title: Glucuronidation: driving factors and their impact on glucuronide disposition.
abstract: Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.
authors.affiliation: a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China.|b Hubei Provincial Technology and Research Center for Comprehensive Development of Medicinal Herbs, Hubei University of Medicine , Shiyan , Hubei , China.
authors.forename: Guangyi
authors.initials: G
authors.lastname: Yang
authors.affiliation: c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.
authors.forename: Shufan
authors.initials: S
authors.lastname: Ge
authors.affiliation: c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.
authors.forename: Rashim
authors.initials: R
authors.lastname: Singh
authors.affiliation: c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Basu
authors.affiliation: c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Shatzer
authors.affiliation: d Department of Thoracic and Cardiomacrovascular Surgery , Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zen
authors.affiliation: e Department of Digestive Diseases Surgery , Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Liu
authors.affiliation: c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Tu
authors.affiliation: a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China.
authors.forename: Chenning
authors.initials: C
authors.lastname: Zhang
authors.affiliation: a Department of Pharmacy , Institute of Wudang Herbal Medicine Research, Taihe Hospital, Hubei University of Medicine , Shiyan , Hubei , China.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Wei
authors.affiliation: f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.affiliation: f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhu
authors.affiliation: f Department of Pharmacy , Institute of Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou , Guangdong , China.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.|g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China.
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.affiliation: c Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX , USA.|g Department of Pharmacy , College of Pharmacy, Hubei University of Medicine , Shiyan , Hubei , China.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
mesh_terms: D000818:Animals; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D010599:Pharmacokinetics
chemical_list: D020719:Glucuronides; D014453:Glucuronosyltransferase
keywords: Glucuronidation; UGT; disposition; efflux transporters; glucuronides; interplay; recycling; uptake transporters