In vivo evaluation of thiolated poly(acrylic acid) as a drug absorption modulator for MRP2 efflux pump substrates
In vivo evaluation of thiolated poly(acrylic acid) as a drug absorption modulator for MRP2 efflux pump substrates
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DOI：
10.1016/j.ejpb.2009.03.008
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发表时间：
2009-08-01
影响因子：
4.9
通讯作者：
Bernkop-Schnuerch, Andreas
中科院分区：
文献类型：
--
作者：
Greindl, Melanie;Foeger, Florian;Bernkop-Schnuerch, Andreas
最近，一些聚合物被报道通过抑制肠道外排泵来调节药物吸收，如多药耐药蛋白(MRPs)和P-糖蛋白(P-gp)。本研究的目的是评价硫代化聚丙烯酸(PAA-Cys)作为MRP2外排泵底物的体内药物吸收调节剂的有效性，以磺胺荷丹明101为代表的MRP2底物。体外考察了未修饰的PAA和PAA(250)-半胱氨酸的促透作用。用安装在Ussing式小室中的新鲜切除的大鼠肠粘膜来评价每粒聚合物显示580mU摩尔游离硫醇基团的能力。与缓冲器控制的情况相比。在0.5%未修饰PAA(250)和0.5%(w/v)PAA(250)-Cys存在下，磺胺类药物101的转运效率分别提高了1.3倍和4.0倍。在体内，给大鼠灌胃含4%(w/v)未修饰PAA(250)或4%(w/v)硫代化PAA250的磺胺荷丹明101溶液。PAA(250)-CyS溶液使磺胺荷丹明101的血药浓度-时间曲线下面积(AUC(0-12))较对照增加3.8倍，较未修饰的PAA(250)增加2.2倍。这项体内研究表明，PAA(250)-半胱氨酸显著提高了MRP2底物磺胺若丹明101的口服生物利用度。(C)2009爱思唯尔B.V.保留所有权利。
Recently, several polymers have been reported to Modulate drug absorption by inhibition of intestinal efflux Pumps Such as multidrug resistance proteins (MRPs) and P-glycoprotein (P-gp). The aim of the present study was to evaluate the efficiency of thiolated poly(acrylic acid) (PAA-Cys) to act as a drug absorption modulator for MRP2 efflux pump substrates in vivo, Using sulforhodamine 101 as representative MRP2 Substrate. In vitro, the permeation-enhancing effect Of Unmodified PAA and PAA(250)-Cys. displaying 580 mu mol free thiol groups per grain polymer, was evaluated by using freshly excised rat intestinal mucosa mounted in Ussing-type chambers. In comparison to that of the buffer control. the sulforhodamine 101 transport in the presence of 0.5% unmodified PAA(250) and 0.5% (w/v) PAA(250)-Cys was 1.3- and 4.0-fold improved, respectively. In Vivo, sulforhodamine 101 solutions containing 4% (w/v) Unmodified PAA(250) or 4% (w/v) thiolated PAA250 were orally given to rats. The PAA(250)-CYS Solution increased the area Under the plasma concentration-time curve (AUC(0-12)) of sulforhodamine 101 3.8-fold in comparison to control and 2.2-fold in comparison to Unmodified PAA(250). This in vivo study revealed that PAA(250)-CYS Significantly increased the oral bioavailability of MRP2 substrate sulforhodamine 101. (C) 2009 Elsevier B.V. All rights reserved.