{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T05:50:59Z","timestamp":1760853059472},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":3072,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2000,9]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Because of serious side\u2010effects of thioridazine and tricyclic antidepressants (cardiotoxicity), a possible influence of imipramine and amitriptyline on the pharmacokinetics and metabolism of thioridazine was investigated in a steady state (2\u2010week treatment) in rats.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Imipramine and amitriptyline (5 and 10\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup> i.p., respectively) elevated 30 and 20 fold, respectively, the concentration of thioridazine (10\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup> i.p.) and its metabolites (N\u2010desmethylthioridazine, 2\u2010sulphoxide, 2\u2010sulphone, 5\u2010sulphoxide) in blood plasma. Similar, yet weaker increases in the thioridazine concentration were found in the brain. Moreover, an elevation of thioridazine\/metabolite ratios was observed.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Imipramine and amitriptyline added to control liver microsomes <jats:italic>in vitro<\/jats:italic> inhibited the metabolism of thioridazine <jats:italic>via<\/jats:italic> N\u2010demethylation (an increase in K<jats:sub>m<\/jats:sub>), mono\u20102\u2010sulphoxidation (an increase in K<jats:sub>m<\/jats:sub> and a decrease in V<jats:sub>max<\/jats:sub>) and 5\u2010sulphoxidation (mainly a decrease in V<jats:sub>max<\/jats:sub>). Amitriptyline was a more potent inhibitor than imipramine of the thioridazine metabolism.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The varying concentration ratios of antidepressant\/thioridazine <jats:italic>in vivo<\/jats:italic> appear to be more important to the final result of the pharmacokinetic interactions than are relative direct inhibitory effects of the antidepressants on thioridazine metabolism observed <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Besides direct inhibition of the thioridazine metabolism, the decreased activity of cytochrome P\u2010450 towards 5\u2010sulphoxidation, produced by chronic joint administration of thioridazine and the antidepressants, seems to be relevant to the observed <jats:italic>in vivo<\/jats:italic> interaction.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The obtained results may also point to inhibition of another, not yet investigated, metabolic pathway of thioridazine, which may be inferred from the simultaneous elevation of concentrations of both thioridazine and the measured metabolites.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2000) <jats:bold>131<\/jats:bold>, 287\u2013295; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0703540\">10.1038\/sj.bjp.0703540<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0703540","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T20:51:55Z","timestamp":1106945515000},"page":"287-295","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Pharmacokinetics and metabolism of thioridazine during co\u2010administration of tricyclic antidepressants"],"prefix":"10.1111","volume":"131","author":[{"given":"Wladyslawa A","family":"Daniel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Syrek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Haduch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacek","family":"W\u00f3jcikowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"587","article-title":"On the serum concentrations and antipsychotic effects of thioridazine, thioridazine side\u2010chain sulfoxide and thioridazine side\u2010chain sulfone in chronic psychotic patients","volume":"21","author":"AXELSSON R.","year":"1977","journal-title":"Curr. 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