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This phase\u2010II metabolite was shown to interact with the clinically relevant hepatic transporter organic anion transporting polypeptide (OATP) 1B1. In recent years, coproporphyrin I (CPI) was established as a Tier 1 biomarker for OATP1B\u2010mediated interactions among other endogenous substrates like CPIII. To evaluate whether levels of the biomarker are affected by ezetimibe treatment, we assessed the impact of ezetimibe and ezetimibe\u2010glucuronide on OATP1B1\u2010mediated transport of CPs in\u00a0vitro. Then, we quantified CP levels in serum samples of healthy volunteers treated with a single oral dose of ezetimibe (20\u2009mg) alone or in combination with rifampin (600\u2009mg). Results from our in\u00a0vitro experiments showed a significant reduction in cellular CPI accumulation in the presence of ezetimibe\u2010glucuronide with an IC<jats:sub>50<\/jats:sub> of 1.97\u2009\u03bcM [95% CI: 1.04 to 3.96], while CPIII accumulation was impacted by 10\u2009\u03bcM and above. In the in\u00a0vivo study, we observed peak CP concentrations 1.33\u2009h after dosing, which is closest to the <jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub> of the ezetimibe metabolite. Co\u2010administration of ezetimibe with rifampin resulted in even higher serum CP levels. The AUC<jats:sub>0\u201324h<\/jats:sub> of CPI and CPIII increased two\u2010 and threefold, respectively, after concomitant dosing compared to ezetimibe alone. Moreover, we quantified CP levels in cumulative urine from both study phases where the renally excreted amount (<jats:italic>A<\/jats:italic><jats:sub>e<\/jats:sub>) of CPI and CPIII increased after ezetimibe and rifampin co\u2010administration compared to ezetimibe alone. In conclusion, our findings indicate that rifampin co\u2010administration results in additional inhibition of OATP1B1 in\u00a0vivo.<\/jats:p>","DOI":"10.1111\/cts.70041","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T13:40:05Z","timestamp":1728481205000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Increased coproporphyrin serum levels in healthy volunteers treated with the cholesterol uptake inhibitor ezetimibe"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2830-2126","authenticated-orcid":false,"given":"Jonny","family":"Kinzi","sequence":"first","affiliation":[{"name":"Biopharmacy, Department of Pharmaceutical Sciences University of Basel  Basel 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