (isoenzymes).
The superfamily of CYP450 enzyme is
categorized into families and subfamilies
based on similarity in aminoacid
sequences.

15. Dr.
Ramesh
Bhandari
These are named by the root symbol
CYP (cytochrome P450), followed by
a number designating the family,
e.g. CYP2 (>40% similarity in
aminoacid sequence), a letter
denoting the subfamily, e.g. CYP2C
(>55% similarity in aminoacid
sequence), and a final number
indicating the specific isoenzyme,
e.g. CYP2C19.

16. Dr.
Ramesh
Bhandari
 CYP2C19*1/*1 - Homozygous wild type
 CYP2C19*1/*2 - Heterozygous mutant type
 CYP2C19*2/*2 - Homozygous mutant type
 CYP2C19*2/*3 - Heterozygous mutant type
CYP Genotype Nomenclature:

17. Dr.
Ramesh
Bhandari
CYP450 DISTRIBUTION
 Majority of CYPs is found in the liver, but certain
CYPs are also present in the cells of the
intestine.
 The mammalian CYPs are bound to the
endoplasmic reticulum, and are therefore
membrane bound.

18. Dr.
Ramesh
Bhandari
CYP450 METABOLIC
CONTRIBUTION
CYP2D6, 30%
CYP2C9, 10%
CYP1A2, 2%
CYP3A4, 55%
OTHERS, 3%
CYP2D6
CYP2C9
CYP1A2
CYP3A4
OTHERS

19. Dr.
Ramesh
Bhandari
PHASE I ENZYMES KNOWN TO
HAVE POLYMORPHISM
 CYP2C9: Phenytoin, Warfarin, NSAIDs etc
 CYP2C19: Omeprazole, Diazepam etc
 CYP2D6: >60 drugs like antidepressants.
 CYP1A2: Theophylline, Clozapine etc.

20. Dr.
Ramesh
Bhandari
PHASE II ENZYMES KNOWN TO
HAVE POLYMORPHISM
 N Acetyltransferase: Isoniazid, hydralazine
 Thiopurine S Methyl transferase: Azathioprine
 UDP glucuronosyl transferase: Irinotecan

21. Dr.
Ramesh
Bhandari
GENETIC POLYMORPHISM OF
CYP2C19
 Highly polymorphic drug metabolizing enzyme.
 30 variant alleles of CYP2C19 reported.
 CYP2C19*2 & *3 is the phenotype for poor
metabolizer.
 Mainly found in asians 29-35% and 5-9% respectively.
 Omeprazole results in higher plasma concentrations,
hence greater efficacy in lowering gastric pH than
extensive metabolizer.
 CYP2C19*17 type results in ultra metabolizing
capacity.
 This results in lack of efficacy of clopidogrel.
(clopidogrel activated by CYP2C19).

22. Dr.
Ramesh
Bhandari
GENETIC POLYMORPHISM OF
CYP2D6
 It is a large isozyme family that affects
metabolism of many drugs. It is highly
polymorphic.
 >70 allelic variants have been reported.
 Antidepressants, antiarrhythmics etc are
metabolized by CYP2D6.
 0-19% African and 1% Asian have poor
metabolizer phenotype of CYP2D6
resulting in increased plasma
concentration.

23. Dr.
Ramesh
Bhandari
 Genetic polymorphism of CYP2D6 was first
investigated with debrisoquine which results in
exaggerated hypotensive response.
 If tricyclic antidepressants are administered in
PM phenotype then increase in plasma
concentration results CNS Depression.
 If metabolism is required for a drug to have
activity, the patient with PM phenotype is more
likely to have therapeutic failure.(Tamoxifen)
 UM phenotyping (Amitryptyline) therapeutic
failure.

24. Dr.
Ramesh
Bhandari
 Codeine is converted to morphine by a
CYP2D6- O- demethylation reaction to
provide analgesic effects. But if
administered with UM phenotype patient
morphine toxicity can occur.

25. Dr.
Ramesh
Bhandari
GENETIC POLYMORPHISM OF
CYP2C9
 30 different allelic variants.
 CYP2C9*2 & *3 most common.
 Both of these variant result in reduced activity.
 CYP2C9 is a major contributor of warfarin.
 When the patient has one of those 2 polymorphism the
dose of warfarin should be reduced.
 It the dose is not reduced then there is an increase risk of
bleeding.
 NSAIDs, ARBs also affected by polymorphism of
CYP2C19 but due to high therapeutic indices wont show
any effect. (except phenytoin)

26. Dr.
Ramesh
Bhandari
GENETIC POLYMORPHISM OF
CYP1A2
 Responsible for metabolism of 5% drugs (Fluvoxamine,
clozapine, olanzapine and theophylline.
 Approx. 15% of Japanese, 5% of the Chinese, and 5% of
the Australian populations are classified as poor
metabolizer.
 Most frequent variant CYP1A2*1F allele – results in an
increased expression. Hence Enhanced level of enzyme
level clears the drug faster. Eg: Failures for Clozapine in
smokers.
 CYP1A2*1C – Results in decreased expression and
seen in 25% of the Asian Populations.

27. Dr.
Ramesh
Bhandari
GENETIC POLYMORPHISM OF
CYP3A4
 Most abundantly found in the liver.
 Metabolize 50% of the clinically used drugs.
 20 allelic variants known.
 Limited data to show any clinical significance
for CYP3A4 substrate.
 CYP3A4*1B – may influence gene expression.
 CYP3A4*2 – decreased clearance of CCB
nifedipine.

28. Dr.
Ramesh
Bhandari
GENETIC POLYMORPHISM OF
N-ACETYLTRANSFERASE
 NAT1 and NAT2 genes – code for NAT
activity.
 Both genes are highly polymorphic but NAT2
gene is related to fast and slow acetylators.
 Several NAT2 alleles *5,*6,*7,*10,*14 & *17
are either null genes or encode of defective
enzymes results in slow acetylator phenotype.
 Slow acetylators of isoniazid exhibit an
increased blood levels of the drug resulting
increase incidence of neurotoxicity.

29. GENETIC
POLYMORPHISM IN
DRUG TRANSPORTER

30. Dr.
Ramesh
Bhandari
DRUG TRANSPORTER
Transporters are proteins that carry
either endogenous compounds or
xenobiotics across biological
membranes.
Transporter can be either efflux or
influx proteins.
Genetic variation such as SNPs of the
transporters can cause differences in
the efflux or influx of drugs.

31. Dr.
Ramesh
Bhandari
There are 2 superfamilies of transport
proteins that have important effects on
the absorption, distribution and
excretion of drugs:
A.ATP Binding Cassette (ABC)
transporters
B. Solute carrier transporters.

32. Dr.
Ramesh
Bhandari
ABC TRANSPORTERS
 Present in cellular and intracellular membranes
and responsible for either importing or removing
the substances from cells and tissues.
 Only the following three gene families are important
for drug transport and multiple drug resistance in
tumor cells:
1. ABCB1 gene, encoding MDR1 (P-
Glycoprotein)
2. ABCC family (ABCC1 through ABCC6) or
multidrug resistance proteins (MRP)
3. ABCG2 (breast cancer resistance protein)

33. Dr.
Ramesh
Bhandari
1. MDR1 (P-GLYCOPROTEIN)
The MDR1 or ABCB1 gene code for
the efflux protein P-glycoprotein that
is frequently associated with drug
resistance to antineoplastic agents.
At lease 66 SNPs in ABCB1 gene
reported.
Among them 3 most studied SNPs
include 2 synonymous and 1 non
synonymous variants.

34. Dr.
Ramesh
Bhandari
The synonymous variants results in
decreased expression of PGP due to
mRNA expression, unstable mRNA or
alteration in protein folding.
Effects of these SNPs have been studied
with digoxin and docetaxel which shows
inconsistent with increased blood levels or
no change compared with wild type gene.

35. Dr.
Ramesh
Bhandari
2. ABCC TRANSPORTER
FAMILY
 These are also known as multidrug resistance
associated proteins (MRPs).
 Found in brain, liver, kidney, and intestine.
 MRP1(ABCC1), MRP2(ABCC2), and
MRP3(ABCC3) are commonly known to effect the
drug disposition.
 These transporters can be expressed in cancer cells
which confers resistance to the chemotherapeutic
agent tamoxifen.
 Polymorphism is rare.

36. Dr.
Ramesh
Bhandari
3. ABCG2 TRANSPORTER
 ABCG2 is also known as Breast cancer resistance
protein (BCRP), Placenta specific ABC transporter
(ABCP), and mitoxantrone resistance protein
(MXR).
 It is important in limiting bioavailability of
certain drugs, concentrating drugs in breast milk
and protecting fetus from drugs in maternal
circulation.
 It is highly expressed in the GIT, liver, placenta
and influences the absorption and distribution of a
wide variety of drugs and organic anions.

37. Dr.
Ramesh
Bhandari
SOLUTE CARRIER PROTEINS
 Transport ions and organic substances across
biological membranes.
 These includes organic cation transporter (OCT)
organic anion transporter protein (OATP).
 Located througout the body.
 OATP1B1 (coded by SLCO1B1 gene) is a hepatic
influx transporter with at least 40 SNP reported
that result in either altered expression or activity of
OATP1B1.
 Among them one SNP (c.521T>C) has been
associated with an increased risk of simvastatin
induced myopathy due to lower plasma clearance.

38. GENETIC
POLYMORPHISM IN
DRUG TARGETS

39. Dr.
Ramesh
Bhandari
DRUG TARGETS
Drug targets include receptors,
enzymes, ion channels and
intracellular signalling proteins.
Genetic polymorphisms occur
commonly for drug target proteins
including receptors, enzymes, ion
channels and intracellular signalling
proteins.

40. Dr.
Ramesh
Bhandari
RECEPTOR GENOTYPES: DRUG
RESPONSE
β1 receptor: located in heart and kidney.
2 common non synonymous SNPs in the β1
receptor gene are located at codons 49
(Ser>Gly) and 389 (Arg>Gly).
Hypertensive patients who were homozygous
for both Ser49 and Arg389 had greater
reduction in diastolic BP with metoprolol
monotherapy compared with carriers of the
Gly49 and/or Gly389 alleles.

41. Dr.
Ramesh
Bhandari
ENZYME GENES: DRUG
RESPONSE
Vitamin K epoxide reductase (VKOR) is
an typical example of genetic variation to
drug response.
Warfarin exerts its anticoagulation effects
by inhibiting VKOR, thus preventing
carboxylation of clotting factors II, VII, IX
and X.
VKORC1 gene encodes for VKOR
enzyme.

42. Dr.
Ramesh
Bhandari
Polymorphism in the VKORC1 coding
region cause rare case of warfarin
resistance.
VKORC1*2,*3 & *4.
Carriers of these polymorphism either
require high dose of warfarin or fail to
respond to any dose of warfarin.