Effect of voriconazole on the pharmacokinetics of diclofenac.
The nonsteroidal anti-inflammatory drug diclofenac is extensively metabolized by cytochrome P450 (CYP) enzymes, mainly by CYP2C9. Our objective was to study the effect of voriconazole, a potent inhibitor of several CYP enzymes, on the pharmacokinetics of diclofenac. This study had a two-way, open, crossover design and included 10 healthy Caucasian male subjects. In the control phase, the subjects ingested a single 50-mg oral dose of diclofenac. In the voriconazole phase, the subjects ingested voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, and 50 mg diclofenac was given 1 h after the last dose of voriconazole. Plasma diclofenac concentrations were determined for up to 24 h post-dose. In the voriconazole phase, the area under the plasma concentration-time curve of diclofenac was 178% (95% CI 143-212%; P < 0.001) and the peak plasma concentration was 214% (95% CI 128-300%; P < 0.05) of the respective control value. Voriconazole did not affect significantly the elimination half-life or time to maximum concentration of diclofenac. The renal clearance of diclofenac was decreased by 47% (95% CI -76% to -16%; P < 0.01) by voriconazole. In conclusion, voriconazole increased exposure to diclofenac, probably mainly by inhibition of its cytochrome P450 (CYP)-mediated metabolism. The inhibition of CYP2C9, and to some extent that of CYP3A4 and CYP2C19 enzymes during the first-pass metabolism of diclofenac seems to be involved in the interaction. The clinical importance of the interaction between voriconazole and diclofenac remains to be studied, but lower doses of diclofenac may be adequate for patients receiving voriconazole.
Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Turku University Hospital, Turku, Finland. vilhyn@utu.fi
Ville-Veikko
VV
Hynninen
Klaus T
KT
Olkkola
Kari
K
Leino
Stefan
S
Lundgren
Pertti J
PJ
Neuvonen
Anders
A
Rane
Mika
M
Valtonen
Kari
K
Laine
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D004008:Diclofenac; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D065819:Voriconazole