This document provides an overview of pharmacogenomics. It defines pharmacogenomics as the study of how an individual's genetic inheritance affects their response to drugs. It discusses how genetic variants like mutations and single nucleotide polymorphisms can influence drug efficacy and toxicity based on variations in drug-metabolizing enzymes and receptors. The document also outlines some of the potential benefits of personalized medicine based on pharmacogenomic insights, as well as some limitations to its implementation in clinical practice.

2. OUTLINE
Introduction
Variants and SNPs
Personalized medicine
PK/ PD In pharmacogenetics
Clinical significance & practice
Benefits and limitations
Conclusion

3. +
PHARMACOGENOMICS
Study of how an individual's genetic inheritance affects the
body's response to drugs

4. INTRODUCTION
Pharmacogenomics deals with the influence of genetic
variation on drug response by co-relating gene
expression or polymorphism with a drug’s efficacy
or toxicity
It intends to identify individuals who are either more
likely or less likely to respond to a drug, as well as
those who require altered dose of certain drugs

5. GENETICS VS. GENOMICS
Pharmacogenetics is often a study of the variations in
a targeted gene, or group of functionally related
genes for variability in drug response
Refers to how variation in one single gene
influences the response to a single drug
Pharmacogenomics is the use of genetic information
to guide the choice of drug and dose on an
individual basis.
Broader term, which studies how all of the genes (the
genome) can influence responses to drugs

6. POTENTIAL OF
PHARMACOGENOMICS

8. THE FOUNDATION OF PHARMACOGENOMICS:
Mutation: difference in the DNA code that occurs in
less than 1% of population
 Often associated with rare diseases
 Cystic fibrosis, sickle cell anemia, Huntington’s disease
Polymorphism: difference in the DNA code that
occurs in more than 1% of the population
 A single polymorphism is less likely to be the main cause of
a disease
 Polymorphisms often have no visible clinical impact

9. A Single Nucleotide Polymorphism (SNP) are DNA
sequence variation that occurs when a single
nucleotide in the genome sequence is altered.
Occur in at least 1% of the population and make up
about 90% of all human genetic variation

10. SNP

11. POLYMORPHISMS
May result in a different amino acid or stop codon
May result in a change in protein function
No effect
Genetic polymorphisms in drug-metabolizing
enzymes, transporters, receptors, and other drug
targets inter individual differences in the efficacy
and toxicity of many medications

12. ONE SIZE FITS ALL PERSONALIZED MEDICINE

13. PERSONALIZED MEDICINE
It refers to an approach of clinical practice where a
particular treatment is not chosen based on the
‘average patient’ but on characteristic of an individual
patient

14. GOALS OF PHARMACOGENETICS
GOALS OF PHARMACOGENETICS

15. HOW DOES IT AFFECT THE
DRUGS??

16. POLYMORPHISM OF ENZYMES & DRUG
METABOLISM
 The cytochrome P-450 mixed-function oxidase (CYP)
 N-acetyltransferase (NAT1 and NAT2)
 Thiopurine-S-methyltransferase (TPMT)
 Uridine-5 diphosphate glucuronyl transferase-
Polymorphisms of UGT1A1 and UGT2B7 play important
roles in the phase II metabolism of certain drugs.

18. Cytochrome P450 enzymes
a) CYP2D6
 Metabolism of 20-25% of marketed drugs
 Polymorphism best studied
 Drugs: SSRI, TCA, beta blockers, antipsychotics
b) CYP2C19
 More than 20 polymorphism reported
 Drugs: PPI, Mephenytoin,N-demethylation of TCA(
amitryp, clomipramine, nortryp)
 Proguanil to cycloguanil

19. c) CYP 2C9
 Biotransformation of warfarin, phenytoin, fluvastatin,
several NSAIDS, Antidiabetics
c) CYP3A4/5
 Most abundant
 Seen in human liver
 Metabolism of more than 50% of drugs
 20 variants identified
Eg: CYP3A4*16, CYP3A4*2, CYP3A4*7

20. Enzymes (%) of drug
metabolism
Example drugs
CYP2C9 10 Warfarin, Fluvastatin, Tolbutamide, ibuprofen,
mefenamic acid,, losartan, diclofenac
CYP2C19 25 S-mephenytoin, amitriptyline, diazepam,
omeprazole, proguanil, hexobarbital,
imipramine
CYP2D6 20-30 Debrisoquine, metoprolol, sparteine,
propranolol, encainide, codeine,
dextromethorphan, clozapine, desipramine,
haloperidol, amitriptyline, imipramine
CYP3A4 40-45 Erythromycin, ethinylestradiol, nifedipine,
triazolam, cyclosporine, amitriptyline,
imipramine
CYP3A5 1-2 Erythromycin, ethinylestradiol, nifedipine,
triazolam, cyclosporine, amitriptyline,
aldosterone

21. Roche
FDA approved

22. ROCHE AMPLICHIP P450
TEST
The Roche AmpliChip CYP450 Test is intended to
identify a patient's CYP2D6 and CYP2C19 genotype
from genomic DNA extracted from a whole blood
sample
 An aid to clinicians in determining therapeutic
strategy and treatment dose for therapeutics

23.  N-acetyltransferase (NAT1 and NAT2)
 Hepatic cytosolic NAT 2
 Fast & slow acetylators
 Drugs: Sulfapyridine, sulfamethoxypyridazine, hydralazine,
INH, procainamide, phenelzine
Sch hydrolysis
 Pseudocholinesterases in plasma
 Scoline apnea

24. Red cell enzyme defects
G6PD- Sulfonamides, primaquine, dapsone,
nalidixic acid, nitrofurantoin, doxorubicin
Glutathione reductase deficiency
Methemoglobin reductase deficiency
Porphyria
Porphobilinogen deaminase defect
↑ ALA synthase AIP
 Barbiturates, carbamazepine,
Phenytoin, INH, dapsone
Malignant hyperthermia

25.  Insulin resistance
 Polygenic[ Ark-I, Atl, Minn]
 Insulin receptor α subunit
 Arrhythmia with antiarrhythmics
 Torsades de pointes
 Genetic abnormality in k+ channel(polymorphism)
 Resistance to drug effects
 Vit D resistance rickets
 Coumarin resistance( polymorphism of vit K reductase)

27. Drug targets
 Haloperidol & D2 receptor
 HER 2 & trastuzumab
Drug development
Identifies patient group who would have high or
low likelihood of responding to the agent
EGFR mutation & response to gefitinib
HLA polymorphism HLA-B*5701 & hypersensitivity
with Abacavir
APOE & Tacrine in AD

29. LIMITATIONS:
 Many genes are involved in drug action, making the
drug target very difficult
 Insufficient validation of study results
 Identification of small inter-individual variation in
everyone’s gene is very difficult
 Expensive
 Ethical issues

30. THANK YOU