Investigation into the Roles of Hepatic Uptake Transporters in the Enterohepatic Recycling of Phenolic Glucuronides

Drug in vivo exposure decides the drug efficacy. Drug in vivo exposure depends on different ways of drug disposition. Enterohepatic recycling (EHR) serves as an important drug disposition process, which could increase drug in vivo exposure by facilitating the recycle and reabsorption of a drug. The enterohepatic recycling of parent compounds was well studied, but the recycling process of the metabolites were barely investigated. Our recent study indicated that Phase Ⅱ metabolites (glucuronides) could be recycled efficiently as well as their aglycones. Methods: To study the mechanism of the EHR of the glucuronides, a hepatic portal vein infusion model and a small intestine perfusion model were established on Wistar rat. A cell uptake study was conducted on 3 OATP over-expressed cell lines to elucidate the uptake mechanism of glucuronides. To analyze all the biological samples, an LC/MS method was established and validated. Results: Our results indicated that glucuronides were able to participate in the EHR as well as their aglycones. Up to 90% of glucuronides could be recovered from bile after infused to liver. OATPs played a significant role in the EHR of glucuronides. The cell uptake results and recycle ratio fitted with substrate-inhibition model, which indicated that hepatic uptake is the-rate limiting step in EHR of glucuronides. Conclusion: There is another recycling pathway different traditional understanding of enterohepatic recycling. We termed it as “hepatoenteric recycling”, where the roles of metabolism organ and recycling organ are switched. The study would complement the general understanding of enterohepatic recycling and help give a more accurate prediction of drug in vivo efficacy.