Drug-drug interactions that arise by the alteration of the pharmacokinetics of one drug by another are of concern to the pharmaceutical industry, drug regulatory agencies, health-care professionals and patients. However, distinction needs to be made between interactions that only result in alterations in exposure levels and interactions that truly have an impact on efficacy and patient safety. To make this distinction, both the magnitude of the pharmacokinetic interaction and the therapeutic index of the affected drug must be taken into account. In this review, a description of the mechanistic underpinnings of drug interactions that has been developed over the past two decades is presented, with particular emphasis on drug-metabolizing enzymes and clearance concepts. The research approaches used to study drug interactions in vitro and in vivo are described. Finally, an accounting of major pharmacokinetic drug-drug interactions is made, organized by the drug-metabolizing enzyme or transporter protein affected. For each drug-metabolizing enzyme and transporter discussed, a position is offered on the severity of the issue of whether a new drug were to affect, or be affected by, a drug interaction through alteration of the activity of that enzyme.
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