Study Finds Ezetimib, Rifampin May Increase Coproporphyrin Concentrations in Healthy Patients

Single-dose ezetimibe (Zetia; Merck and Schering-Plough Pharmaceuticals) increases serum coproporphyrin I (CPI) concentrations in healthy patients, study finds. The researchers indicate that coadministration of ezetimibe and rifampin (Rifadin; Lupin Pharmaceuticals Inc) further enhances the impact on CPI serum levels, as well as 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.

The findings show that coadministration of ezetimibe and rifampin, both potent OATP1B1 substrates, leads to an additional increase in CPI levels. Image Credit: © luchschenF - stock.adobe.com

CPI is an endogenous biomarker of OATP1B, an organic anion transporting polypeptide responsible for transporting substances including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs into the liver for hepatic clearance. OATP1B dysfunction can cause statin-induced myopathy and hyperbilirubinemia. CPI is considered a tier 1 biomarker for OATP1B and helps clinicians monitor OATP1B function, particularly in patients receiving multiple therapies that may inhibit the transporter.^1-3

Ezetimibe is an inhibitor of intestinal cholesterol meant to reduce elevated levels of total cholesterol, low-density lipoprotein cholesterol, Apo B, and non-high-density lipoprotein cholesterol in patients with primary hyperlipidemia, either alone or in combination with a statin. In the study, researchers quantified CP levels in serum samples of healthy volunteers treated with a single 20 mg oral dose of ezetimibe alone or in combination with a 600 mg dose of rifampin, an antibiotic, to determine whether levels of CPIwere affected by ezetimibe treatment.^2,4

The ezetimibe monotherapy in vitro experiments showed a significant reduction in 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. This reduction highlights the potential role of ezetimibe in modulating transporter function beyond its cholesterol-lowering effects. In the in vivo experiment, the researchers reported peak CP concentrations 1.33 hour after dosing, which is closest to the tmax of the ezetimibe metabolite.²

When investigating co-administration of ezetimibe and rifampin, they observed an even higher increase of serum CP levels. The combination treatment increased the AUC0–24h of CPI and CPIII by 2- and 3-fold, respectively, compared with ezetimibe alone. Data also showed that healthy participants from the last cohort had 75% higher median CPI serum levels of 0.70 nM [95% CI: 0.44 to 1.89].²

The findings show that coadministration 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. Furthermore, the study supports CPI as a reliable biomarker for monitoring OATP1B1. Understanding these interactions may enhance personalized medicine approaches in managing cholesterol and reducing adverse drug reactions.

REFERENCES

1. Takita H, Scotcher D, Chu X, Yee KL, et al. Coproporphyrin i as an endogenous biomarker to detect reduced oatp1b activity and shift in elimination route in chronic kidney disease. Clin Pharmacol Ther. June 28, 2022. doi:10.1002/cpt.2672

2. Kinzi J, Grube M, Seibert I, et al. Increased coproporphyrin serum levels in healthy volunteers treated with the cholesterol uptake inhibitor ezetimibe. Clin Transl Sci. October 9, 2024. doi:10.1111/cts.70041

3. Shan Z, Yang X, Liu H, et al. Cryo-EM structures of human organic anion transporting polypeptide oatp1b1. Cell. September 6, 2023. doi:10.1038/s41422-023-00870-8

4. Daily medication pearl: ezetimibe (zetia). Pharmacy Times. August 3, 2022. Accessed October 16, 2024. https://www.pharmacytimes.com/view/daily-medication-pearl-ezetimibe-zetia-

5. Rifampin capsules. Cleveland Clinic. Accessed October 16, 2024. https://my.clevelandclinic.org/health/drugs/18812-rifampin-capsules