Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail".
Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO.
Department of Medicine, Bassett Healthcare, Cooperstown, NY 13326, USA.
Siwaporn
S
Chainuvati
Anne N
AN
Nafziger
J Steven
JS
Leeder
Andrea
A
Gaedigk
Gregory L
GL
Kearns
Edward
E
Sellers
Yanhua
Y
Zhang
Angela D M
AD
Kashuba
Elizabeth
E
Rowland
Joseph S
JS
Bertino
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan; D004338:Drug Combinations; D005838:Genotype; D006801:Humans; D008874:Midazolam; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009853:Omeprazole; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors; D015203:Reproducibility of Results; D014815:Vitamins / Q000493:pharmacokinetics; D014859:Warfarin; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D004338:Drug Combinations; D010726:Phosphodiesterase Inhibitors; D014815:Vitamins; D002110:Caffeine; D014859:Warfarin; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D014969:Xanthine Oxidase; D010089:Oxidoreductases, N-Demethylating; D000123:Acetyltransferases; D009853:Omeprazole; D008874:Midazolam