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Effects of Parecoxib, a Parenteral COX-2–Specific Inhibitor, on The

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Effects of Parecoxib, a Parenteral COX-2–Specific Inhibitor, on The Anesthesiology 2002; 96:88–95 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Effects of Parecoxib, a Parenteral COX-2– specific Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Propofol Andra Ibrahim, M.D.,* Sang Park, Ph.D.,† Jennifer Feldman, B.S.,‡ Aziz Karim, Ph.D.,§ Evan D. Kharasch, M.D., Ph.D.ʈ Background: Parecoxib, a cyclooxygenase-2–specific inhibi- ment, with intended use perioperatively as an analgesic tor with intended perioperative analgesic and antiinflamma- agent.1,2 Parecoxib may be administered preoperatively tory use, is a parenterally administered inactive prodrug under- going rapid hydrolysis in vivo to the active cyclooxygenase-2 or postoperatively for its analgesic and antiinflammatory inhibitor valdecoxib. Both parecoxib and valdecoxib inhibit effects. Both parenteral parecoxib and oral valdecoxib human cytochrome P450 2C9 (CYP2C9) activity in vitro. Thus, a have shown efficacy in pain relief that is similar to the Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/96/1/88/404640/0000542-200201000-00020.pdf by guest on 26 September 2021 potential exists for in vivo interactions with other CYP2C9 sub- currently available parenteral nonselective cyclooxygen- strates, including propofol. This investigation determined the ase inhibitor, ketorolac, and superior to placebo.3–5 influence of parecoxib on the pharmacokinetics and pharma- codynamics of bolus dose propofol in human volunteers. Moreover, parecoxib has significantly fewer side effects 1 Methods: This was a randomized, balanced crossover, place- (gastrointestinal, platelet aggregation) than ketorolac. bo-controlled, double-blind, clinical investigation. Twelve Parecoxib is a parenterally administered inactive pro- healthy 21- to 37-yr-old subjects were studied after providing drug that undergoes rapid amide hydrolysis in vivo to institutional review board–approved written informed consent. the pharmacologically active COX-2 inhibitor, valde- Each subject received a 2-mg/kg intravenous propofol bolus 1 h 2 after placebo (control) or 40 mg intravenous parecoxib on two coxib (fig. 1). Valdecoxib is metabolized primarily to occasions. Venous concentrations of propofol, parecoxib, and 1-hydroxyvaldecoxib, catalyzed by hepatic cytochrome parecoxib metabolites were determined by mass spectrometry. P450s (CYP) 2C9 and 3A4.6 Because valdecoxib is a Pharmacokinetic parameters were determined by noncompart- substrate for hepatic CYPs 2C9 and 3A4 and both pare- mental analysis. Pharmacodynamic measurements included coxib and valdecoxib are inhibitors of CYP2C9, there is clinical endpoints, cognitive function (memory, Digit-Symbol Sub- stitution Tests), subjective self-assessment of recovery (Visual An- a potential for parecoxib and valdecoxib interactions alog Scale) performed at baseline, 15, 30, 60 min after propofol, with other similarly metabolized drugs. The only com- and sedation depth measured by Bispectral Index. monly used anesthetic that undergoes significant metab- Results: Propofol plasma concentrations were similar be- olism by CYP2C9 is propofol.7 The first aim of this tween placebo- and parecoxib-treated subjects. No significant investigation was to determine the effect of parecoxib differences were found in pharmacokinetic parameters (Cmax, clearance, elimination half-life, volume of distribution) or phar- on the pharmacokinetics (systemic clearance) of propo- macodynamic parameters (clinical endpoints [times to: loss of fol, and the second aim was to determine the effect of consciousness, apnea, return of response to voice], Bispectral parecoxib on the pharmacodynamics (hypnotic effects, Index scores, Digit-Symbol Substitution Test scores, memory, hemodynamic response, and recovery profile) of Visual Analog Scale scores, propofol EC ). 50 propofol. 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. Methods PARECOXIB is a highly selective nonsteroidal cyclooxy- Participants genase-2 (COX-2) inhibitor undergoing clinical develop- Twelve healthy subjects (six men and six women; age, 29 Ϯ 5 yr) within 30% of normal body weight (75 Ϯ 13 kg) were studied after providing institutional review board– * Assistant Professor, † Research Scientist, ‡ Research Study Coordinator, De- approved written informed consent (University of Wash- partment of Anesthesiology, University of Washington. § Senior Director, Clin- ical Pharmacokinetics, Pharmacia, Inc., Peapack, New Jersey. ʈ Professor of ington, Seattle, WA). Individuals were excluded if they Anesthesiology and Medicinal Chemistry (Adjunct), Vice-Chair for Research, were pregnant, were taking benzodiazepines, barbiturates, Department of Anesthesiology, University of Washington. opioids, nonsteroidal antiinflammatory drugs (NSAIDs), or Received from the Department of Anesthesiology, University of Washington, Seattle, Washington, and Puget Sound Veteran’s Affairs Health Care System, drugs known to cause induction or inhibition of hepatic Seattle, Washington. Submitted for publication March 30, 2001. Accepted for enzymes, or were at risk for aspiration. Subjects fasted for publication August 29, 2001. Supported by Pharmacia, Inc., Peapack, New Jersey, and National Institutes of Health grant Nos. K24DA00417 and a minimum of 6 h before initiation of study. Sample size M01RR00037 (to the University of Washington General Clinical Research was determined using calculations based on interindividual Center). Presented in part annual meeting of the American Society of Anesthe- siologists, San Francisco, California, October 16, 2000. Dr. Kharasch has con- variability in propofol clearance because intraindividual sulted for Pharmacia, Inc. Aspect Medical Systems, Natick, Massachusetts, pro- variability was unknown. Power analysis using published vided the Bispectral Index monitor, cable, and software. propofol clearances suggested that a 25% difference in Address correspondence to Dr. Kharasch: Department of Anesthesiology, Box 356540, University of Washington, 1959 Northeast Pacific Street, RR-442 HSB, propofol clearance between placebo and parecoxib could Seattle, Washington 98195. Address electronic mail to: [email protected]. Reprints will not be available from the authors. Individual article reprints may be be detected with 80% power using 12 subjects, assuming purchased through the Journal Web site, www.anesthesiology.org. an estimated SD for the difference of 0.11. Anesthesiology, V 96, No 1, Jan 2002 88 PARECOXIB EFFECTS ON PROPOFOL DISPOSITION 89 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/96/1/88/404640/0000542-200201000-00020.pdf by guest on 26 September 2021 Fig. 1. Major metabolic pathways of parecoxib in humans in vivo. Study Design ard 5890 II-5972A MSD, Wilmington, DE) using a fully This was a randomized, balanced crossover, placebo- validated assay conducted according to Good Laboratory controlled, double-blind, clinical investigation. Each sub- Practice. Plasma (200 ␮l), 50 ␮l sodium hydroxide (1 M), ject served as his or her own control and underwent and 600 ␮l ethyl acetate-heptane (1:1) containing the physical and laboratory examination (hematology, bio- internal standard thymol (150 ng) were vortexed in a chemistry, urinalysis, hepatitis B surface antigen test, microcentrifuge tube and centrifuged (3 min at 1,400g), drug toxicology tests) both before the initiation and after and the upper organic layer was transferred to an au- the completion of the study. tosampler vial for analysis. After samples were intro- Subjects received a propofol (2 mg/kg intravenous) duced onto a 30 m ϫ 0.32 mm ϫ 0.25 ␮m DB-5 column bolus over 20 s on two occasions: 1 h after placebo (J & W, Folsom, CA) by splitless injection, chromatogra- (control) and 1 h after 40 mg intravenous parecoxib. phy was at a constant flow of 3 psi helium carrier gas. This dose and timing of parecoxib administration was Oven temperature was 50°C for 1 min and then in- selected to mimic intended clinical use (typically an creased to 120°Cat25°C/min, to 180°Cat10°C/min, hour before anesthetic induction). The sequence was and to 300° at 30°C/min and was then held for 1 min. randomized, and the two sessions were separated by The injector and transfer line temperatures were 240 7–14 days. Peripheral intravenous catheters were in- and 300°C, respectively. Detection (electron impact) serted in separate arms for drug administration and was with selected ion monitoring of propofol (m/z blood sampling. Supplemental oxygen and monitoring 163.1) and thymol (m/z 135.1). Propofol was quantified (electrocardiography, blood pressure, pulse oximetry) from integrated peak area ratios using calibration were provided for all subjects. An investigator adminis- standards in plasma (0.02–5.0 ␮g/ml). Coefficients of tered propofol and, if necessary, provided bag and mask variation were 8, 5, and 4% for interday and 6, 5, and ventilation while subjects were unconscious or apneic. 4% intraday quality control samples at 0.02, 0.5, and A trained independent observer, who was blinded to the 4 ␮g/ml. Accuracy and recovery were greater than 89% purpose of the investigation and the identity of the drug at all concentrations. The linear range was 0.02–5 ␮g/ml pretreatment, was present throughout the study period (r2 Ͼ 0.97), and the limit of quantitation was defined as to record hemodynamic and other effect data and to the
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