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.