Lack of single-dose disulfiram effects on cytochrome P-4502C9, 2C19, 2D6, and 3A4 activities: Evidence for specificity toward P-450 2E1

Disulfiram and its primary metabolite diethyldithiocarbamate are effective mechanism-based inhibitors of cytochrome P-450 2E1 (CYPPE1)(1) in vitro. Si ngle-dose disulfiram diminishes CYPPE1 activity in vivo and has been used t o identify CYP2E1 participation in human drug metabolism and prevent CYP2E1 -mediated toxification. Specificity of single-dose disulfiram toward CYPPE1 in vivo, however, remains unknown. This investigation determined single-do se disulfiram effects on human CYP 2C9, 2C19, 2D6, and 3A4 activities in vi vo. In four randomized crossover experiments, volunteers received isoform-s elective probes (oral tolbutamide, mephenytoin, dextromethorphan, or i.v. m idazolam) on two occasions, 10 h after oral disulfiram or after no pretreat ment (controls). Plasma and/or urine parent and/or metabolite concentration s were measured by HPLC or gas chromatography-mass spectrometry. CYP2C9, 2C 19, 2D6, and 3A4 activities were determined from the tolbutamide metabolic ratio, 4'-hydroxymephenytoin excretion, and dextromethorphan/dextrorphan ra tios in urine and midazolam systemic clearance, respectively. Midazolam cle arance (670 +/- 190 versus 700 +/- 240 ml/min, disulfiram versus controls), dextromethorphan/dextrorphan metabolic ratio (0.013 +/- 0.033 versus 0.015 +/- 0.035), 4'-hydroxymephenytoin excretion (122 +/- 22 Versus 128 +/- 25 mu mol), and tolbutamide metabolite excretion (577 +/- 157 versus 610 +/- 2 08 pmol) were not significantly altered by disulfiram pretreatment, althoug h:the tolbutamide metabolic ratio was slightly diminished after disulfiram (60 +/- 17 versus 81 +/- 40, p < .05). Results show that single-dose disulf iram does not cause clinically significant inhibition of human CYP2C9, 2C19 , 2D6, and 3A4 activities in vivo. When single-dose disulfiram is used as a n in vivo probe for P-450, inhibition of drug metabolism suggests selective involvement of CYPPE1. Single-dose disulfiram should not cause untoward dr ug interactions from inhibition of other P-450 isoforms.