{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:42:09Z","timestamp":1784612529890,"version":"3.55.0"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,8,3]],"date-time":"2015-08-03T00:00:00Z","timestamp":1438560000000},"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":[[2015,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The long\u2010term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose\u2010corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated<jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sixty\u2010five tacrolimus\u2010 and 10 cyclosporine\u2010treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8\u2010h area under the concentration\u2010time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Tacrolimus clearance decreased gradually throughout the entire first year but only in<jats:italic>CYP3A5<\/jats:italic>*<jats:italic>3<\/jats:italic>\/*<jats:italic>3<\/jats:italic>homozygous recipients (25.6\u2009\u00b1\u200911.1\u2009l h<jats:sup>\u20131<\/jats:sup>at day 7; 17\u2009\u00b1\u20099.1\u2009l h<jats:sup>\u20131<\/jats:sup>at month 12;<jats:italic>P<\/jats:italic>&lt; 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924\u2009\u00b1\u2009443\u2009ml min<jats:sup>\u20131<\/jats:sup>at day 7<jats:italic>vs<\/jats:italic>. 730\u2009\u00b1\u2009344\u2009ml min<jats:sup>\u20131<\/jats:sup>at month 1;<jats:italic>P<\/jats:italic>&lt; 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9\u2009ml min<jats:sup>\u20131<\/jats:sup>for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The maturation of tacrolimus disposition in the first year after renal transplantation observed in<jats:italic>CYP3A5*3\/*3<\/jats:italic>homozygous patients can partly be explained by a (steroid tapering\u2010related) decline in CYP3A4 activity and a progressive increase in haematocrit.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12703","type":"journal-article","created":{"date-parts":[[2015,6,26]],"date-time":"2015-06-26T14:53:25Z","timestamp":1435330405000},"page":"548-559","source":"Crossref","is-referenced-by-count":50,"title":["Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit"],"prefix":"10.1111","volume":"80","author":[{"given":"Hylke","family":"de Jonge","sequence":"first","affiliation":[{"name":"Departments of Nephrology and Renal Transplantation University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Vanhove","sequence":"additional","affiliation":[{"name":"Departments 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":"Laboratory of Nephrology, Department of Microbiology and Immunology University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Verbeke","sequence":"additional","affiliation":[{"name":"Translational Research Center for Gastrointestinal Disorders (TARGID) University Hospitals Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk R. 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