pharmacogenomics is a new drug discovry approach. It is the study of how genes affect a person's response to drugs, combining pharmacology and genomics

1. Pharmacogenomics
PHARMACOLOGY-VI
By:-
Manisha Pahal
M. Pharmacy (2nd sem)
Pharmacology
Deptt. of Pharmaceutical sciences
M.D.U. Rohtak

2. • “One fits all”
medication
• Personalized
medication

4. • Pharmacogenomics is the study of how genes affect
a person’s response to drugs. This relatively new field
combines pharmacology (the science of drugs) and genomics
(the study of genes and their functions) to develop effective,
safe medications and doses that will be tailored to a person’s
genetic makeup.

5. Genotyping
Collect blood
Isolate DNA from the blood cells
Amplify no. of copies of DNA by PCR
Genotype by sequencing or probing

6. Genome variants (Polymorphism)
• Single nucleotide polymorphism (SNP) is a variation at a single
position in a DNA sequence among individuals. If more than 1%
of a population does not carry the same nucleotide at a specific
position in the DNA sequence, then this variation can be
classified as a SNP. If a SNP occurs within a gene, then the gene is
described as having more than one allele.
…CTAGATACGAACTGCATC…
…CTAGATACGGACTGCATC…
• Mutation is a difference in DNA sequence among individuals, or
populations. Sources include SNPs, sequence repeats, insertions,
deletions and recombination.

7. Consequences of genetic polymorphism
• May result in a different amino acid or stop codon
• May result in a change in protein function or quantity
• No effect
• Genetic polymorphisms in drug-metabolizing enzymes,
transporters, receptors, and other drug targets have been
linked to inter individual differences in the efficacy and toxicity
of many medications.

9. • Genome variants influence drug effects via
alterations in a drug’s pharmacokinetics or via
modulation of a drug’s pharmacodynamics.

10. Predictive prescribing
Patient genotypes are usually categorized into the following predicted phenotypes:
• Ultra-Rapid Metabolizer: Patients with substantially increased metabolic activity.
• Extensive Metabolizer: Normal metabolic activity.
• Intermediate Metabolizer: Patients with reduced metabolic activity.
• Poor Metabolizer: Patients with little to no functional metabolic activity.

11. Drug-metabolizing enzymes
 There are several known genes which are largely responsible for variances
in drug metabolism and response via
• Cytochrome P450s
• VKORC1
• TPMT
 Cytochrome P450
• The most prevalent drug-metabolizing enzymes are the Cytochrome
P450 (CYP) enzymes ( membrane-bound, heme-containing protein
characterized by 450 nm spectral peak when complexed with carbon
monoxide). The human CYP family consists of 57 genes, with 18 families
and 44 subfamilies.
• CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 are most commonly used
enzymes. These genes account for the metabolism of approximately 80-
90% of currently available prescription drugs.

12. Enzymes Fraction of drug
metabolism (%)
Example drugs
CYP2C9 10 Tolbutamide, ibuprofen, mefenamic acid,
tetrahydrocannabinol, losartan,
diclofenac
CYP2C19 25 S-mephenytoin, amitriptyline, diazepam,
omeprazole, proguanil, hexobarbital,
propranolol, 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

13. Enzymes responsible for biotransformation

14. CYP2C9

15. Allele frequencies(%) of CYP2C9 polymorphism

16. • CYP2C9*2 & CYP2C9*3 – PM
• Warfarin – prolonged bleeding time ,
increased incidence of severe bleeding.
• Glipizide, tolbutamide – low blood sugar.

17. CYP2C19

19. • CYP2C19*2, CYP2C19*3 – Poor metabolizers
• Diazepam – prolonged sedation in PM
• Omeprazole – decrease cure rate in PM
• Clopidogrel – increase bleeding in PM

22. CYP2D6

25. • CYP2D6*4 – Tamoxifen – poor metabolizer
• CYP2D6*9,*10,*17 – PM- increased toxicity of
antidepressants & antipsychotics, lack of analgesic
effect of codein.
• CYP2D6*2 – Ultra Rapid- rapid clearance and
decreased efficacy of antidepressants.

26. CYP3A4 and variants

29. VKORC1

32. TPMT

34. Effect on AZT of TPMT Polymorphism

35. Phase II enzymes

36. Pharmacogenomics in drug
transport

39. P- glycoprotein

40. P- glycoprotein variants affecting Fexofenadine
plasma concentration

41. • OATP-C*5 & OATP-C*9 – Increase level of
provastatin , inc toxicity & reduced efficacy.

42. Pharmacogenomics in receptor
response

44. Amphichip
• Determine the genotype of the patient in terms of
two CYPP450 enzymes: 2D6 and 2C19
• FDA approved the test on December 24, 2004. The
AmphiChip CYP450 test is the first FDA
approved pharmacogenetic test.

45. Barriers of pharmacogenomics
 Complexity of finding gene variations that affect drug
response
• Millions of SNPs must be identified and analyzed to determine
their involvement in drug response.
• Limited knowledge of which genes are involved with each drug
response.
• Confidentiality, privacy and the use and storage of genetic
information.
 Educating healthcare providers & patients
• Physicians must execute an extra diagnostic step to determine
which drug is best suited to each patient.

46.  Disincentives for drug companies to make multiple
pharmacogenomic products.
• Most pharmaceutical companies have been successful with
their "one size fits all" approach to drug development.
• For small market- Pharmaceutical companies has to spend
hundreds of millions of dollars on pharmacogenomics based
drug development.

47. Pharmacogenomics in clinical trial

48. Applications

49. References
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