Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-β-glucuronide
Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-β-glucuronide
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乳腺癌耐药蛋白和多药耐药蛋白 2 介导 Leonurine-10-O-β-葡萄糖醛酸的处置
DOI：
10.2174/1389200221999201116142742
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发表时间：
2020
影响因子：
2.3
通讯作者：
Lijun Zhu
中科院分区：
文献类型：
--
作者：
Xiaocui Li;Yushan Xie;Wei Qu;Xiaojun Ou;Xiaowen Ou;Chuang Wang;Xiaoxiao Qi;Ying Wang;Zhongqiu Liu;Lijun Zhu
背景资料：益母草碱（Leonurine，Leo）是一种很有前途的降血脂药物，已被批准用于临床试验，在体内被广泛代谢为具有生物活性的益母草碱-10-O-β-葡糖苷酸（L-10-G）。目的：探讨乳腺癌耐药蛋白（Bcrp）和多药耐药蛋白2（Mrp 2）对L-10-G.研究方法：采用外排转运蛋白基因敲除小鼠模型，研究了利奥的药代动力学、组织分布和肠灌注。还检查了通过肝脏和肠微粒体的酶动力学。结果如下：静脉注射Leo后，Bcrp 1-/-和Mrp 2-/-小鼠L-10-G的AUC 0-∞值分别是野生型FVB小鼠的1.55倍和16.80倍（P < 0.05）。经口给药后，Mrp 2-/-小鼠L-10-G的AUC 0-∞值比野生型FVB小鼠增加2.82倍（P < 0.05）。灌胃Leo 10和25 min后，Mrp 2-/-小鼠胆汁中L-10-G的蓄积量分别比野生型FVB小鼠低3倍和22倍（P < 0.05）。Bcrp 1-/-和Mrp 2-/-小鼠的L-10-G肠道排泄量分别为野生型FVB小鼠的2.22倍和2.68倍（P < 0.05）。Bcrp 1-/-和Mrp 2-/-小鼠肝微粒体中L-10-G的清除率降低，肠微粒体中L-10-G的清除率升高（P < 0.05）。compared.to结论：Bcrp和Mrp 2均参与L-10-G的处置，且Mrp 2的影响上级。
Background: Leonurine (Leo), a promising antilipemic agent that has been approved for clinical trials, is extensively metabolized into bioactive Leonurine-10-O-β-glucuronide (L-10-G) in vivo..Objective: To explore the effects of breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2) on the.disposition of L-10-G..Methods: The pharmacokinetics, tissue distribution and intestinal perfusion of Leo were studied by using efflux transporter.gene knockout mouse models. The enzyme kinetics via liver and intestinal microsomes were also examined..Results: After intravenous injection with Leo, the AUC0-∞ values of L-10-G in Bcrp1-/- and Mrp2-/- mice were 1.55-fold and.16.80-fold higher, respectively, than those in wild-type FVB mice (P < 0.05). After oral administration, the AUC0-∞ value of.L-10-G showed a 2.82-fold increase in Mrp2-/- mice compared with that in wild-type FVB mice (P < 0.05). After gavage.with Leo for 10 and 25 min, the bile accumulation of L-10-G in Mrp2-/- mice was 3-fold and 22-fold lower, respectively,.than that in wild-type FVB mice (P < 0.05). Besides, the intestinal excreted amount of L-10-G showed 2.22-fold and 2.68-.fold decrease in Bcrp1-/- and Mrp2-/- mice, respectively, compared with that in wild-type FVB mice (P < 0.05). The clearance of L-10-G decreased in liver microsomes and increased in intestinal microsomes of Bcrp1-/- and Mrp2-/- mice compared.to the wild-type FVB mice (P < 0.05)..Conclusion: Both Bcrp and Mrp2 are involved in the disposition of L-10-G, and Mrp2 exhibits a superior influence.