Prediction of human drug metabolizing enzyme induction.
New chemical entities are routinely screened in vitro and in vivo for their ability to induce cytochrome P450s (CYP), other drug-metabolizing enzymes and possibly transporters in an attempt to more accurately predict clinical parameters such as drug-drug interactions and clearance in humans. Some of these potential therapeutic agents can cause induction of the metabolism of another molecule or auto-induction thereby increasing their own metabolism and elimination, as well as potentially any molecules metabolized by the same enzyme(s). Key CYPs in the 1A, 2B, 2C, and 3A families have all been shown to be inducible. It would be clearly advantageous to know the potential for a compound to induce drug metabolizing enzymes or transporters prior to clinical development, and many in vitro systems have been developed for this purpose. Newer computational technologies are also being applied in order to attempt to predict induction from the molecular structure alone before a molecule is even synthesized or tested. This review will cover the various in vitro and in silico methods developed for prediction of key inducers of CYPs and other proteins, as well as the limitations of such technologies and applications in the future.
Mankowski
Dayna C
DC
Rib-X Pharmaceuticals, Inc., New Haven, CT 06511, USA.
Ekins
Sean
S
D000818:Animals; D000090702:Constitutive Androstane Receptor; D004790:Enzyme Induction / Q000187:drug effects*; D004798:Enzymes / Q000096:biosynthesis* / Q000378:metabolism*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; D004798:Enzymes; D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D014157:Transcription Factors