title: Cerebrospinal fluid and plasma pharmacokinetics of the cyclooxygenase 2 inhibitor rofecoxib in humans: single and multiple oral drug administration.
abstract: 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.
authors.affiliation: *Department of Anesthesiology, Rush Medical College at Rush University Medical Center, Chicago, Illinois; and †Merck Frosst Canada, Kirkland, Quebec, Canada.
authors.forename: Asokumar
authors.initials: A
authors.lastname: Buvanendran
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kroin
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Tuman
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Lubenow
authors.forename: Dalia
authors.initials: D
authors.lastname: Elmofty
authors.forename: Pauline
authors.initials: P
authors.lastname: Luk
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D013450:Sulfones / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib