The influence of parecoxib, a parenteral cyclooxygenase-2 specific inhibitor, on the pharmacokinetics and clinical effects of midazolam.
Parecoxib, a parenteral cyclooxygenase-2 inhibitor, is undergoing clinical development as an analgesic/antiinflammatory drug for perioperative use. Parecoxib, an inactive prodrug, is hydrolyzed in vivo to valdecoxib, a substrate for hepatic cytochrome P450 (CYP) 3A4. Thus, potential exists for interactions with other CYP3A4 substrates. In this investigation, we determined the influence of parecoxib on the pharmacokinetics and clinical effects of midazolam, a CYP3A4 substrate, in volunteers. This was a randomized, balanced crossover, placebo-controlled, double-blinded clinical investigation. Twelve healthy subjects aged 23-41 yr were studied after providing IRB-approved informed consent. Midazolam 0.07 mg/kg IV infusion was administered 1 h after placebo (control) or parecoxib 40 mg IV. Venous midazolam concentrations were determined by using liquid chromatography-mass spectrometry/mass spectrometry assay. Pharmacokinetic variables were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical end-points, cognitive function (memory; digit symbol substitution tests), subjective self-assessment of recovery (visual analog scales), and bispectral index. Midazolam plasma concentrations were similar between placebo and parecoxib-treated subjects. No differences were found in midazolam pharmacokinetics (maximal observed plasma concentration, clearance, elimination half-life, volume of distribution) or pharmacodynamics (clinical end-points, digit symbol substitution tests, memory, visual analog scales, bispectral index). Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam infusion. Parecoxib did not affect CYP3A4 activity as assessed using midazolam clearance as the in vivo probe.


CONCLUSIONS
Parecoxib, a parenteral cyclooxygenase-2 inhibitor intended for perioperative use as an analgesic/antiinflammatory drug, is a substrate for hepatic cytochrome P450 3A4. The potential for a drug interaction with midazolam, an in vivo CYP3A4 probe, was tested in healthy volunteers. Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam.
Department of Anesthesiology, University of Washington, 1959 NE Pacific, Seattle, WA 98195, USA.
Andra
A
Ibrahim
Aziz
A
Karim
Jennifer
J
Feldman
Evan
E
Kharasch
D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009325:Nausea / Q000139:chemically induced; D012018:Reflex / Q000187:drug effects; D014839:Vomiting / Q000139:chemically induced
D016861:Cyclooxygenase Inhibitors; D006993:Hypnotics and Sedatives; D007555:Isoxazoles; D003577:Cytochrome P-450 Enzyme System; C409945:parecoxib; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam