{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T04:09:25Z","timestamp":1780805365111,"version":"3.54.1"},"reference-count":49,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,9,20]],"date-time":"2016-09-20T00:00:00Z","timestamp":1474329600000},"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":[[2016,12]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>We compared the CYP3A4 metrics weight\u2010corrected midazolam apparent oral clearance (MDZ Cl\/F\/W) and plasma 4\u03b2\u2010hydroxycholesterol\/cholesterol (4\u03b2\u2010OHC\/C) as they relate to tacrolimus (TAC) Cl\/F\/W in renal transplant recipients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>For a cohort of 147 patients, 8\u00a0h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4\u03b2\u2010OHC\/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe. All patients were genotyped for common polymorphisms in<jats:italic>CYP3A4<\/jats:italic>,<jats:italic>CYP3A5<\/jats:italic>and<jats:italic>P450 oxidoreductase<\/jats:italic>, among others.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>MDZ Cl\/F\/W, 4\u03b2\u2010OHC\/C\/W, EBT and TAC Cl\/F\/W were all moderately correlated (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.262\u20130.505). Neither MDZ Cl\/F\/W nor 4\u03b2\u2010OHC\/C\/W explained variability in TAC Cl\/F\/W in CYP3A5 expressors (<jats:italic>n<\/jats:italic>\u00a0=\u00a029). For CYP3A5 non\u2010expressors (<jats:italic>n<\/jats:italic>\u00a0=\u00a0118), factors explaining variability in TAC Cl\/F\/W in a MDZ\u2010based model were MDZ Cl\/F\/W (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.201), haematocrit (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.139), TAC formulation (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.107) and age (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.032; total<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.479). In the 4\u03b2\u2010OHC\/C\/W\u2010based model, predictors were 4\u03b2\u2010OHC\/C\/W (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.196), haematocrit (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.059) and age (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.057; total<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.312). When genotype information was ignored, predictors of TAC Cl\/F\/W in the whole cohort were 4\u03b2\u2010OHC\/C\/W (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.167), MDZ Cl\/F\/W (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.045); Tac QD formulation (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.036), and haematocrit (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.032; total<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.315). 4\u03b2\u2010OHC\/C\/W, but not MDZ Cl\/F\/W, was higher in CYP3A5 expressors because it was higher in CYP3A4*1b carriers, which were almost all CYP3A5 expressors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A MDZ\u2010based model explained more variability in TAC clearance in CYP3A5 non\u2010expressors. However, 4\u03b2\u2010OHC\/C\/W was superior in a model in which no genotype information was available, likely because 4\u03b2\u2010OHC\/C\/W was influenced by the CYP3A4*1b polymorphism.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13083","type":"journal-article","created":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T22:38:51Z","timestamp":1470695931000},"page":"1539-1549","source":"Crossref","is-referenced-by-count":29,"title":["Comparative performance of oral midazolam clearance and plasma 4\u03b2\u2010hydroxycholesterol to explain interindividual variability in tacrolimus clearance"],"prefix":"10.1111","volume":"82","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5712-6294","authenticated-orcid":false,"given":"Thomas","family":"Vanhove","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology KU Leuven \u2013 University of Leuven Leuven Belgium"},{"name":"Department of Nephrology and Renal Transplantation University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hylke","family":"de Jonge","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology KU Leuven \u2013 University of Leuven Leuven Belgium"},{"name":"Department of Nephrology and Renal Transplantation University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri\u00ebtte","family":"de Loor","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Renal Transplantation University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Annaert","sequence":"additional","affiliation":[{"name":"Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences KU Leuven \u2013 University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Diczfalusy","sequence":"additional","affiliation":[{"name":"Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Karolinska University Hospital Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk R. J.","family":"Kuypers","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology KU Leuven \u2013 University of Leuven Leuven Belgium"},{"name":"Department of Nephrology and Renal Transplantation University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,9,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1037"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13354"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0009-9236(95)90153-1","article-title":"Pharmacokinetics of tacrolimus in liver transplant patients","volume":"57","author":"Jusko WJ","journal-title":"Clin Pharmacol Ther"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0090-9556(24)15298-1","article-title":"The disposition of 14C\u2010labeled tacrolimus after intravenous and oral administration in healthy human subjects","volume":"27","author":"M\u00f6ller A","year":"1999","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/11317550-000000000-00000"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.13.133"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.03.009"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(96)90177-0"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2012.109"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105127200"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2008.03309.x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M201712200"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.132"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-008-0492-8"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku286"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.5414\/CPP47709"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.128"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12425"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270009360041"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12701"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12537"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.113.052316"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.72"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12492"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-014-1675-0"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12707"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00028.2003"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.3.1215"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth457"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1086\/319501"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.1576"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2010.03.016"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2010.03773.x"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/72.3.302"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-9236(95)90261-9"},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/S0090-9556(25)07474-4","article-title":"Disposition of tacrolimus (FK 506) in rabbits. Role of red blood cell binding in hepatic clearance","volume":"21","author":"Piekoszewski W","year":"1993","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-013-1584-7"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3282f50ee9"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.113.054171"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.18.1588"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0127995"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-199408000-00001"},{"key":"e_1_2_10_44_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0026-895X(25)09441-6","article-title":"Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3)","volume":"38","author":"Wrighton SA","year":"1990","journal-title":"Mol Pharmacol"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1997.0537"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(99)70029-9"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(01)45600-1"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.2165\/11593890-000000000-00000"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2012.04232.x"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.13691"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbcp.13083","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.13083","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T16:19:50Z","timestamp":1749053990000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.13083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,20]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016,12]]}},"alternative-id":["10.1111\/bcp.13083"],"URL":"https:\/\/doi.org\/10.1111\/bcp.13083","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,20]]}}}