{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T23:30:21Z","timestamp":1789947021038,"version":"4.0.1"},"reference-count":55,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,2,20]],"date-time":"2015-02-20T00:00:00Z","timestamp":1424390400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"AWD.pharma GmbH & Co. KG, Radebeul, Germany"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>\u2010acetyltransferases (<jats:styled-content style=\"fixed-case\">NAT<\/jats:styled-content>) that conjugate the less toxic metabolite<jats:styled-content style=\"fixed-case\">D13223<\/jats:styled-content>, and by glucuronosyltransferases (<jats:styled-content style=\"fixed-case\">UGT<\/jats:styled-content>) and glutathione<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>\u2010transferases (<jats:styled-content style=\"fixed-case\">GST<\/jats:styled-content>) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of<jats:styled-content style=\"fixed-case\">NAT2<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">UGT1A1<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">GSTP1<\/jats:styled-content>on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Metabolic disposition of flupirtine was measured after intravenous administration (100\u2009mg), after swallowing an immediate\u2010release (<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>) tablet (100\u2009mg) and after repeated administration of modified release (<jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>) tablets (400\u2009mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Flupirtine<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>was rapidly but incompletely absorbed (\u223c72%). Repeated administration of flupirtine<jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>showed lower bioavailability (\u223c60%). Approximately 12% of bioavailable flupirtine<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>and 8% of bioavailable flupiritine<jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>was eliminated as mercapturic acid derivatives into the urine independent of the<jats:styled-content style=\"fixed-case\">UGT1A1<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">NAT2<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">GSTP1<\/jats:styled-content>genotype. Carriers of variant<jats:styled-content style=\"fixed-case\">GSTP1<\/jats:styled-content>alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for<jats:styled-content style=\"fixed-case\">ABCB1<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">ABCC2<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of<jats:styled-content style=\"fixed-case\">UGT1A1<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">NAT2<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">GSTP1<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12522","type":"journal-article","created":{"date-parts":[[2014,9,29]],"date-time":"2014-09-29T12:34:46Z","timestamp":1411994086000},"page":"501-513","source":"Crossref","is-referenced-by-count":28,"title":["Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2,<scp>UGT1A1<\/scp>and GSTP1"],"prefix":"10.1111","volume":"79","author":[{"given":"Werner","family":"Siegmund","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology University Medicine Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Modess","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology University Medicine Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eberhard","family":"Scheuch","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology University Medicine Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Methling","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Keiser","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology University Medicine Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Nassif","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology University Medicine Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Rosskopf","sequence":"additional","affiliation":[{"name":"Department of Pharmacology of the Center of Drug Absorption and Transport (C_DAT) University Medicine Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Bednarski","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Medicinal Chemistry University of Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Borlak","sequence":"additional","affiliation":[{"name":"Centre for Pharmacology and Toxicology Hannover Medical School Hannover 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