Effect of disulfiram-mediated CYP2E1 inhibition on the disposition of vesnarinone

Vesnarinone is an orally administered inotropic agent that is metabolized i n vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpos e of this study was to assess the contribution of CYP2E1 activity to the di sposition of vesnarinone in humans by characterizing the pharmacokinetics b efore and after disulfiram-mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg were determined in normal healthy volunteers (N = 7) before and after daily disulfiram administration (250 mg). Chlorzoxazone 25 0 mg was also administered before, during, and after disulfiram administrat ion to serve as a positive control for CYP2E1 inhibition. Disulfiram treatm ent decreased 6-hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest decrease in vesnarinone apparent oral clearance (5.7 +/- 1.0 vs. 5.0 +/- 0.5 ml/min; p = 0.022). In contrast to the modest effe ct on the parent drug, disulfiram treatment substantially increased plasma concentrations of the primary metabolite OPC-18692. The C-max of OPC-18692 was increased approximately 7-fold, and the area under the plasma concentra tion-time curve was increased 18-fold (2.9 +/- 0.9 vs. 53. 7 +/- 33.2 mu g. h/ml; p = 0.006). The results indicate that CYP2E1 inhibition has only a mo dest, clinically insignificant effect on vesnarinone disposition but marked ly increases plasma concentrations of the OPC-18692 metabolite. The pharmac ological properties of this metabolite have not been fully defined; thus, t he clinical importance of this observation depends on whether this metaboli te contributes to any of the toxicity associated with vesnarinone administr ation. (C) 1999 the American College of Clinical Pharmacology.