Evaluation of flurbiprofen urinary ratios as in vivo indices for CYP2C9 activity

Br J Clin Pharmacol. 2007 Apr;63(4):477-87. doi: 10.1111/j.1365-2125.2006.02781.x. Epub 2006 Oct 19.


Aims: We investigated flurbiprofen pharmacokinetics in 12 volunteers to develop a phenotypic trait measure that correlates with the fractional clearance to 4'-hydroxyflurbiprofen. The effect of the CYP2C9 inhibitor fluconazole on flurbiprofen metabolism was also evaluated.

Methods: Flurbiprofen pharmacokinetics were evaluated before and after the first and seventh doses of fluconazole. The urinary recovery ratio was calculated as FLRR = 4'-OHF/[4'-OHF + F(tot)] and the urinary metabolic ratio was calculated as FLMR = 4'-OHF/F(tot), where 4'-OHF and F(tot) represent total (conjugated and unconjugated) amounts recovered in urine.

Results: There was a statistically significant relationship between the 4'-OHF formation clearance (4OHCLf) and both the 8-h FLRR and the 8-h FLMR with and without administration of fluconazole. The flurbiprofen apparent oral clearance (CL/F) was decreased by 53% [90% confidence interval (CI) -58, -48] and 64% (90% CI -69, -59), respectively, after administration of one and seven doses of fluconazole when compared with administration of flurbiprofen alone; similarly, the 4OHCLf decreased by 69% (90% CI -74, -64) and 78% (90% CI -83, -73), the 8-h FLRR decreased by 35% (90% CI -41, -29) and 40% (90% CI -46, -35) and the 8-h FLMR decreased by 61% (90% CI -65, -58) and 67% (90% CI -70, -63). The magnitude of decrease in CL/F and 4OHCLf was greater after seven doses compared with after one dose of fluconazole (P < 0.005).

Conclusions: This study provides strong evidence that both the 8-h FLRR and the 8-h FLMR are suitable phenotypic indices for CYP2C9 activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adult
  • Antifungal Agents / pharmacology*
  • Biomarkers / metabolism
  • Cytochrome P-450 Enzyme System / metabolism*
  • Female
  • Fluconazole / pharmacology*
  • Flurbiprofen / pharmacokinetics
  • Flurbiprofen / urine*
  • Genotype
  • Humans
  • Male
  • Phenotype


  • Antifungal Agents
  • Biomarkers
  • Flurbiprofen
  • Fluconazole
  • Cytochrome P-450 Enzyme System