RT Journal Article
SR Electronic
T1 Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Determine the Disposition of Esculetin-7-O-glucuronide and 4-Methylesculetin-7-O-glucuronide
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.083493
DO 10.1124/dmd.118.083493
A1 Yuhuan Li
A1 Wenjie Song
A1 Xiaojun Ou
A1 Guangkuo Luo
A1 Yushan Xie
A1 Rongjin Sun
A1 Ying Wang
A1 Xiaoxiao Qi
A1 Ming Hu
A1 Zhongqiu Liu
A1 Lijun Zhu
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/01/02/dmd.118.083493.abstract
AB Esculetin-7-O-glucuronide (ET-G) and 4-Methylesculetin-7-O-glucuronide (4-ME-G) are the main glucuronide of esculetin (ET) and 4-methylesculetin (4-ME), respectively. The disposition mediated by efflux transporters for glucuronide has significant influence on the pharmacokinetic profile and efficacy of bioactive compounds. In the current study, transporter gene knockout mice and Caco-2 cells were used to explore the effects of breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2) on the disposition of ET-G and 4-ME-G. After oral or intravenous administration of ET and 4-ME, the AUC0-∞ values of ET, 4-ME, and their glucuronides (ET-G and 4-ME-G) were remarkably and significantly increased in most Bcrp1-/- and Mrp2-/- mice compared with those in wild-type FVB mice (P < 0.05). These results were accompanied with a significant increase of Cmax values (P < 0.05). In Caco-2 monolayers, the efflux and clearance rates of ET-G and 4-ME-G were markedly reduced by the BCRP inhibitor Ko143 and MRP2 inhibitor MK571 on the apical side (P < 0.05). In an intestinal perfusion study, the excretion of ET-G was significantly decreased in perfusate and increased in plasma in Bcrp1-/- mice compared with those in wild-type FVB mice (P < 0.05). The 4-ME-G concentration was also decreased in the bile in transporter gene-knockout mice. ET and 4-ME showed good permeability in both Caco-2 momolayers (P*app ≥ 0.59 x 10−5 cm/s) and duodenum (P*app ≥ 1.81). In conclusion, BCRP and MRP2 are involved in excreting ET-G and 4-ME-G. ET and 4-ME are likely absorbed via passive diffusion in the intestines.