Introduction to Pharmacogenetics Jamaluddin Shaikh, Ph.D. Associate Professor School of Pharmacy, University of Nizwa Lecture 2 February 14, 2012

Pharmacogenomics Pharmacogenomics is the study of the relationship between the interindividual variability of a candidate's genes and the influence of this variation on drug disposition and effects.

Drug Response Factors Drugs may be administered in various ways: Orally, Sublingually, Intravenously, Intramuscularly, Subcutaneously, Transdermally, Intranasally, or via Inhalation. In general, there is a direct relationship between the dose of a drug that is administered and intensity of pharmacologic response. Individuals vary in their response to standard doses of prescription and non-prescription drugs due to: 1. Drug specific factors. 2. Patient specific factors. 3. Regimen specific factors.

Drug Response Factors Drug specific factors: Disposition of the drug Drug receptor interaction Site of Biological Effect Patient specific factors: Environmental/Diet Exposures Mental/Psychological Status Genetic Constitution Organ Function Enzyme Activity Age/Sex Drug Interactions

Drug Response Factors Regimen specific factors: Dosage Form Dosage Interval Route Dose Amount Genetic constitution affects both: Drug disposition (pharmacokinetics) Receptor-mediated cellular responses (pharmacodynamics).

Pharmacokinetics and Pharmacodynamics Pharmacokinetics (PK) : Effects of body on the drugs Absorption Distribution Metabolism Excretion Pharmacodynamics (PD): Effects of the drugs on body

Inherited variability in drug disposition and response For major classes of drugs, a large proportion of patients do not show enough response, or may experience adverse drug reactions in response to recommended doses. Inherited variations in drug response are common and some tests that incorporate pharmacogenomics into clinical practice are now available. So, we can use these pharmacogenomic tests to assist in individualizing therapy of patients. For inherited variations in drug response, the genotype underlies all of the changes in drug disposition and response (phenotype), and ultimately results in a clinical outcome.

Inherited variability in drug disposition and response The genotype shows candidate gene's influence on drug disposition and effects

Allele Allele: is a different form of a gene. There may be numerous alleles for any gene. The diploid cells contain two copies of each of the 22 non sex chromosomes. The 'normal' or more common allele is called the wild type. Modified or altered alleles may be called mutant allele. If the allele is copied and one copy is inherited from the mother and the other from the father: Similar alleles mean the individual is homozygous for that genetic variation. Different alleles mean the individual is heterozygous. There may be many mutant alleles to a particular gene.

Allele

Genotype Vs Phenotype Genotype is the genetic composition, or the actual alleles present in an individual, whereas, a phenotype is the way that the genotype or alleles physically manifest themselves.

Polymorphism The major pharmacogenomic effects on drug response are due to polymorphic expression of gene products relating to drug metabolism, drug transporters, and drug receptors.  Polymorphism occurs when two or more clearly different phenotypes exist in the same population of a species

Clinical value of a pharmacogenetic testing Certain types of drug therapy may not benefit from pharmacogenetic testing, either: 1. Because therapy has a wide therapeutic and safety range. 2. Because of good clinical ability to monitor and predict response. However, other types of drug therapy may benefit from pharmacogenetic testing, either: 1. Because diseases have a poor response to therapy. 2. Because of poor clinical ability to monitor and predict response.

Human Genome Pharmacogenomics is not just a concept about how information from the Human genome Project can be used in health care.  Nowadays, targeted drugs and pharmacogenomic testing is applicable in several areas of therapeutics.  We are however at the beginning of a long process of understanding the human genome and how it influences disease processes and their response to drug therapy.