{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:25:40Z","timestamp":1790706340654,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T00:00:00Z","timestamp":1725321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Tacrolimus is widely used to treat pediatric nephrotic range proteinuria (NRP). Diltiazem, a CYP3A4\/5 inhibitor, is often administered with tacrolimus, affecting its pharmacokinetic profile. The impact of this combination on tacrolimus exposure, particularly in CYP3A5*3 genetic polymorphism, remains unclear in pediatric NRP patients. This study aimed to evaluate the effects of diltiazem on tacrolimus pharmacokinetics, focusing on the CYP3A5*3 polymorphism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a retrospective clinical study involving pediatric NRP patients, divided into two groups: those receiving tacrolimus with diltiazem and those receiving tacrolimus alone. Propensity score matching (PSM) was used to balance the baseline characteristics between the groups. We compared daily dose-adjusted trough concentrations (C<jats:sub>0<\/jats:sub>\/D) of tacrolimus in both the original and PSM cohorts. The influence of diltiazem on tacrolimus C<jats:sub>0<\/jats:sub>\/D, stratified by CYP3A5*3 genetic polymorphism, was assessed in a self-controlled case series study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Before PSM, the tacrolimus C<jats:sub>0<\/jats:sub>\/D in patients taking diltiazem was significantly higher compared to those with tacrolimus alone (75.84 vs. 56.86\u00a0ng\/mL per mg\/kg, <jats:italic>P<\/jats:italic> = 0.034). This finding persisted after PSM (75.84 vs. 46.93\u00a0ng\/mL per mg\/kg, <jats:italic>P<\/jats:italic>= 0.028). In the self-controlled case study, tacrolimus C<jats:sub>0<\/jats:sub>\/D elevated about twofold (75.84 vs. 34.76\u00a0ng\/mL per mg\/kg, <jats:italic>P<\/jats:italic> &amp;lt; 0.001) after diltiazem administration. CYP3A5 expressers (<jats:italic>CYP3A5*1\/*1 and *1\/*3<\/jats:italic>) and CYP3A5 non-expressers (<jats:italic>CYP3A5*3\/*3<\/jats:italic>) experienced a 1.8-fold and 1.3-fold increase in tacrolimus C<jats:sub>0<\/jats:sub>\/D when combined with diltiazem, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Diltiazem significantly increased tacrolimus C<jats:sub>0<\/jats:sub>\/D, with CYP3A5*3 expressers showing higher elevations than non-expressers among pediatric NRP patients. These findings highlight the importance of personalized tacrolimus therapy based on CYP3A5*3 genotypes in pediatric patients taking diltiazem.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1463595","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T04:39:17Z","timestamp":1725338357000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Drug-drug interaction between diltiazem and tacrolimus in relation to CYP3A5 genotype status in Chinese pediatric patients with nephrotic range proteinuria: a retrospective study"],"prefix":"10.3389","volume":"15","author":[{"given":"Qiaoling","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuebin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyu","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/s0966-3274(96)80040-2","article-title":"Diltiazem minimizes tubular damage due to FK506-mediated nephrotoxicity following ischemia and reperfusion in rats","volume":"4","author":"Becker","year":"1996","journal-title":"Transpl. 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