{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:14:51Z","timestamp":1790795691188,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,4,21]],"date-time":"2006-04-21T00:00:00Z","timestamp":1145577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2006,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a randomized, double\u2010blind, two\u2010phase cross\u2010over study, nine healthy subjects took 25\u2003mg rofecoxib or placebo daily for 4\u2003days and, on day 4, each ingested 4\u2003mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24\u2003h. On day 3, a caffeine test was performed to estimate CYP1A2 activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Rofecoxib increased the area under the plasma concentration\u2013time curve (AUC<jats:sub>0\u2013\u221e<\/jats:sub>) of tizanidine by 13.6\u2010fold [95% confidence interval (CI) 8.0, 15.6;<jats:italic>P<\/jats:italic>\u2003&lt;\u20030.001), peak plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) by 6.1\u2010fold (4.8, 7.3;<jats:italic>P<\/jats:italic>\u2003&lt;\u20030.001) and elimination half\u2010life (<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>) from 1.6 to 3.0\u2003h (<jats:italic>P\u2003<\/jats:italic>&lt;\u20030.001). Consequently, rofecoxib markedly increased the blood pressure\u2010lowering and sedative effects of tizanidine (<jats:italic>P\u2003<\/jats:italic>&lt;\u20030.05). Rofecoxib increased several fold the tizanidine\/M\u20103 and tizanidine\/M\u20104 ratios in plasma and urine and the tizanidine\/M\u20105, tizanidine\/M\u20109 and tizanidine\/M\u201010 ratios in urine (<jats:italic>P\u2003<\/jats:italic>&lt;\u20030.05). In addition, it increased the plasma caffeine\/paraxanthine ratio by 2.4\u2010fold (95% CI 1.4, 3.4;<jats:italic>P<\/jats:italic>\u2003=\u20030.008) and this ratio correlated with the tizanidine\/metabolite ratios. Finally, the AUC<jats:sub>0\u221225<\/jats:sub>of rofecoxib correlated with the placebo phase caffeine\/paraxanthine ratio (<jats:italic>r\u2003<\/jats:italic>=\u20030.80,<jats:italic>P<\/jats:italic>\u2003=\u20030.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2006.02653.x","type":"journal-article","created":{"date-parts":[[2006,4,21]],"date-time":"2006-04-21T22:45:50Z","timestamp":1145659550000},"page":"345-357","source":"Crossref","is-referenced-by-count":53,"title":["Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects"],"prefix":"10.1111","volume":"62","author":[{"given":"Janne T.","family":"Backman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjo J.","family":"Karjalainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko","family":"Neuvonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jouko","family":"Laitila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pertti J.","family":"Neuvonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,4,21]]},"reference":[{"key":"e_1_2_7_2_2","volume-title":"Summary of Safety\u2010Related Drug Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER).","year":"2002"},{"key":"e_1_2_7_3_2","doi-asserted-by":"crossref","unstructured":"Kick A Bertoli R Moschovitis G Caduff Janosa P Cerny A. [Extreme sinus bradycardia (30\/min) with acute right heart failure under tizanidine (Sirdalud). Possible pharmacological interaction with rofecoxib (Vioxx)]. Med Klin (Munich) 2005; 100: 213\u20136.","DOI":"10.1007\/s00063-005-1024-2"},{"key":"e_1_2_7_4_2","doi-asserted-by":"crossref","unstructured":"Topol EJ. Failing the public health\u2014rofecoxib Merck and the FDA. N Engl J Med 2004; 351: 1707\u20139.","DOI":"10.1056\/NEJMp048286"},{"key":"e_1_2_7_5_2","unstructured":"VIOXX (Rofecoxib Tablets and Oral Suspension). Whitehouse Station NJ: Merck Inc. 2002. 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