Journal of Pharmacy Practice

A young science serves its purpose if it leads not only to new knowledge, but to new insights and concepts. This article opens with examples to illustrate some former thinking that the introduction of pharmacogenetic has overcome. Pharmacogenetic case histories from discovery to the present illustrate the interlocking of observations, technical advances, and changing concepts. There are striking biological similarities between pharmacogenetics and those inborn factors that cause resistance to infectious disease: Both represent person-to-person variations that may help the survival of populations, one when facing massive toxic exposures, the other when facing plagues and epidemics. Thus pharmacogenetics represents a biologically necessary variability of the defenses against chemical intruders, and this includes drugs. While this variability is desirable, drug toxicity occurring on the basis of this variability must be avoided. The most successful defendants against toxicity due to polymorphic (ie, high incidence) variants should be the designers of new drugs. The only defender concerned with rare variants can be the attentive clinician.

Many factors can influence the metabolism and disposition of drugs. Genetically determined differences in an individual's capacity to metabolize drugs are known causes of interindividual and interethnic variabilities in drug disposition and response. In general, a poor metabolizer for a specific metabolic pathway would likely develop adverse effects, and an extensive metabolizer for the same metabolic pathway might have less than optimal response. Although there are different types of polymorphism in drug metabolism, polymorphisms in debrisoquine-type oxidation, S-mephenytoin oxidation, and N-acetylation have been the most extensively studied. This article will present the basic concepts of pharmacogenetics, review the major types of metabolic polymorphisms, outline ways to determine phenotyping and genotyping differences in metabolizing enzyme activities, and discuss how these differences relate to drug metabolism, response, and toxicity. When evaluating drug response and adverse reactions in individual patients, an awareness of genetic differences in metabolic capacities would help contribute to optimization in drug therapy.

Inter-individual variability in the response to numerous drugs can be traced to a number of sources. One source of variability in drug response is the variability associated with the metabolic capacity of an individual. The component of metabolic capacity that will be the focus of this article is that determined by heredity. Pharmacogenetics is frequently referred to as the study of the effects of heredity on the disposition and response to medications. This article will review the pharmacokinetic and pharmacodynamic significance of pharmacogenetics as it pertains to a select number of cardiovascular agents. The enzyme systems responsible for drug metabolism discussed in this article will be limited to the P-450IID6 and N-acetylation pathways. Given the extensive use of cardiovascular agents in clinical practice that are affected by this genetic polymorphism, it is important for the practicing pharmacist to be aware of this phenomenon and its implications. Hopefully, the knowledge gained from this article will help practicing pharmacists to appreciate the clinical significance of polymorphic drug metabolism and provide a basis for the application of this knowledge to a variety of practice settings.