A convenient five‐drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study

• Published in: British journal of clinical pharmacology Vol. 58; no. 3; pp. 288 - 297
• Main Authors: Sharma, Ashish, Pilote, Sylvie, Bélanger, Pierre M., Arsenault, Marie, Hamelin, Bettina A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.09.2004; Blackwell Science; Blackwell Science Inc
• Subjects: Adult; Biological and medical sciences; caffeine; Caffeine - pharmacology; chlorzoxazone; Chlorzoxazone - pharmacology; cocktail; CYP1A2; CYP2C9; CYP2D6; CYP2E1; CYP3A4; Cytochrome P-450 Enzyme System - drug effects; cytochrome P450s; dapsone; Dapsone - pharmacology; Drug Combinations; Drug Metabolism; General pharmacology; Humans; Male; Medical sciences; metoprolol; Metoprolol - pharmacology; N‐acetyltransferase; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Phenformin - pharmacology; Pilot Projects; tolbutamide; Tolbutamide - pharmacology; Sulfone; Isozyme; Dapsone; CYP3A4; Chlorzoxazone; β1-Adrenergic receptor; CYP2D6; cocktail; Xanthine derivatives; Antagonist; Caffeine; Human; Drug combination; Metoprolol; Healthy subject; Enzyme; Cytochrome P450; cytochrome P450s; Tolbutamide; CYP2C9; Sulfonylureas; CYP1A2; Drug-metabolizing enzyme; N- acetyltransferase; CYP2E1; Beta blocking agent
• DOI: 10.1111/j.1365-2125.2004.02162.x
• ISSN: 0306-5251

Aims 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.