Validation of incorporating flurbiprofen into the Pittsburgh cocktail.
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.


CONCLUSIONS
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.
Zgheib
Nathalie K
NK
Center for Clinical Pharmacology, University of Pittsburgh, Pittsburgh, PA 15219-3138, USA.
Frye
Reginald F
RF
Tracy
Timothy S
TS
Romkes
Marjorie
M
Branch
Robert A
RA
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002753:Chlorzoxazone / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003622:Dapsone / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D003647:Debrisoquin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005480:Flurbiprofen / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008617:Mephenytoin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged
D007527:Isoenzymes; D002110:Caffeine; D005480:Flurbiprofen; D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D002753:Chlorzoxazone; D008617:Mephenytoin; D003647:Debrisoquin