This document discusses how genetic polymorphisms can influence how individuals respond to drugs. It explains that genetics can account for 20-95% of variability in drug effects between people. Sequence variants in genes encoding drug-metabolizing enzymes, transporters, and targets can impact drug disposition and response. Specifically, it describes genetic polymorphisms that influence the cytochrome P450 enzyme CYP3A5 and the drug transporter P-glycoprotein, and how these affect the metabolism and transport of various medications. The document stresses that pharmacogenomic studies are helping to elucidate the inherited basis of differing drug responses.

1. S.Prasanth Kumar, Bioinformatician Pharmacogenomics Pharmacogenomics & Drug Design S.Prasanth Kumar, Bioinformatician S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA www.facebook.com/Prasanth Sivakumar FOLLOW ME ON ACCESS MY RESOURCES IN SLIDESHARE prasanthperceptron CONTACT ME [email_address]

2. The Process of Disposition, Metabolism & Action Metabolizing Enzymes Circulation Excretion Conjugation with Plasma Target Not in CNS Exert its Action Target in CNS Exert its Action Pass via BBB

3. Monogenic Vs Polygenic Wt Wt Wt m m m Wt Wt Wt m m m Wt Wt m m m Wt

4. 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. Pharmacogenomic studies are rapidly elucidating the inherited nature of these differences in drug disposition and effects , thereby enhancing drug discovery and providing a stronger scientific basis for optimizing drug therapy on the basis of each patient’s genetic constitution . Pharmacogenomic Studies

5. Pharmacogenomic Studies It is well recognized that different patients respond in different ways to the same medication. Genetics can account for 20 to 95 percent of variability in drug disposition and effects. 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 Unlike other factors influencing drug response, inherited determinants generally remain stable throughout a person’s lifetime.

6. Pharmacogenomic Studies It is well recognized that different patients respond in different ways to the same medication. Genetics can account for 20 to 95 percent of variability in drug disposition and effects. 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 Unlike other factors influencing drug response, inherited determinants generally remain stable throughout a person’s lifetime .

7. Pharmacogenomic Studies Pharmacogenomics uses genome-wide approaches to elucidate the inherited basis of differences between persons in the response to drugs. More than 1.4 million single-nucleotide polymorphisms were identified in the initial sequencing of the human genome, with over 60,000 of them in the coding region of genes.

8. Genetic Polymorphisms Influencing Drug Disposition There are more than 30 families of drug-metabolizing enzymes in humans CYP3A family of P-450 enzymes About three quarters of whites and half of blacks have a genetic inability to express functional CYP3A5 . The lack of functional CYP3A5 may not be readily evident, because many medications metabolized by CYP3A5 are also metabolized by the universally expressed CYP3A4 . For medications that are equally metabolized by both enzymes, the net rate of metabolism is the sum of that due to CYP3A4 and that due to CYP3A5

9. 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. Genetic Polymorphisms Influencing Drug Disposition 1 2 3 Functional CYP3A5 protein 1 2 3 UGA Nonfunctional CYP3A5 protein

10. Genetic Polymorphisms Influencing Drug Disposition CYP3A4 increase observed in Normal Individual CYP3A5 increase observed in Normal Individual

11. Genetic Polymorphisms Influencing Drug Transport Transport proteins have an important role in regulating the absorption, distribution, and excretion of many medications. Members of the adenosine triphosphate (ATP)–binding cassette family of membrane Transporters are among the most extensively studied transporters involved in drug disposition and effects. A member of the ATP-binding cassette family, P-glycoprotein , is encoded by the human ABCB1 gene (also called MDR1 ). A principal function of P-glycoprotein is the energy-dependent cellular efflux of substrates , including bilirubin, several anticancer drugs, cardiac glycosides, immunosuppressive agents, glucocorticoids, human immunodeficiency virus (HIV) type 1 protease inhibitors, and many other medications

12. Genetic Polymorphisms Influencing Drug Transport The expression of P-glycoprotein in many normal tissues suggests that it has a role in the excretion of xenobiotics and metabolites into urine, bile, and the intestinal lumen . At the blood–brain barrier, P-glycoprotein in the choroid plexus limits the accumula tion of many drugs in the brain , including digoxin,ivermectin, vinblastine, dexamethasone, cyclosporine, domperidone, and loperamide. A synonymous single-nucleotide polymorphism that does not alter the amino acid encoded in exon 26 (3435C->T) has been associated with variable expression of P-glycoprotein in the duodenum

13. Genetic Polymorphisms Influencing Drug Transport Structure of P-glycoprotein

14. Genetic Polymorphisms Influencing Drug Transport

15. Genetic Polymorphism of Drug Targets Genetic variation in drug targets (e.g., receptors) can have a profound effect on drug efficacy, with over 25 examples already identified Sequence variants with a direct effect on response occur in the gene for the b 2-adrenoreceptor, affecting the response to b 2-agonists Arachidonate 5-lipoxygenase (ALOX5), affecting the response to ALOX5 inhibitors angiotensin-converting enzyme (ACE), affecting the actions of ACE inhibitors.

16. Genetic Polymorphisms with Indirect Effects on Drug Response Polymorphisms in genes encoding proteins that are neither direct targets of medications nor involved in their disposition have been shown to alter the response to treatment in certain situations For example, inherited differences in coagulation factors can predispose women taking oral contraceptives to deep-vein or cerebral-vein thrombosis, Polymorphisms in the gene for the cholesterol ester transfer protein have been linked to the progression of atherosclerosis with pravastatin therapy

17. Genetic Polymorphisms in Polygenic Determinants

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