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

Abstract

Disulfiram and its primary metabolite diethyldithiocarbamate are effective mechanism-based inhibitors of cytochrome P-450 2E1 (CYP2E1)1 in vitro. Single-dose disulfiram diminishes CYP2E1 activity in vivo and has been used to identify CYP2E1 participation in human drug metabolism and prevent CYP2E1-mediated toxification. Specificity of single-dose disulfiram toward CYP2E1 in vivo, however, remains unknown. This investigation determined single-dose disulfiram effects on human CYP 2C9, 2C19, 2D6, and 3A4 activities in vivo. In four randomized crossover experiments, volunteers received isoform-selective probes (oral tolbutamide, mephenytoin, dextromethorphan, or i.v. midazolam) on two occasions, 10 h after oral disulfiram or after no pretreatment (controls). Plasma and/or urine parent and/or metabolite concentrations were measured by HPLC or gas chromatography-mass spectrometry. CYP2C9, 2C19, 2D6, and 3A4 activities were determined from the tolbutamide metabolic ratio, 4'-hydroxymephenytoin excretion, and dextromethorphan/dextrorphan ratios in urine and midazolam systemic clearance, respectively. Midazolam clearance (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 micromol), and tolbutamide metabolite excretion (577 +/- 157 versus 610 +/- 208 micromol) were not significantly altered by disulfiram pretreatment, although the tolbutamide metabolic ratio was slightly diminished after disulfiram (60 +/- 17 versus 81 +/- 40, p <.05). Results show that single-dose disulfiram does not cause clinically significant inhibition of human CYP2C9, 2C19, 2D6, and 3A4 activities in vivo. When single-dose disulfiram is used as an in vivo probe for P-450, inhibition of drug metabolism suggests selective involvement of CYP2E1. Single-dose disulfiram should not cause untoward drug interactions from inhibition of other P-450 isoforms.