Abstract ID: A20
Abstract Title: HUMAN BLOOD-BRAIN-BARRIER PENETRATION OF ORAL ROFECOXIB, A SELECTIVE CYCLOOXYGENASE-2 (COX-2) INHIBITOR: A SINGLE DOSE PHARMACOKINETIC STUDY
Poster Type: Discussion
ABSTRACT BODY
Introduction:Injection of complete Freund’s adjuvant in the rat paw leads to hyperalgesia and a large increase in COX-2 mRNA levels in the lumbar spinal cord within a few hours post-injection (1). In animal models of pain, intrathecal COX-2 inhibitors can reduce hyperanalgesia (1,2). The analgesic efficacy of an oral COX-2 inhibitor may be related to blood-brain-barrier penetration (3). Rofecoxib is a selective COX-2 inhibitor that is effective orally for arthritic and acute postoperative pain. The administration of rofecoxib before and after knee surgery has been shown to improve outcome (4). When given orally to rats, rofecoxib levels in the cerebrospinal fluid (CSF) were between 19-35% of the plasma level (5). The purpose of this study is to investigate the blood-brain-barrier penetration of this compound when administered orally to patients.
Materials and Methods: Following IRB approval and informed consent, 7 patients with intrathecal pumps implanted for chronic pain were recruited. None of the patients were taking any COX- inhibitors. Simultaneous CSF (100 mL) and plasma (500 mL) samples were obtained (baseline). The CSF sample was obtained using the side port assess kit under sterile conditions. A single 50 mg tablet of rofecoxib was administered orally and plasma and CSF samples were obtained at 1, 2, 4, 6, 8, 10 and 24 hours post-rofecoxib administration. Rofecoxib concentrations were assayed by quantitative HPLC.
Results:The time course of rofecoxib concentration in CSF and plasma, along with the CSF/plasma concentration ratio are shown in Fig. 1. The peak concentration in both CSF and plasma occurs at approximately 4 h after drug administration. The plasma Cmax = 0.293 mg/ml and the CSF Cmax = 0.0446 mg/ml. The mean ratio of AUCcsf/AUCpl calculated over a 24-hour period is 0.144.
Discussion:Following oral administration of a single 50 mg dose the amount of rofecoxib in the CSF is 14.4% of that in plasma when measured over a 24 hour time period. This relatively good blood-brain-barrier penetration of rofecoxib in humans is consistent with the likehood that, similar to animals, human spinal COX-2 inhibition contributes to analgesia.
References:(1) Nature 2001; 410:471.(2) Reg Anesth Pain Med 2002; 27: 451-455.(3) J Neurosci 2001:21:5847.(4) JAMA 2003; 290: 2411-18(5) Anesthesiology 2001;95: A868.
ATTACHED FILES
A20_Pharmacokinetics PP 7 patients.ppt
Reg Anesth Pain Med 2004; 29(2):A20