Valdecoxib does not interfere with the CYP2D6 substrate metoprolol.
OBJECTIVE
We reported recently that celecoxib inhibits the metabolism of the cytochrome P450 (CYP)2D6 substrate metoprolol in volunteers. Valdecoxib, the active metabolite of parecoxib, has also been claimed to interfere with the metabolism of CYP2D6 substrates. However, little support for this contention is available despite the intensive use of parecoxib in the perioperative setting. Therefore, the objective of this study was to examine the effect of valdecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol.


METHODS
An open, randomized, 3-period crossover study was performed in 15 healthy male volunteers. Metoprolol (50 mg) was given in all 3 periods without, or following a 7-day pre-treatment with valdecoxib (20 mg, o.d.) or rofecoxib (25 mg, o.d.), to achieve steady state conditions of COX-2 inhibitors in Periods 2 and 3. In a small group of extensive metabolizers (EM/EM), short-term application of twice the dose was investigated.


RESULTS
No effect of valdecoxib (20 mg/d) or rofecoxib (25 mg/d) were detected on the area under the plasma concentration-time curve of metoprolol (323 +/- 333 to 324 +/- 296 or 309 +/- 256 microg x h/l) or at a higher dose. No significant changes of pharmacokinetic or pharmacodynamic parameters of metoprolol were apparent.


CONCLUSIONS
We conclude that, at therapeutic doses, valdecoxib and rofecoxib do not influence the CYP2D6 substrate metoprolol.
Werner
U
U
Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University of Erlangen-Nuremberg, Germany. ulrike-werner@arcor.de
Lamprecht
C
C
Werner
D
D
Schaefer
S
S
Wuttke
H
H
Hinz
B
B
Fromm
M F
MF
Brune
K
K
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018592:Cross-Over Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D019389:Cytochrome P-450 CYP2D6; D007555:Isoxazoles; D007783:Lactones; D008790:Metoprolol; D011355:Prodrugs; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; C406224:valdecoxib; D000096926:Benzenesulfonamides