Drug-metabolism research challenges in the new millennium: individual variability in drug therapy and drug safety.

One of the most challenging research areas in pharmacology in the new millennium is to understand why individuals respond differently to drug therapy and to what extent that individual variability in disposition is responsible for the observed differences in therapeutic efficacy and adverse reactions. To answer these complex questions, drug-metabolism research will rely on multidisciplinary approaches more than ever to investigate the many components involved in drug metabolism and disposition. Major research challenges include the following: (1) the genetic variation of drug targets (receptors, enzymes, etc.), drug transporters (multispecific organic anion transporter, P-glycoprotein, alpha-1-acid glycoprotein, etc.), and drug-metabolizing enzymes (cytochrome P450s and other enzymes); (2) the structure and function of all genetic variants of drug receptors, transporters, and metabolizing enzymes; (3) the induction, repression, and inhibition of all components involved in drug disposition; (4) the development of noninvasive in vivo methods to determine the physiological significance of various components in the handling of specific therapeutic agents in humans; (5) the mechanism of idiosyncratic adverse drug reactions; and (6) the pharmacokinetic and pharmacodynamic relationships to explain the individual differences in therapeutic efficacy and drug safety. Thus successful drug-metabolism research in the new millennium must integrate receptor biology, enzymology, recombinant DNA technology, biochemical toxicology, and drug disposition into study design and conduct balanced in vitro and in vivo experiments to allow a full understanding of the mechanisms of individual variability in drug therapy and drug safety.