Mechanism‐based inactivation of human CYP3A4 by a piperazine‐containing compound (615.5)

Abstract

Human cytochrome P450 enzymes (CYPs) are monooxygenases that are responsible for metabolism of a variety of small compounds including many pharmaceutical drugs. The main drug metabolizing CYP is CYP3A4 that metabolizes around half of drugs. Some drugs are known to inhibit CYP3A4, lowering the ability of CYP3A4 to metabolize other compounds leading to adverse events. 1‐[(2‐Ethyl‐4‐methyl‐1H‐imidazol‐5‐yl)‐methyl]‐4‐[4‐trifluoromethyl‐2pyrinyl]piperazine (EMTPP), while not a pharmaceutical drug, contains a piperazine group and substituted imidazole ring frequently found in pharmaceutical compounds. EMTPP is also similar in structure to SCH66712 and both EMTPP and SCH 66712 have previously been described as inactivators of CYP2D6 [Hutzler, Steenwyk, Smith, Walker, Wienkers (2004) Chem Res Toxicol 17, 174‐184; Nagy, Mocny, Diffenderfer, Hsi, Butler, Arthur, Fletke, Palamanda, Nomeir, Furge (2011) Drug Metab Dispos 39, 974‐983]. Our group has also recently shown SCH66712 to be a potent inactivator CYP3A4 and hypothesized that EMTPP would be as well. In this study, time‐ and concentration‐dependent inactivation of CYP3A4 by EMTPP was observed. Furthermore, the partition ratio for potency of EMTPP inactivation of CYP3A4 was measured along with possible routes of inactivation. This study lends insight into similarities between CYP2D6 and CYP3A4 for interaction with inactivators.Grant Funding Source: Supported by NIH 1R15‐GM086767‐02