Duration of cytochrome P-450 2E1 (CYP2E1) inhibition and estimation of functional CYP2E1 enzyme half-life after single-dose disulfiram administrationin humans

Disulfiram (DSF) is a mechanism-based inhibitor of cytochrome P-450 2E1 (CY P2E1), resulting in loss of CYP2E1 protein and activity, which may be usefu l in preventing CYP2E1-mediated xenobiotic toxicity. The duration of inhibi tion after a single DSF dose is, however, unknown. The purpose of this inve stigation was to determine this duration, and CYP2E1 formation and degradat ion rates, in humans. Oral chlorzoxazone (CLZ) was used as the selective in vivo probe for CYP2E1. Healthy subjects received CLZ to determine baseline CYP2E1 activity (CLZ plasma clearance and 6-hydroxychlorzoxazone fractiona l metabolic clearance). One week later, DSF (500 mg orally) was administere d at bedtime, and CLZ administered the following morning and 3, 6, 8, 10, a nd 13 days after DSF. A terminal DSF metabolite, 2-thiothiazolidine-4 carbo xylic acid, was also measured in each 24-h urine sample. The mean CLZ clear ance and 6-hydroxychlorzoxazone fractional metabolic clearance on the first day declined to 10.2 and 5.5% of baseline values, indicating rapid and pro found CYP2E1 inhibition. CYP2E1 activity returned to half that of control o n day 3, and to baseline values on day 8. Assuming zero-order synthesis and first-order degradation, the in vivo CYP2E1 synthesis rate and degradation half-life was estimated to be 11 +/- 5 nmol/h and 50 +/- 19 h, respectivel y. Significant amounts of 2-thiothiazolidine-4 carboxylic acid were present only on day 1, suggesting that the return of in vivo CYP2E1 activity was n ot caused by inhibitor washout, but by enzyme resynthesis. Results regardin g CYP2E1 disposition may be useful for modeling the effects of CYP2E1 induc ers and inhibitors. For prevention of CYP2E1-mediated bioactivation, depend ing on protoxicant disposition, a second DSF dose might be necessary to com pletely prevent toxicity.