Increased coproporphyrin serum levels in healthy volunteers treated with the cholesterol uptake inhibitor ezetimibe

Ezetimibe undergoes glucuronidation that results in the active metabolite ezetimibe phenoxy-glucuronide (ezetimibe-glucuronide). This phase-II 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-mediated 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-glucuronide on OATP1B1-mediated transport of CPs in vitro. Then, we quantified CP levels in serum samples of healthy volunteers treated with a single oral dose of ezetimibe (20 mg) alone or in combination with rifampin (600 mg). Results from our in vitro experiments showed a significant reduction in cellular CPI accumulation in the presence of ezetimibe-glucuronide with an IC₅₀ of 1.97 μM [95% CI: 1.04 to 3.96], while CPIII accumulation was impacted by 10 μM and above. In the in vivo study, we observed peak CP concentrations 1.33 h after dosing, which is closest to the t_max of the ezetimibe metabolite. Co-administration of ezetimibe with rifampin resulted in even higher serum CP levels. The AUC_0-24h of CPI and CPIII increased two- 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 (A_e) of CPI and CPIII increased after ezetimibe and rifampin co-administration compared to ezetimibe alone. In conclusion, our findings indicate that rifampin co-administration results in additional inhibition of OATP1B1 in vivo.