CYP induction-mediated drug interactions: in vitro assessment and clinical implications.
Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed.
Lin
Jiunn H
JH
Department of Preclinical Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania, USA. jiunn_lin@merck.com
D000818:Animals; D000090702:Constitutive Androstane Receptor; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis* / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D015195:Drug Design; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects* / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D010599:Pharmacokinetics; D010600:Pharmacology; D000077297:Pregnane X Receptor; D020239:Receptor Cross-Talk; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D019392:Cytochrome P-450 CYP2E1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A