Pharmacology And Genetics Of Human Drug Response Are Complementary

From a pharmacological viewpoint, individual responsiveness depends on the intrinsic properties of the drug at hand and can be analyzed from observations of its pharmacokinetic and the pharmacodynamic properties. Often the plasma drug concentration or pattern of drug metabolites correlates with an unusual therapeutic effect or an adverse drug reaction, and observations of parameters such as peak and steady-state levels of the drug in plasma, half-lives of drugs in plasma, the ratio of parent drug to metabolite, or the urinary pattern of drug metabolites are successfully employed to study the dose-response and dynamics of the response. Other indices may be examined, depending on the intrinsic properties of the drug, such as red blood cell counts, white blood cell counts, hormone levels, blood pressure, enzyme inhibition, clotting factor activity, intraocular pressure, respiratory air flow, and so on. Using observations such as these, the pharmacologist would determine whether an unusual drug response was a consequence of a defect in the absorption, distribution, or elimination of the drug, or of a receptor or another protein targeted by the drug.

Geneticists, on the other hand, are attuned to look for differences that discriminate one person from another, and would regard person-to-person differences in drug response as a sign of a possible inborn difference between the responders. In many populations, phenotypic criteria enable individuals to be classified into two, or more, types of responders. The geneticist would draw on information about the affected person and about the biological relatives of the affected person to explain the differential response. The relative roles of heredity and environment would be gauged from studies in identical and fraternal twins; from family studies it would be determined whether the response was monogenic or polygenic and what the mode of transmission of the trait from parents to offspring is. Comparative studies in different populations would turn up differences in response due to new mutations and differences in etiology and prevalence of ethnic and geographic origin. Studies of biologically unrelated persons would provide the raw material from which differences in the frequency of phenotypes and genotypes of individuals and populations could be determined.

Consider first the framework for dissecting the basis of variations in drug response from a pharmacological perspective. The framework for identifying the sources of genetic variation will be considered later.

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