101Genotyping involves identifi cation of defi ned genetic mutations that give rise to
the specifi c drug metabolism phenotype. These mutations include genetic altera-
tions that lead to overexpression (gene duplication), absence of an active protein
(null allele), or production of a mutant protein with diminished catalytic capacity
(inactivating allele). Genetic mutations can be screened by molecular diagnostic
methods. Although genome-wide association studies have long been considered an
avenue for improving diagnostics, prognostics, and treatment, an important current
application is in pharmacogenetics for improving drug safety and reducing adverse
reactions to drugs.
Role of Pharmacogenetics in Pharmaceutical Industry
Genes infl uence pharmacodynamics and pharmacokinetics. Sequence variations in
drug disposition genes can alter the pharmacokinetics of a drug, while sequence
variations in drug target genes can change the pharmacodynamics of the drug. The
two most common strategies to test a pharmacogenetic question are the candidate-
gene approach and genome wide association study. Pharmacogenetics has a three-
fold role in the pharmaceutical industry, which is relevant to the development of
personalized medicines:
- For study of the drug metabolism and pharmacological effects.
- For predicting genetically determined adverse reactions.
- Drug discovery and development and as an aid to planning clinical trials.
Study of the Drug Metabolism and Pharmacological Effects
Most drugs are metabolized to some extent. Metabolism results in detoxifi cation or
elimination of the drug or activation of the prodrug to the biologically active form.
It may even result in the formation of toxic metabolites. From a pharmacological
point of view, pathways of drug metabolism can be classifi ed as either phase I reac-
tions (oxidation, reduction and hydrolysis) or phase II conjugation reactions (acety-
lation, reduction and hydrolysis). Phase II reactions may occur prior to phase I and
may not be followed by oxidation, reduction or hydrolysis.
Causes of Variations in Drug Metabolism
Given the complex interplay among the many factors that infl uence a drug dose,
determination of an appropriate dose of a particular drug for a given patient will
eventually require knowledge about both genetic and nongenetic factors that affect
Role of Pharmacogenetics in Pharmaceutical Industry