SINGLE-DOSE DISULFIRAM INHIBITION OF CHLORZOXAZONE METABOLISM - A CLINICAL PROBE FOR P450-2E1

Disulfiram and its reduced metabolite diethyldithiocarbamate have been identified previously as selective mechanism-based inhibitors of huma n fiver microsomal cytochrome P450 2E1 in vitro. In animals, a single oral dose of disulfiram has been shown to produce a rapid and selectiv e inactivation of hepatic P450 2E1 content and catalytic activity in v ivo. This investigation explored the efficacy of single dose disulfira m as an inhibitor of human P450 2E1 activity in vivo. Clinical P450 2E 1 activity was assessed by the 6-hydroxylation of chlorzoxazone, a met abolic pathway catalyzed selectively by P450 2E1. Six healthy voluntee rs received 750 mg oral chlorzoxazone on two occasions in a crossover design, 10 hours after 500 mg oral disulfiram, or after no pretreatmen t (control subjects). Disulfiram pretreatment markedly decreased chlor zoxazone elimination clearance to 15% of control values (from 3.28 +/- 1.40 to 0.49 +/- 0.07 ml/kg/min, p < 0.005), prolonged the eliminatio n half-life (from 0.92 +/- 0.32 to 5.1 +/- 0.9 hours, p < 0.00 1), and caused a twofold increase in peak plasma chlorzoxazone concentrations (20.6 +/9. 9 versus 38.7 +/- 10.3 mug/ml, p < 0.001). Disulfiram also profoundly decreased the formation clearance of 6-hydroxychlorzoxazon e, from 2.30 +/- 0.93 to 0.17 +/- 0.05 ml/kg/min (p < 0.005). These fi ndings show that a single dose of disulfiram significantly diminishes the activity of human P450 2E1 in vivo. The efficacy of single-dose di sulfiram as an inhibitor of human P450 2E1 suggests that this modality for manipulating clinical P450 2E1 activity may provide a useful prob e for delineating P450 2E1 participation in human drug biotransformati on or for the treatment of poisoning by P450 2E1-activated toxins.