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ANESTHETIC PHARMACOLOGY

Cerebrospinal Fluid and Plasma Pharmacokinetics of the Cyclooxygenase 2 Inhibitor Rofecoxib in Humans: Single and Multiple Oral Drug Administration

Asokumar Buvanendran, MD^*, Jeffrey S. Kroin, PhD^*, Kenneth J. Tuman, MD^*, Timothy R. Lubenow, MD^*, Dalia Elmofty, MD^*, and Pauline Luk, BS

*Department of Anesthesiology, Rush Medical College at Rush University Medical Center, Chicago, Illinois; and Merck Frosst Canada, Kirkland, Quebec, Canada

Address correspondence and reprint requests to Asokumar Buvanendran, MD, Department of Anesthesiology, 1653 W. Congress Pkwy., Rush University Medical Center, Chicago, IL 60612. Address e-mail to Asokumar{at}aol.com.

Cerebrospinal fluid (CSF) pharmacokinetics of orally administered cyclooxygenase 2 inhibitors, with single or multiple dosing, is of clinical relevance because it may relate to the analgesic efficacy of these drugs. We enrolled 9 subjects with implanted intrathecal catheters in the study. After 50-mg oral rofecoxib administration, the CSF drug concentration lagged slightly behind the plasma drug concentration. The ratio of the 24-h area under the drug-concentration curve (AUC) in CSF to plasma was 0.142. After daily dosing of rofecoxib 50 mg/d for 9 days, rofecoxib concentrations in plasma and CSF were larger on Day 9 than on Day 1, with the 24-h AUC on Day 9 more than twice the Day 1 AUC for both plasma and CSF. After nine consecutive daily doses of rofecoxib, the AUC_CSF/AUC_plasma ratio was 0.159. The important findings of this study are that CSF rofecoxib levels are approximately 15% of plasma levels and that repeated daily dosing more than doubles the AUC in CSF.

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