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PII‐37
Author(s) -
Zgheib N.,
Frye R.,
Tracy T.,
Romkes M.,
Branch R.
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.2005.12.162
Subject(s) - flurbiprofen , debrisoquine , pharmacology , cyp2c9 , drug , chlorzoxazone , pharmacokinetics , mephenytoin , metabolite , medicine , active metabolite , caffeine , drug interaction , chemistry , cyp2d6 , metabolism , cytochrome p450 , cyp2c19 , cyp2e1
BACKGROUND We have previously shown that flurbiprofen (F) metabolism to 4′‐hydroxy‐flurbiprofen (OH‐F) provides an in vivo measure of CYP2C9 activity. The fractional metabolic clearance to OH‐F is closely associated with the flurbiprofen recovery ratio (FRR= OH‐F/OH‐F+F)(r=0.8488, p<0.0001, N=12). This study evaluates the possibility of incorporating flurbiprofen to the currently validated five‐drug Pittsburgh cocktail. METHODS In a three‐way cross‐over design with randomized order of drug administration, 12 healthy subjects (age ± SD, 29.9 ± 6.6) were enrolled. Each subject received F (50mg) and the Pittsburgh five‐drug cocktail (caffeine 100mg, mephenytoin 100mg, debrisoquine 10mg, chlorzoxazone 250mg, dapsone 100mg) separately and in combination on three occasions over five 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 the metabolizing enzymes. RESULTS There were no statistically significant differences in any of the indices, whether assessed as part of the five‐drug cocktail, six‐drug cocktail, or in the case of flurbiprofen, individually. The percentage change of the trait measures observed is illustrated below. The six‐drug cocktail was well tolerated. CONCLUSION The results show that flurbiprofen can be administered within the validated Pittsburgh cocktail without interaction to provide a measure of CYP2C9 activity. Clinical Pharmacology & Therapeutics (2005) 79 , P46–P46; doi: 10.1016/j.clpt.2005.12.162