Pharmacogenetics

Pharmacogenetics, a term recognized in pharmacology in the pregenomic era, is the study of influence of genetic factors on action of drugs as opposed to genetic causes of disease. Now it is the study of the linkage between the individual’s genotype and the individual’s ability to metabolize a foreign compound. The pharmacological effect of a drug depends on pharmacodynamics (interaction with the target or the site of action) and pharmacokinetics (absorption, distribution and metabolism). It also covers the influence of various factors on these processes. Drug metabolism is one of the major determinants of drug clearance and the factor that is most often responsible for interindividual differences in pharmacokinetics.

The differences in response to medications are often greater among members of a population than they are within the same person or between monozygotic twins at different times. The existence of large population differences with small intrapatient variability is consistent with inheritance as a determinant of drug response. It is estimated that genetics can account for 20 to 95% of variability in drug disposition and effects. Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications.

Although interindividual variations in drug response result from effects of age, sex, disease or drug interactions, genetic factors represent an important influence in drug response and efficacy and remain constant throughout life. This has led to the recognition of the discipline “pharmacogenetics” since the 1950s, which can be viewed an as integration of gene profiling and pharmaceutical chemistry. From this initial definition, the scope has broadened so that it overlaps with pharmacogenomics.

Pharmacogenomics, a distinct discipline within genomics, carries on that tradition by applying the large-scale systemic approaches of genomics to understand the basic mechanisms and apply them to drug discovery and development. Pharmacogenomics now seeks to examine the way drugs act on the cells as revealed by the gene expression patterns and thus bridges the fields of medicinal chemistry and genomics. Some of the drug response markers are examples of interplay between pharmacogenomics and pharmacogenetics; both are playing an important role in the development of personalized medicines. The two terms - pharmacogenetics and pharmacogenomics - are sometimes used synonymously but one must recognize the differences between the two as shown in Table 18.1.

Table 18.1 Pharmacogenetic vs. pharmacogenomic studies

© Jain PharmaBiotech

Biomarkers and Pharmacogenetics

Identification and characterization of a large number of genetic polymorphisms (biomarkers) in drug metabolizing enzymes and drug transporters in an ethnically diverse group of individuals may provide substantial knowledge about the mechanisms of inter-individual differences in drug response. Pharmacogenetics is used in preclinical investigations for biomarkers of drug-response or drug-induced toxicity, identification of genes with variants that may define patient populations, identification proteins as potential biomarkers, or the comparison of the response in human and clinical animal models. Application of pharmacogenetic biomarkers should be able to predict adverse reactions in clinical trials. Role of pharmacogenetic biomarkers in personalized medicine is shown in Fig. 18.1.