Effects of parecoxib, a parenteral COX-2-specific inhibitor, on the pharmacokinetics and pharmacodynamics of propofol.
BACKGROUND
Parecoxib, a cyclooxygenase-2-specific inhibitor with intended perioperative analgesic and antiinflammatory use, is a parenterally administered inactive prodrug undergoing rapid hydrolysis in vivo to the active cyclooxygenase-2 inhibitor valdecoxib. Both parecoxib and valdecoxib inhibit human cytochrome P450 2C9 (CYP2C9) activity in vitro. Thus, a potential exists for in vivo interactions with other CYP2C9 substrates, including propofol. This investigation determined the influence of parecoxib on the pharmacokinetics and pharmacodynamics of bolus dose propofol in human volunteers.


METHODS
This was a randomized, balanced crossover, placebo-controlled, double-blind, clinical investigation. Twelve healthy 21- to 37-yr-old subjects were studied after providing institutional review board-approved written informed consent. Each subject received a 2-mg/kg intravenous propofol bolus 1 h after placebo (control) or 40 mg intravenous parecoxib on two occasions. Venous concentrations of propofol, parecoxib, and parecoxib metabolites were determined by mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical endpoints, cognitive function (memory, Digit-Symbol Substitution Tests), subjective self-assessment of recovery (Visual Analog Scale) performed at baseline, 15, 30, 60 min after propofol, and sedation depth measured by Bispectral Index.


RESULTS
Propofol plasma concentrations were similar between placebo- and parecoxib-treated subjects. No significant differences were found in pharmacokinetic parameters (Cmax, clearance, elimination half-life, volume of distribution) or pharmacodynamic parameters (clinical endpoints [times to: loss of consciousness, apnea, return of response to voice], Bispectral Index scores, Digit-Symbol Substitution Test scores, memory, Visual Analog Scale scores, propofol EC(50)).


CONCLUSIONS
Single-bolus parecoxib, in doses to be used perioperatively, does not alter the disposition or the magnitude or time course of clinical effects of bolus propofol. Effects on a propofol infusion were not evaluated.
Ibrahim
Andra
A
Department of Anesthesiology, University of Washington, Seattle, 98195, USA.
Park
Sang
S
Feldman
Jennifer
J
Karim
Aziz
A
Kharasch
Evan D
ED
D000328:Adult; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004311:Double-Blind Method; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D015742:Propofol / Q000493:pharmacokinetics*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000502:physiology
D018686:Anesthetics, Intravenous; D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D003577:Cytochrome P-450 Enzyme System; C409945:parecoxib; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D015742:Propofol