RT Journal Article
SR Electronic
T1 Lack of Single-Dose Disulfiram Effects on Cytochrome P-450 2C9, 2C19, 2D6, and 3A4 Activities: Evidence for Specificity Toward P-450 2E1
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 717
OP 723
VO 27
IS 6
A1 Kharasch, Evan D.
A1 Hankins, Douglas C.
A1 Jubert, Carole
A1 Thummel, Kenneth E.
A1 Taraday, Julie K.
YR 1999
UL http://dmd.aspetjournals.org/content/27/6/717.abstract
AB 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 μmol), and tolbutamide metabolite excretion (577 ± 157 versus 610 ± 208 μmol) 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. The American Society for Pharmacology and Experimental Therapeutics