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Clinical cases suggest CBD may alter tacrolimus exposure, but the mechanism of this interaction is unknown. We hypothesize that cannabidiol will inhibit tacrolimus metabolism in\u00a0vitro mainly through CYP3A5 inhibition. In pooled human liver microsomes (HLMs) and recombinant (r) CYP3A4 and CYP3A5 enzymes, tacrolimus (1\u2009\u03bcM) metabolism was determined using substrate depletion method in the absence (control) and the presence of 10\u2009\u03bcM CBD, 7\u2010hydroxyCBD, and 7\u2010carboxyCBD. Ketoconazole (1\u2009\u03bcM) served as a positive control for the inhibition of CYP3A. Linear regression analyses were performed to obtain kinetic parameters of the depletion. Tacrolimus depletion half\u2010life was 2.54, 0.922, and 0.351\u2009min with pooled HLMs, rCYP3A4, and rCYP3A5, respectively. In pooled HLMs, CBD and 7\u2010hydroxyCBD increased tacrolimus half\u2010life by 0.8\u2010 and 2.3\u2010fold (both <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), respectively. In rCYP3A4, CBD, 7\u2010hydroxyCBD, and ketoconazole prolonged tacrolimus half\u2010life by 5.8\u2010, 14\u2010, and 7.7\u2010fold, respectively. In rCYP3A5, CBD, 7\u2010hydroxyCBD, and ketoconazole prolonged half\u2010life by 29.3\u2010, 19.7\u2010, and 0.1\u2010fold, respectively. In all experiments, 7\u2010carboxyCBD had minimal effect on tacrolimus depletion. CBD and 7\u2010hydroxyCBD inhibited tacrolimus metabolism in\u00a0vitro. CBD showed stronger inhibition in rCYP3A5 than rCYP3A4. The demonstrated CYP3A5 selectivity of cannabidiol may contribute to the in\u00a0vitro identification of CYP3A5 substrates in new drug development. Our results support the potential of a clinical drug\u2013drug interaction between CBD and tacrolimus.<\/jats:p>","DOI":"10.1111\/cts.70152","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T02:58:33Z","timestamp":1739242713000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of Tacrolimus Metabolism by Cannabidiol and Its Metabolites In\u00a0Vitro"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2101-5116","authenticated-orcid":false,"given":"Gerald C.","family":"So","sequence":"first","affiliation":[{"name":"Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Bo Li","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Medicine Indiana University School of Medicine  Indianapolis Indiana 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