Premium
Validation of incorporating flurbiprofen into the Pittsburgh cocktail
Author(s) -
Zgheib Nathalie K.,
Frye Reginald F.,
Tracy Timothy S.,
Romkes Marjorie,
Branch Robert A.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.06.005
Subject(s) - mephenytoin , flurbiprofen , chlorzoxazone , debrisoquine , pharmacology , crossover study , paraxanthine , cyp1a2 , metabolite , pharmacokinetics , cyp2d6 , chemistry , medicine , cyp2c19 , placebo , cytochrome p450 , cyp2e1 , metabolism , alternative medicine , pathology
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