Intravenous parecoxib rapidly leads to COX-2 inhibitory concentration of valdecoxib in the central nervous system.

Author(s): Mehta V, Johnston A, Cheung R, Bello A, Langford RM

Affiliation(s): Anaesthetic Laboratory, St Bartholomew's Hospital, London, UK. Vivek.mehta@mac.com

Publication date & source: 2008-03, Clin Pharmacol Ther., 83(3):430-5. Epub 2007 Aug 8.

Publication type: Comparative Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't

Evidence in animal studies supports widespread induction of cyclooxygenase-2 (COX-2) in the central nervous system (CNS) following tissue injury, probably mediated by cytokines, transducing the signal across the blood-brain barrier. CNS COX-2 blockade is a possible therapeutic target for drugs that are able to reach adequate CNS levels and abolish the prostaglandin E2-induced central sensitization. This human pharmacokinetic study investigated valdecoxib cerebrospinal fluid (CSF) and plasma concentrations over time in 37 patients following 40 mg of single-dose intravenous parecoxib. High-performance liquid chromatography/tandem mass spectrometry analysis was performed. Valdecoxib was first detectable in the CSF at 15 min postdosing, increased rapidly until 50 min, and thereafter remained between 6 and 14 ng/ml. This is the first human study demonstrating CNS COX-2 inhibitor penetration as early as 15 min. CSF valdecoxib concentration rapidly reached in vitro IC50 (inhibitory concentration 50) (1.57 ng/ml) by 17 min and remained consistently higher thereafter.