Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Determine the Disposition of Esculetin-7-O-Glucuronide and 4-Methylesculetin-7-O-Glucuronide
Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Determine the Disposition of Esculetin-7-O-Glucuronide and 4-Methylesculetin-7-O-Glucuronide
复制标题
乳腺癌耐药蛋白和多药耐药蛋白2决定七叶亭-7-O-葡萄糖醛酸和4-甲基七叶亭-7-O-葡萄糖醛酸的处置
DOI：
10.1124/dmd.118.083493
复制
发表时间：
2019-03-01
影响因子：
3.9
通讯作者：
Zhu, Lijun
中科院分区：
文献类型：
--
作者：
Li, Yuhuan;Song, Wenjie;Zhu, Lijun
7-O-葡萄糖醛酸苷（ET-G）和4-甲基七叶酮（4-ME）-7-O-葡萄糖醛酸苷（4-ME-G）分别是ET和4-ME的主要葡萄糖醛酸苷。葡糖苷酸外排转运蛋白介导的处置对生物活性化合物的药代动力学特征和疗效具有显著影响。本研究采用转运蛋白基因敲除小鼠和Caco-2细胞，探讨乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白2（MRP 2）对ET-G和4-ME-G处置的影响。经口或静脉给予ET和4-ME后，大多数Bcrp 1（-/-）和Mrp 2（-/-）小鼠ET、4-ME及其葡萄糖醛酸苷（ET-G和4-ME-G）的血药浓度-时间曲线下面积均显著增加（P < 0.05）。与此同时，血药浓度也显著升高（P < 0.05）。在Caco-2细胞单层中，BCRP抑制剂Ko 143和MRP 2抑制剂MK 571均能显著降低ET-G和4-ME-G的排出率和清除率（P < 0.05）。肠灌流实验中，Bcrp 1（-/-）小鼠灌流液中ET-G的排泄量明显低于野生型FVB小鼠（P < 0.05），血浆中ET-G的排泄量明显高于野生型FVB小鼠（P < 0.05）。转运蛋白基因敲除小鼠胆汁中4-ME-G浓度也降低。ET和4-ME在Caco-2单层[表观渗透率（P-app）>= 0.59 x 10（-5）cm/s]和十二指肠（P-app >= 1.81）中均显示出良好的渗透性。总之，BCRP和MRP 2参与了ET-G和4-ME-G的排泄。ET和4-ME最有可能通过肠道中的被动扩散吸收。
Esculetin (ET)-7-O-glucuronide (ET-G) and 4-methylesculetin (4-ME)-7-O-glucuronide (4-ME-G) are the main glucuronide of ET and 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-associated protein 2 (MRP2) on the disposition of ET-G and 4-ME-G. After oral or i.v. administration of ET and 4-ME, the area under the plasma concentration-time curve from time 0 to the last data point or infinity 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 maximum plasma concentration 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 monolayers [apparent permeability (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 most likely absorbed via passive diffusion in the intestines.