gdgs pharmacogenomis

1. PRESENTED BY-
GYANDEEP GUPTA
FPB-MA-502

2. Introduction
 The term ‘Pharmacogenomics’ comes from the words
‘pharmacology’ and ‘genomics’.
 Pharmacogenomics is the study of the role of the
genome in drug response.
 Pharmacogenomics analyzes how the genetic makeup of
an individual affects response to drugs(Ermak,.2015).

4. • It deals with the genetic variation on drug
response by correlating –
» gene expression
»SNP
»pharmacokinetics and pharmacodynamics
(drug absorption, distribution, metabolism,
and elimination).
»drug receptor target effects.
• Both SNPs and CNVs play a role in
pharmacogenomics, in different phenotypic
outcomes and measures. (Vaiopoulou, 2003)

5. Genetics and metabolism of drugs

6. It is well recognized that different patients respond in
different ways to the same medication.

7. • Numerous examples of cases in which inter
individual differences in drug response are
due to sequence variants in genes encoding
drug-metabolizing enzymes, drug
transporters, or drug targets.
• How variants formed ?
• SNP and addition,
• Deletion,
• Duplication of nucleotide
bases

9. • Pharmacogenomics aims to develop to optimize drug
therapy, with respect to the animal’s genotype, to
ensure maximum efficacy with minimum adverse
effects. (Becquemont, 2009).
• Through the utilization of pharmacogenomics,
Pharmaceutical drug treatments can deviate from
what is dubbed as the "one-dose-fits-all" approach.
• It hopes to achieve better treatment outcomes, greater
efficacy, minimization of the occurrence of drug
toxicities and adverse drug reactions (ADRs).
• Drug efficacy is not influenced by variations in drug-
metabolizing genes but also by polymorphisms in
genes that encode drug receptors, transporters, and
drug targets. (Vaiopoulou, 2003)

11. Polymorphism of enzymes responsible for
drug metabolism
• Most drugs undergo phase I metabolism, which
involves oxidation, reduction, or hydrolysis. Such
reactions transform the drug into a more polar water-
soluble metabolite.(Guengerich,2001)
• Some drugs can undergo phase II metabolism, which
entails conjugation of a polar group to the drug
molecule to make it more polar.(Akagah, et al 2008).
• Enzymes responsible for such transformations may
show a wide variation in enzymatic activities due to
genetic polymorphisms.

13. Genetic Polymorphisms Influencing Drug Disposition
• CYP3A family of P-450 enzymes
The most prevalent drug-metabolizing enzymes are the
Cytochrome P450 (CYP) enzymes.
• the most commonly tested CYPs include: CYP2D6,
CYP2C19, CYP2C9, CYP3A4 and CYP3A5. These genes
account for the metabolism of approximately 80-90% of
currently available prescription drugs (Hart.,et al 2008).
• Across all species of fish, 137 genes encoding P450s have
been identified. These genes are classified into 18 CYP
families (Uno.,et al 2012).
• CYP3A induction leads to an increased metabolism of the
administered substance due to upregulated enzymes. This can
cause adverse reactions,like inflammation of the liver
(hepatitis) (Willson and Kliewer, 2002).

14. The genetic basis of CYP3A5 deficiency is predominantly a
single-nucleotide polymorphism in intron 3 that creates a cryptic
splice site causing 131 nucleotides of the intronic sequence to be
inserted into the RNA, introducing a termination codon that
prematurely truncates the CYP3A5 protein
1 2 3
Functional CYP3A5 protein Nonfunctional CYP3A5 protein
UGA

15. An example of different CYP2D6 alleles and
their effects on enzyme function

16. • Other enzyme like
• The cytochrome P-450 mixed-function oxidase (CYP)
• N-acetyltransferase (NAT1 and NAT2)
• Thiopurine-S-methyltransferase (TPMT)
• Polymorphism of uridine-5 diphosphate glucuronyl transferase
(UDP-glucuronyl transferase)
• Enzymes responsible for such transformations may show a
wide variation in enzymatic activities due to genetic
polymorphisms.
• The goal of pharmacogenomics is to understand such genetic
variations in order to predict the response of a particular drug
in a particular patient.

17. • Several transporters have been shown to have
pharmacogenomic relationships with drug
pharmacokinetics or effect.
• The best example of a drug transporter:
• Multidrug-resistant transporter and
• P-glycol- protine /MDR1
Polymorphisms of the transporter and
receptor proteins:

18. Pharmacogenetics testing methods
• AmpliChip CYP450-Using FDA-approved test kit.
• Determine the genotype of the patient in terms of two
CYPP450 enzymes: 2D6 and 2C19.
• FDA approved the test on December 24, 2004. The
AmpliChip CYP450 test is the first FDA
approved pharmacogenetic test.

20. Pharmacogenetics testing methods
• Technologies and methods that used in
pharmacogenetics:
1. The DNA microarray
2. pyro-sequencing
3. Mass Spectrometry
4. Fluorescence based-platform
5. RFLP and RTPCR and their types (such as PCR-5
QPCR)

21. Detection of SNPs by hybridization.
• Blood is collected from a patient and
Genomic DNA is isolated from lymphocytes.
A PCR reaction is performed to amplify and tag DNA
fragments containing the SNP of interest.
Tagged DNA fragments are hybridized to SNP probes bound
to a solid matrix.
Mismatched fragments are washed away. Hybridized
fragments are fluorescently labelled and detected
Determine the SNP genotype.

23. Application of pharmacogenomics

24. Limitations of Pharmacogenomics
• The drug response is probably affected by multiple
genes.
• Drug response might be predicted from a certain
pattern of polymorphisms rather than only a single
polymorphism.
• Holding sensitive information on someone’s genetic
make up raises questions of privacy and security and
ethical dilemmas in disease prognosis and treatment
choices.

25. Future prospects
• Research in the field of pharmacogenetics is
moving in two main directions:
• 1) identify specific genes and their products
that are associated with different diseases and
may be targets for new treatments.
• 2) Identification of genes and allelic variants
of genes that may affect the response to drugs
for diseases.

26. Conclusion
• Identification of diseases related to genes and specific
drugs- more drug specific cure
• Categorizing of human diseases at genome level
• Can adopt primary and secondary preventive
measures
• Maximal patient care and minimum ADR
• Right drug, in right dose for the right
patient at right time

28. References
• Uno, T., Ishizuka, M. and Itakura, T., 2012. Cytochrome P450 (CYP) in
fish. Environmental toxicology and pharmacology, 34(1), pp.1-13.
• Hart, S.N., Wang, S., Nakamoto, K., Wesselman, C., Li, Y. and Zhong,
X.B., 2008. Genetic polymorphisms in cytochrome P450 oxidoreductase
influence microsomal P450-catalyzed drug metabolism. Pharmacogenetics
and genomics, 18(1), pp.11-24.
• Willson, T.M. and Kliewer, S.A., 2002. PXR, CAR and drug metabolism.
Nature reviews. Drug discovery, 1(4), p.259.
• Ermak, G., 2015. Emerging Medical Technologies. World Scientific
Publishing Co Inc.
• Becquemont, L., 2009. Pharmacogenomics of adverse drug reactions:
practical applications and perspectives. Pharmacogenomics, 10(6), pp.961-
969.

29. • Vaiopoulou, A., Gazouli, M. and Karikas, G.A., 2013. Pharmacogenomics:
Current applications and future prospects towards personalized
therapeutics. J Buon, 18, pp.570-578.
• Guengerich, F.P., 2001. Common and uncommon cytochrome P450
reactions related to metabolism and chemical toxicity. Chemical research in
toxicology, 14(6), pp.611-650.
• Akagah, B., Lormier, A.T., Fournet, A. and Figadère, B., 2008. Oxidation
of antiparasitic 2-substituted quinolines using metalloporphyrin catalysts:
scale-up of a biomimetic reaction for metabolite production of drug
candidates. Organic & biomolecular chemistry, 6(24), pp.4494-4497.