title: Transport-Glucuronidation Classification System and PBPK Modeling: New Approach To Predict the Impact of Transporters on Disposition of Glucuronides.
abstract: Glucuronide metabolites require the action of efflux transporters to exit cells due to their hydrophilic properties. In this study, we proposed a transport-glucuronidation classification system and developed a PBPK model to predict the impact of BCRP on systemic exposure of glucuronides. The clearance by UGTs in S9 fractions and the efflux clearance of glucuronides by BCRP in human UGT1A9-overexpressing HeLa cells were incorporated in the classification system and PBPK model. Based on simulations for glucuronide AUC for theoretical compounds in the classification system, it was indicated that BCRP was more important for compounds with greater efflux clearance of their glucuronides by BCRP regardless of differences in clearance by UGTs. Pharmacokinetic studies were performed in WT and Bcrp1 (-/-) mice for 8 compounds to verify our predictions. Among eight compounds, the glucuronide AUC of daidzein and genistein increased significantly in Bcrp1 (-/-) mice, while only slight increases in systemic exposure were observed for other glucuronides. The results from pharmacokinetic studies were in agreement with the predictions except for resveratrol, which was effluxed predominantly by transporters other than BCRP. Therefore, for glucuronides that were predominantly mediated by BCRP, this study provided a useful approach in predicting the impact of BCRP on its disposition and the potential DDIs involving BCRP.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston , 1441 Moursund Street, Houston, Texas 77030, United States.
authors.forename: Shufan
authors.initials: S
authors.lastname: Ge
authors.affiliation: Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine , 100 Shizi Street, Nanjing 210028, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston , 1441 Moursund Street, Houston, Texas 77030, United States.
authors.forename: Taijun
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston , 1441 Moursund Street, Houston, Texas 77030, United States.
authors.forename: Beibei
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston , 1441 Moursund Street, Houston, Texas 77030, United States.
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston , 1441 Moursund Street, Houston, Texas 77030, United States.
authors.forename: Ming
authors.identifier: 0000-0003-0606-2336
authors.initials: M
authors.lastname: Hu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C501412:Abcg2 protein, mouse; D020719:Glucuronides; D013267:Stilbenes; D014453:Glucuronosyltransferase; D000077185:Resveratrol
keywords: BCRP; PBPK modeling; glucuronide disposition; transport−glucuronidation classification system