caa a22 4500 47581911X CHVBK 20180406123817.0 cr unu---uuuuu 170329e20000501xx s 000 0 eng 10.1007/s002280050736 doi (NATIONALLICENCE)springer-10.1007/s002280050736 Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans [Elektronische Daten] [M. Depré, E. Ehrich, A. Van Hecken, I. De Lepeleire, A. Dallob, P. Wong, A. Porras, B. J. Gertz, P. J. De Schepper] Objective: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (VioxxTM), characterized in vitro as a COX-2 inhibitor. Methods: Four panels of healthy men (n=8 per panel) were administered rofecoxib (n=6) (25, 100, 250, 375 mg) or placebo (n=2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose. Results: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient. Conclusion: The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis. Springer-Verlag Berlin Heidelberg, 2000 Key words Rofecoxib nationallicence Pharmacokinetics nationallicence COX-2 specificity nationallicence Depré M. Centre of Clinical Pharmacology, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium e-mail: Marleen.Depre@uz.kuleuven.ac.be Tel.: +32-16-348602; Fax: +32-16-348601, BE aut Ehrich E. Merck and Co., Inc., Rahway NJ, USA, US aut Van Hecken A. Centre of Clinical Pharmacology, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium e-mail: Marleen.Depre@uz.kuleuven.ac.be Tel.: +32-16-348602; Fax: +32-16-348601, BE aut De Lepeleire I. Merck and Co., Inc., Brussels, Belgium, BE aut Dallob A. Merck and Co., Inc., Rahway NJ, USA, US aut Wong P. Merck and Co., Inc., Rahway NJ, USA, US aut Porras A. Merck and Co., Inc., Rahway NJ, USA, US aut Gertz B. J. Merck and Co., Inc., Rahway NJ, USA, US aut De Schepper P. J. Centre of Clinical Pharmacology, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium e-mail: Marleen.Depre@uz.kuleuven.ac.be Tel.: +32-16-348602; Fax: +32-16-348601, BE aut https://doi.org/10.1007/s002280050736 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050736 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Depré M. Centre of Clinical Pharmacology, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium e-mail: Marleen.Depre@uz.kuleuven.ac.be Tel.: +32-16-348602; Fax: +32-16-348601, BE aut NATIONALLICENCE 700 1- Ehrich E. Merck and Co., Inc., Rahway NJ, USA, US aut NATIONALLICENCE 700 1- Van Hecken A. Centre of Clinical Pharmacology, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium e-mail: Marleen.Depre@uz.kuleuven.ac.be Tel.: +32-16-348602; Fax: +32-16-348601, BE aut NATIONALLICENCE 700 1- De Lepeleire I. Merck and Co., Inc., Brussels, Belgium, BE aut NATIONALLICENCE 700 1- Dallob A. Merck and Co., Inc., Rahway NJ, USA, US aut NATIONALLICENCE 700 1- Wong P. Merck and Co., Inc., Rahway NJ, USA, US aut NATIONALLICENCE 700 1- Porras A. Merck and Co., Inc., Rahway NJ, USA, US aut NATIONALLICENCE 700 1- Gertz B. J. Merck and Co., Inc., Rahway NJ, USA, US aut NATIONALLICENCE 700 1- De Schepper P. J. Centre of Clinical Pharmacology, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium e-mail: Marleen.Depre@uz.kuleuven.ac.be Tel.: +32-16-348602; Fax: +32-16-348601, BE aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer