Absorption and distribution of etoricoxib in plasma, CSF, and wound tissue in patients following hip surgery--a pilot study

Abstract

The perioperative administration of selective cyclooxygenase-2 (COX-2)-inhibitors to avoid postoperative pain is an attractive option: they show favorable gastro-intestinal tolerability, lack inhibition of blood coagulation, and carry a low risk of asthmatic attacks. The purpose of this study was to determine the cerebrospinal fluid (CSF), plasma, and tissue pharmacokinetics of orally administered etoricoxib and to compare it with effect data, i.e., COX-2-inhibition in patients after hip surgery. The study was performed in a blinded, randomized, parallel group design. A total of 12 adult patients were included who received 120 mg etoricoxib (n = 8) or placebo (n = 4) on day 1 post-surgery. Samples from plasma, CSF, and tissue exudates were collected over a period of 24 h post-dosing and analyzed for etoricoxib and prostaglandin E(2) (PGE(2)) using liquid chromatography-tandem mass spectrometry and immuno-assay techniques. CSF area under the curve (AUC) [AUCs((O-24h))] for etoricoxib amounted to about 5% of the total AUC in plasma (range: 2-7%). Individual CSF lag times with respect to (50%) peak plasma concentration were </=2 h in all but one case (median: 1 h). PGE(2) production in tissue was significantly blocked by the COX-2 inhibitor starting with the appearance of etoricoxib in tissue and lasting for the whole observation period of 24 h (P < 0.01). In conclusion, etoricoxib reaches the CSF and site of surgery at effective concentrations and reduces PGE(2) production at the presumed site of action.

Figures

Fig. 1

Time course of etoricoxib and prostaglandin E2 (PGE2) concentrations in tissue exudates. PGE2 concentrations are shown as differences to baseline values. Sample times are midpoints of collection intervals (means ± SEM; placebo group n = 3; etoricoxib group n = 8). Absolute PGE2 concentrations and statistical data are given in Table 1

Fig. 2

Etoricoxib concentrations in three different matrixes (plasma, cerebrospinal fluid [CSF] and tissue exudates, semi logarithmical presentation). Not quantifiable concentrations were set to the LOQ of 0.2 ng/mL (means ± SEM; n = 8). Tissue exudate sampling times are midpoints of collection intervals. Note: it took about 2 h until tissue exudate reached the end of the Redon drain (sample recovery)

Fig. 3

a Plasma and cerebrospinal fluid (CSF) concentrations after administration of 120 mg etoricoxib orally to eight patients (linear presentation, means ± SEM). b Corresponding time course of individual and mean CSF/plasma concentration ratios indicating the relative etoricoxib penetration into the CSF; mean data (black) are based on complete data sets from five patients only, but all individual patient data (n = 8) are presented (patients data, gray); descriptive data are given in Table 3