Intravenous parecoxib rapidly leads to COX-2 inhibitory concentration of valdecoxib in the central nervous system.
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.
Anaesthetic Laboratory, St Bartholomew's Hospital, London, UK. Vivek.mehta@mac.com
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V
Mehta
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Johnston
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R
Cheung
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Bello
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RM
Langford
D000368:Aged; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D013997:Time Factors; D000096926:Benzenesulfonamides
D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D013449:Sulfonamides; C406224:valdecoxib; D000096926:Benzenesulfonamides; C409945:parecoxib; C496540:PTGS2 protein, human