Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail"

Background: Simultaneous administration of several probes enhances the util ity of phenotyping, but poor specificity, side effects, and use of drugs no t approved by the Food and Drug Administration limit the usefulness of prio r phenotyping cocktails. Objectives: To evaluate potential drug-drug interactions associated with us e of a cocktail of caffeine, omeprazole, dextromethorphan, and midazolam fo r simultaneous phenotyping of CYP1A2, CYP2C19, CYP2D6, CYT3A, N-acetyltrans ferase-2, and xanthine oxidase. Methods: Twelve subjects received caffeine + dextromethorphan, omeprazole, and midazolam (each alone), and a cocktail of caffeine + dextromethorphan omeprazole + midazolam. Blood samples were collected at 120 minutes for om eprazole and 5/-hydroxyomeprazole, and at 0, 5, 30, 60, 120, 240, 300, and 360 minutes for midazolam. Twelve-hour mine samples were collected for anal ysis of dextromethorphan, caffeine, and metabolites. Results: The median CYP1A2 metabolic ratio after administration of caffeine + dextromethorphan was not significantly different from that obtained with the cocktail (P = .84). Likewise, the median N-acetyltransferase-2, xanthi ne oxidase, and CYP2D6 metabolic ratios were not significantly different af ter cocktail administration (P = .977 for each N-acetyltransferase-2; P = . 795 for xanthine oxidase; P = .75 for CYP2D6). The median CYP2C19 metabolic ratio after cocktail administration was not significantly different from t hat obtained after omeprazole administered alone (P = 1.000). Also, midazol am plasma clearance was not significantly different after cocktail administ ration compared with that after administration of midazolam alone (P = .708 ). The only side effect was sedation, which was associated with intravenous midazolam and occurred to a similar extent after both individual and cockt ail phenotyping. Conclusions: These results indicate no pharmacokinetic or pharmacodynamic i nteractions that would limit the utility of this phenotyping cocktail for s imultaneous measurement of the activity of multiple drug- metabolizing enzy mes.