Validation of incorporating flurbiprofen into the Pittsburgh cocktail*

Zgheib, Nathalie K.; Frye, Reginald F.; Tracy, Timothy S.; Romkes, Marjorie; Branch, Robert A.
September 2006
Clinical Pharmacology & Therapeutics;Sep2006, Vol. 80 Issue 3, p257
Academic Journal
Background: We have previously shown that flurbiprofen metabolism to 4′-hydroxyflurbiprofen provides an in vivo measure of cytochrome P450 (CYP) 2C9 activity. This study evaluated the possibility of incorporating flurbiprofen into the current 5-drug Pittsburgh cocktail.Methods: In a randomized, 3-way, Latin-square, crossover-design study, 24 healthy subjects (mean age [±SD], 47.8 ± 15.1 years) received flurbiprofen (50 mg) and the Pittsburgh 5-drug cocktail (100 mg caffeine, 100 mg mephenytoin, 10 mg debrisoquin [INN, debrisoquine], 250 mg chlorzoxazone, and 100 mg dapsone) separately and in combination on 3 occasions over a period of 5 weeks. Urine was collected from 0 to 8 hours, and plasma was obtained at 4 and 8 hours after drug administration. Parent drug and metabolite concentrations were measured to determine phenotypic indices for each of the metabolizing enzymes.Results: The geometric mean ratio and 90% confidence interval of the phenotypic indices were included within the 80% to 125% bioequivalence range for each of the probe drugs. There were no statistically significant differences between the phenotypic indices determined after administration of the 5-drug and 6-drug cocktails. However, there was a small but statistically significant increase (7.5%, P = .03) in the 8-hour urinary flurbiprofen recovery ratio after administration of the 6-drug cocktail compared with that after administration of flurbiprofen alone. The 6-drug cocktail was well tolerated.Conclusion: The results of this study show that caffeine (CYP1A2), chlorzoxazone (CYP2E1), dapsone (N-acetyltransferase 2), debrisoquin (CYP2D6), flurbiprofen (CYP2C9), and mephenytoin (CYP2C19) can be simultaneously administered in low doses without metabolic interaction.Clinical Pharmacology & Therapeutics (2006) 80, 257–263; doi: 10.1016/j.clpt.2006.06.005


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