Sources of interindividual variability.
The efficacy, safety, and tolerability of drugs are dependent on numerous factors that influence their disposition. A dose that is efficacious and safe for one individual may result in sub-therapeutic or toxic blood concentrations in other individuals. A major source of this variability in drug response is drug metabolism, where differences in pre-systemic and systemic biotransformation efficiency result in variable degrees of systemic exposure (e.g., AUC, C max, and/or C min) following administration of a fixed dose.Interindividual differences in drug biotransformation have been studied extensively. It is well recognized that both intrinsic (such as genetics, age, sex, and disease states) and extrinsic (such as diet, chemical exposures from the environment, and even sunlight) factors play a significant role. For the family of cytochrome P450 enzymes, the most critical of the drug metabolizing enzymes, genetic variation can result in the complete absence or enhanced expression of a functional enzyme. In addition, up- and down-regulation of gene expression, in response to an altered cellular environment, can achieve the same range of metabolic function (phenotype), but often in a less reliably predictable and time-dependent manner. Understanding the mechanistic basis for drug disposition and response variability is essential if we are to move beyond the era of empirical, trial-and-error dose selection and into an age of personalized medicine that brings with it true improvements in health outcomes in the therapeutic treatment of disease.