A convenient five-drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study.
OBJECTIVE
To assess the feasibility of administering at the same time low doses of five probe drugs, metoprolol (25 mg), chlorzoxazone (250 mg), tolbutamide (250 mg), dapsone (100 mg) and caffeine (100 mg) to determine simultaneously the activities of CYP2D6, CYP2E1, CYP2C9, CYP3A4, CYP1A2, N-acetyltransferase-2 and xanthine oxidase.


METHODS
Ten healthy young non-smoking males received the following drugs or combinations of drugs over a 5-week period: week 1) metoprolol; 2) tolbutamide; 3) caffeine, chlorzoxazone and dapsone; 4) caffeine, chlorzoxazone, dapsone and metoprolol; 5) caffeine, chlorzoxazone, dapsone, metoprolol and tolbutamide. The drugs were self-administered at bedtime and urine was collected for the following 8 h.


RESULTS
Mean molar phenotypic ratios obtained after administering metoprolol (mean change of -11%) or tolbutamide (mean change of -0.3%) alone, were not significantly different from those obtained when other drugs were co-administered (P > 0.05). The mean within-subject coefficients of variation were 33%, 18%, 22%, 13%, 16%, 13% and 5% for CYP3A4, CYP2D6, CYP2C9, CYP2E1, CYP1A2, N-acetyltransferase 2 and xanthine oxidase metabolic ratios, respectively. No significant interactions (P > 0.5) were observed during the simultaneous administration of various combinations of the five probe drugs.


CONCLUSIONS
We propose that this cocktail, composed of five widely available drugs, constitutes a promising means of simultaneously determining the activities of the major CYP enzymes in large populations.
The Québec Heart and Lung Institute, Laval Hospital, Québec, Canada. ashish.sharma@biovail.com
Ashish
A
Sharma
Sylvie
S
Pilote
Pierre M
PM
Bélanger
Marie
M
Arsenault
Bettina A
BA
Hamelin
D000328:Adult; D002110:Caffeine / Q000494:pharmacology*; D002753:Chlorzoxazone / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D003622:Dapsone / Q000494:pharmacology*; D004338:Drug Combinations; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D010629:Phenformin / Q000494:pharmacology*; D010865:Pilot Projects; D014044:Tolbutamide / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D002110:Caffeine; D002753:Chlorzoxazone; D003577:Cytochrome P-450 Enzyme System; D003622:Dapsone; D004338:Drug Combinations; D008790:Metoprolol; D010629:Phenformin; D014044:Tolbutamide; C012065:tolbutaphen; D000096926:Benzenesulfonamides