Ezetimibe, a cholesterol absorption inhibitor, when administered as a single dose, elevates serum coproporphyrin I (CPI) concentrations in healthy patients, according to a new study. The research highlights that the co-administration of ezetimibe and rifampin, an antibiotic, further enhances the impact on CPI serum levels and the inhibition of OATP1B1 in vivo, which affects the uptake of cholesterol derivatives and CPI. This suggests a potentially greater risk of OATP1B1-related drug interactions in clinical settings where these medications are prescribed together.
Impact on OATP1B1 Function
CPI serves as an endogenous biomarker for OATP1B, an organic anion transporting polypeptide crucial for transporting various substances, including endogenous metabolites and clinical drugs like bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs, into the liver for hepatic clearance. Dysfunction of OATP1B can lead to statin-induced myopathy and hyperbilirubinemia. CPI is recognized as a tier 1 biomarker for OATP1B, aiding clinicians in monitoring its function, especially in patients receiving multiple therapies that may inhibit the transporter.
Study Details and Findings
The study quantified coproporphyrin levels in serum samples from healthy volunteers treated with a single 20 mg oral dose of ezetimibe alone or in combination with a 600 mg dose of rifampin. In vitro experiments showed that ezetimibe monotherapy significantly reduced cellular CPI accumulation in the presence of ezetimibe-glucuronide, an ezetimibe metabolite, with an IC50 of 1.97 μM [95% CI: 1.04 to 3.96], while the substrate CPIII was impacted by 10 μM and above. The in vivo experiment reported peak coproporphyrin concentrations 1.33 hours after dosing, closely aligning with the tmax of the ezetimibe metabolite.
Synergistic Effect of Ezetimibe and Rifampin
When ezetimibe and rifampin were co-administered, researchers observed an even greater increase in serum coproporphyrin levels. The combination treatment increased the AUC0–24h of CPI and CPIII by 2- and 3-fold, respectively, compared to ezetimibe alone. Data also indicated that participants in the combination cohort had 75% higher median CPI serum levels, measuring 0.70 nM [95% CI: 0.44 to 1.89].
Clinical Implications
The findings indicate that co-administration of ezetimibe and rifampin, both potent OATP1B1 substrates, leads to an additional increase in CPI levels, which can interfere with a clinician’s ability to effectively assess potential drug interactions in patients undergoing combination therapies. The study reinforces CPI's role as a reliable biomarker for monitoring OATP1B1. Understanding these interactions can refine personalized medicine strategies for managing cholesterol and minimizing adverse drug reactions.
