Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects.
OBJECTIVE
Short-term disulfiram administration has been shown to selectively inhibit CYP2E1 activity but the effects of chronic disulfiram administration on the activities of drug metabolizing enzymes is unclear. The purpose of this study was to evaluate the effects of disulfiram given for 11 days on selected drug metabolizing enzyme activities.


METHODS
Seven healthy volunteers were given disulfiram 250 mg daily for 11 days. Activities of the drug metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, CYP2E1 and N-acetyltransferase were determined using the probe drugs caffeine, mephenytoin, debrisoquine, chlorzoxazone, and dapsone, respectively. Chlorzoxazone was administered before disulfiram administration and after the second and eleventh doses of disulfiram, while the other probe drugs were given before disulfiram administration and after the eleventh disulfiram dose.


RESULTS
Disulfiram administration markedly inhibited chlorzoxazone 6-hydroxylation by more than 95%, but did not affect metabolism of debrisoquine or mephenytoin. Caffeine N3-demethylation was decreased by 34% (P < 0.05). Monoacetyldapsone concentrations were markedly elevated by disulfiram administration resulting in a nearly 16-fold increase in the dapsone acetylation index, calculated as the plasma concentration ratio of monoacetyldapsone to dapsone. CYP-mediated dapsone N-hydroxylation was not significantly altered.


CONCLUSIONS
These data suggest that disulfiram-mediated inhibition is predominantly selective for CYP2E1. The magnitude of CYP2E1 inhibition was similar after both acute and chronic disulfiram administration. The effects on caffeine N3-demethylation (CYP1A2) and dapsone metabolism suggest that chronic disulfiram administration may affect multiple drug metabolizing enzymes, which could potentially complicate the use of chronically administered disulfiram as a diagnostic inhibitor of CYP2E1.
Frye
Reginald F
RF
Department of Pharmaceutical Sciences, School of Pharmacy, 807 Salk Hall, University of Pittsburgh, Pittsburgh, PA 15261, USA. rfrye@pitt.edu
Branch
Robert A
RA
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology; D002753:Chlorzoxazone / Q000378:metabolism / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003622:Dapsone / Q000378:metabolism / Q000494:pharmacology; D003647:Debrisoquin / Q000378:metabolism / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008617:Mephenytoin / Q000378:metabolism / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D002110:Caffeine; D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D001191:Arylamine N-Acetyltransferase; D002753:Chlorzoxazone; D008617:Mephenytoin; D004221:Disulfiram; D003647:Debrisoquin