¹Department of Anesthesiology, Medicinal Chemistry, and Pharmaceutics, University of Washington, and the Anesthesiology Service, Puget Sound Veterans Affairs Health Care System, Seattle, Wash.

Correspondence: Evan D. Kharasch, MD, PhD, Professor, Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195. E-mail: kharasch@u.washington.edu

^*Supported by National Institutes of Health grant GM48712 and by National Institutes of Health grant M01 RR00037 to the University of Washington Clinical Research Center.

Received 29 October 1997; Accepted 12 February 1998.

Abstract

Background: Disulfiram and its primary metabolite diethyldithiocarbamate are effective mechanism-based inhibitors of human liver cytochrome P450 2E1 (CYP2E1) in vitro. A single dose of disulfiram, which significantly diminishes human P450 2E1 activity in vivo, has been used to investigate the role of CYP2E1 in human drug metabolism and to prevent CYP2E1-mediated biotransformation. Nevertheless, the specificity of single-dose disulfiram toward human CYP2E1 in vivo is unknown. Because diethyldithiocarbamate also inhibits human liver CYP2A6 in vitro, this investigation explored the effect of single-dose disulfiram on human CYP2A6 activity in vivo.

Methods: CYP2A6 activity was assessed by the 7-hydroxylation of coumarin, which is catalyzed selectively by CYP2A6. Ten healthy volunteers received 50 mg oral coumarin on two occasions in a randomized crossover design, approximately 10 hours after 500 mg oral disulfiram was administered or after no pretreatment (control group). Plasma and urine 7-hydroxycoumarin and plasma coumarin concentrations were determined by HPLC.

Results: The area under the plasma 7-hydroxycoumarin versus time curve (2.69 0.90 g hr/ml) was not decreased after disulfiram pretreatment (3.33 0.93 g hr/ml). Furthermore, maximum plasma concentration (C_max) of 7-hydroxycoumarin (1.4 0.5 versus 1.8 0.6 g/ml) and time to reach C_max (1.0 0.2 and 1.0 0.4 hour) were unchanged by disulfiram pretreatment. Urinary 7-hydroxycoumarin excretion over a 24-hour period (38.9 10.8 mg) was also undiminished by disulfiram pretreatment (45.2 6.6 mg).

Conclusions: Single-dose disulfiram does not inhibit human CYP2A6 activity in vivo. When single-dose disulfiram is used as an in vivo probe for P450, inhibition of drug metabolism suggests involvement of CYP2E1 but not CYP2A6.