{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:39:38Z","timestamp":1792096778211,"version":"4.4.0"},"reference-count":62,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2017,12,15]],"date-time":"2017-12-15T00:00:00Z","timestamp":1513296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidize CLZ to norCLZ and CLZ<jats:italic>N<\/jats:italic>\u2010oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug\u2013drug interactions involving CYP3A4 are also significant but less predictable. To further characterize the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0.2 and 2 \u03bcM) and fluvoxamine (1 and 10 \u03bcM). The CYP3A4\u2010selective inhibitor ketoconazole (2 \u03bcM) impaired CLZ<jats:italic>N<\/jats:italic>\u2010oxide formation in all 14 of the livers used in inhibition studies (\u226550% inhibition) while the CYP1A2\u2010selective inhibitor fluvoxamine (10 \u03bcM) decreased norCLZ formation in nine. Ketoconazole effectively inhibited CLZ metabolism in five of seven livers that catalysed CYP3A4\u2010dependent testosterone 6\u03b2\u2010hydroxylation at or above the median rate and in four other livers with lower intrinsic CYP3A4 activity. Similarly, fluvoxamine (10 \u03bcM) readily inhibited CLZ oxidation in seven livers with high CYP1A2\u2010mediated 7\u2010ethoxyresorufin<jats:italic>O<\/jats:italic>\u2010deethylation activity (at or above the median) and three livers with lower intrinsic CYP1A2 activity. In three livers, CLZ biotransformation was impaired by both ketoconazole and fluvoxamine, consistent with a major role for both CYPs. These findings suggest that the intrinsic activities of CYPs 1A2 and 3A4 are unrelated to the response to CYP\u2010selective inhibitors and that assessment of the activities<jats:italic>in vivo<\/jats:italic>may not assist the prediction of drug\u2013drug interactions.<\/jats:p>","DOI":"10.1111\/bcpt.12933","type":"journal-article","created":{"date-parts":[[2017,11,20]],"date-time":"2017-11-20T15:16:37Z","timestamp":1511190997000},"page":"388-395","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Variation in the Response of Clozapine Biotransformation Pathways in Human Hepatic Microsomes to CYP1A2\u2010 and CYP3A4\u2010selective Inhibitors"],"prefix":"10.1111","volume":"122","author":[{"given":"Michael","family":"Murray","sequence":"first","affiliation":[{"name":"Pharmacogenomics and Drug Development Group, Discipline of Pharmacology School of Medical Sciences Sydney Medical School University of Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei V.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Pharmacogenomics and Drug Development Group, Discipline of Pharmacology School of Medical Sciences Sydney Medical School University of Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Centre for Pharmacology and Therapeutics Imperial College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,12,15]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199307153290303"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199408000-00006"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-5846(01)00320-7"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1994.tb04385.x"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200241070-00001"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1993.197"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e3181f03e30"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyx019"},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/S0022-3565(25)24566-9","article-title":"Metabolism and bioactivation of clozapine by human liver in vitro","volume":"272","author":"Pirmohamed M","year":"1995","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_7_11_1","first-page":"1379","article-title":"Metabolism of clozapine by cDNA\u2010expressed human cytochrome P450 enzymes","volume":"25","author":"Linnet K","year":"1997","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1997.t01-1-00605.x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-2797(99)00006-X"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.108.023671"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.43.100901.135828"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00442557"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0773.1999.tb02016.x"},{"key":"e_1_2_7_18_1","first-page":"23","article-title":"Effect of phenytoin on plasma clozapine concentrations in two patients","volume":"52","author":"Miller DD","year":"1991","journal-title":"J Clin Psychiatry"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-979584"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.genhosppsych.2007.02.004"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/YIC.0b013e32834e8afd"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12888-015-0536-4"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1192\/pb.bp.115.051250"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004714-199408000-00011"},{"key":"e_1_2_7_25_1","first-page":"175","article-title":"Clozapine levels and caffeine","volume":"57","author":"Odom\u2010White A","year":"1996","journal-title":"J Clin Psychiatry"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002280000192"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-013-3007-y"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004714-200112000-00011"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.wnf.0000154222.37887.a8"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.151.12.1840b"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.151.1.123"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1996.00440060103013"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13256-015-0547-2"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050440"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050621"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004850-199905002-00007"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920007780655469"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(98)00033-1"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498258509045007"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498258509045370"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(94)90304-2"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(78)52041-7"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-6915(01)00060-6"},{"key":"e_1_2_7_44_1","first-page":"586","article-title":"Metabolism of dextromethorphan in human liver microsomes: a rapid HPLC assay to monitor cytochrome P450 2D6 activity","volume":"51","author":"Vielnascher E","year":"1996","journal-title":"Pharmazie"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.01144.x"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004714-200002000-00007"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1995.tb04422.x"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498259509061850"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.106.014613"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.110.034009"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050163"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199306000-00012"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2002.121788"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-003-0637-8"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00195913"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(98)90174-6"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1999.00073.x"},{"key":"e_1_2_7_58_1","first-page":"1473","article-title":"Testosterone, 7\u2010benzyloxyquinoline, and 7\u2010benzyloxy\u20104\u2010trifluoromethyl\u2010coumarin bind to different domains within the active site of cytochrome P450 3A4","volume":"29","author":"Lu P","year":"2001","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2016.1154043"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e3181acc372"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(78)90305-7"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e3182666c62"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.124024"}],"container-title":["Basic &amp; Clinical Pharmacology &amp; Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbcpt.12933","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcpt.12933","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T04:58:01Z","timestamp":1751000281000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bcpt.12933"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,15]]},"references-count":62,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,4]]}},"alternative-id":["10.1111\/bcpt.12933"],"URL":"https:\/\/doi.org\/10.1111\/bcpt.12933","archive":["Portico"],"relation":{},"ISSN":["1742-7835","1742-7843"],"issn-type":[{"value":"1742-7835","type":"print"},{"value":"1742-7843","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,15]]},"assertion":[{"value":"2017-08-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-10-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-12-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}