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Rep"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-<jats:italic>N<\/jats:italic>-demethylation (CYP1A1\/2), diclofenac 4\u2032-hydroxylation (CYP2C9), perazine <jats:italic>N<\/jats:italic>-demethylation (CYP2C19) and testosterone 6\u03b2-hydroxylation (CYP3A4). In parallel, <jats:italic>CYP<\/jats:italic> mRNA levels were measured in neuroleptic-treated hepatocytes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10\u00a0\u00b5M, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1\/2, CYP2C9 and CYP2C19.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s43440-020-00157-4","type":"journal-article","created":{"date-parts":[[2020,9,4]],"date-time":"2020-09-04T16:03:41Z","timestamp":1599235421000},"page":"303-308","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4"],"prefix":"10.1007","volume":"73","author":[{"given":"Przemys\u0142aw J.","family":"Danek","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Basi\u0144ska-Ziobro\u0144","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacek","family":"W\u00f3jcikowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W\u0142adys\u0142awa A.","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,9,4]]},"reference":[{"key":"157_CR1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","volume":"138","author":"UM Zanger","year":"2013","unstructured":"Zanger UM, Schwab M. 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