Lack of improvement of oral absorption of ME3277 by prodrug formation is ascribed to the intestinal efflux mediated by breast cancer resistant protein (BCRP/ABCG2)
Lack of improvement of oral absorption of ME3277 by prodrug formation is ascribed to the intestinal efflux mediated by breast cancer resistant protein (BCRP/ABCG2)
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DOI：
10.1007/s11095-005-2487-9
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发表时间：
2005-04-01
影响因子：
3.7
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
--
作者：
Kondo, C;Onuki, R;Sugiyama, Y
目的. ME 3229是亲水性糖蛋白IIb/IIIa拮抗剂（ME 3277）的酯型前药，未能显示出改善的口服吸收。Okudaira等人（J. Pharmacol. Exp. Ther. 294. 580 - 587，2000）提供了一个证据，表明这归因于与P-gp和MRP 2不同的外排系统，其在肠上皮细胞中挤出由ME 3229形成的ME 3277。本研究的目的是检查乳腺癌耐药蛋白（BCRP/ABCG 2）的参与作为ME 3229口服吸收低的原因。采用快速过滤法，使用由表达BCRP的LLC-PK 1细胞制备的膜囊泡，测定了在存在和不存在ATP的情况下ME 3277的转运活性。比较Bcrp 1（-/-）小鼠和野生型小鼠小肠灌流后ME 3229及其代谢产物的血药浓度。在BCRP表达膜囊泡中，ME 3277的ATP依赖性摄取大于对照囊泡。此外，发现在用ME 3229肠灌注60分钟后，ME 3277和PM-5（ME 3229的代谢物）的血浆浓度在Bcrp 1敲除小鼠中分别增加2倍和3倍。BCRP可能与肠道羧酸酯酶有协同作用。这些结果表明，Bcrp 1在ME 3277的肠道外排中起重要作用，并且可能在ME 3229的代谢产物PM-10和PM-11中起重要作用，并且在口服ME 3229后限制其BA。
Purpose. ME3229, an ester-type prodrug of a hydrophilic glycoprotein IIb/IIIa antagonist (ME3277), failed to show improved oral absorption. Okudaira et al. (J. Pharmacol. Exp. Ther. 294. 580 - 587, 2000) provided a piece of evidence that this is ascribed to an efflux system, distinct from P-gp and MRP2, that extrudes ME3277 formed from ME3229 in the intestinal epithelial cells. The aim of the present study is to examine the involvement of breast cancer resistant protein (BCRP/ABCG2) as a cause of low oral absorption of ME3229.Methods. The transport activity of ME3277 in the presence and absence of ATP was determined using a rapid filtration method with the membrane vesicles prepared from LLC-PK1 cells expressing BCRP. The plasma concentrations of ME3229 and its metabolites were compared between Bcrp1(-/-) mice and wild-type mice after a single-pass perfusion of small intestine with ME3229.Results. The ATP-dependent uptake of ME3277 was greater in BCRP-expressing membrane vesicles than that in the control vesicles. Furthermore, it was found that after intestinal perfusion with ME3229 for 60 min, the plasma concentrations of ME3277 and PM-5, a metabolite of ME3229, increased 2-fold and 3-fold, respectively, in Bcrp1 knockout mice. It is possible that BCRP acts synergistically with intestinal carboxylesterases.Conclusion. These results suggest that Bcrp1 plays an important role in the intestinal efflux of ME3277 and, probably, PM-10 and PM-11, metabolites of ME3229, and limits its BA after oral administration of ME3229.