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

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dc.contributor.advisorHu, Ming
dc.contributor.committeeMemberChow, Diana Shu-Lian
dc.contributor.committeeMemberTam, Vincent H.
dc.contributor.committeeMemberGuo, Bin
dc.contributor.committeeMemberZhang, Shuxing
dc.contributor.committeeMemberXie, Huan
dc.creatorTu, Yifan
dc.creator.orcid0000-0002-2728-6753
dc.date.accessioned2020-06-02T04:08:12Z
dc.date.createdMay 2020
dc.date.issued2020-05
dc.date.submittedMay 2020
dc.date.updated2020-06-02T04:08:13Z
dc.description.abstractDrug 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.
dc.description.departmentPharmacological and Pharmaceutical Sciences, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10657/6585
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectPhenolic compounds
dc.subjectGlucuronide
dc.subjectEnterohepatic recycling
dc.subjectHepatic uptake
dc.titleInvestigation into the Roles of Hepatic Uptake Transporters in the Enterohepatic Recycling of Phenolic Glucuronides
dc.type.dcmiText
dc.type.genreThesis
local.embargo.lift2022-05-01
local.embargo.terms2022-05-01
thesis.degree.collegeCollege of Pharmacy
thesis.degree.departmentPharmacological and Pharmaceutical Sciences, Department of
thesis.degree.disciplinePharmaceutics
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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