Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites
Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites
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DOI：
10.1080/00498250500354493
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发表时间：
2005-10-01
期刊：
影响因子：
1.8
通讯作者：
Augustijns, P
中科院分区：
文献类型：
--
作者：
Mallants, R;Van Oosterwyck, K;Augustijns, P
在Caco-2系统、Ussing小室和大鼠在体外排实验中，研究了多药耐药相关蛋白2(MR-P2)在富马酸替诺福韦(DF)及其代谢物[替诺福韦(单)酯和替诺福韦]肠道排泄和肝胆排泄中的作用。在Caco-2模型和Ussing小室中，当加入MRP抑制剂丙磺舒时，没有观察到显著的转运差异。在Ussing小室中，当使用MRP2缺陷大鼠的肠道组织时，转运也是相似的。静脉注射替诺福韦DF后，MRP2缺陷大鼠和丙磺舒治疗大鼠的胆汁中替诺福韦[(单酯)酯]排泄量显著减少。MRP2缺陷大鼠的血药浓度-时间曲线下面积[替诺福韦和替诺福韦(单)酯分别为0.0 1和0.36+0.0 3mU·min(-1)]和丙磺舒治疗组(1.42+/-0.0 4和0.36+/-0.0 2mU·min(-1))较对照组(0.6 4+/-0.0 5和0.15+/-1 0.061 mU·min(-1))增加。在联合应用丙磺舒或使用MRP2缺陷大鼠时，对照组大鼠肠道灌流液中替诺福韦[(单酯)酯]的外观相似。总而言之，MRP2似乎对替诺福韦和替诺福韦(单)酯的肠道处置没有调节作用。然而，抑制(丙磺舒)或完全缺乏MRP2(MRP2缺陷大鼠)显著减少了肝胆消除，这伴随着全身暴露的增加。
The role of multidrug resistance-associated protein 2 (MR-P2) on the intestinal disposition and hepatobiliary elimination of tenofovir disoproxil fumarate (DF) and its metabolites [tenofovir (mono)ester and tenofovir] was studied in the Caco-2 system, Ussing chambers and rat in-situ efflux experiments. In the Caco-2 model and Ussing chambers, no statistically significant differences in transport could be observed when the MRP inhibitor probenecid was included. In Ussing chambers, transport was also similar when using intestinal tissue from MRP2-deficient rats. After intravenous administration of tenofovir DF, the excretion of tenofovir [(mono)ester] in bile was significantly decreased in MRP2-deficient rats and in rats treated with probenecid. The area under the blood concentration-time curve was increased in MRP2-deficient rats [1.0 +/- 0.1 and 0.36 +/- 0.03 mu M.min(-1) for tenofovir and tenofovir (mono)ester, respectively] and rats treated with probenecid (1.42 +/- 0.04 and 0.36 +/- 0.02 mu M.min(-1)) compared with control rats (0.64 +/- 0.05 and 0.15 +/- 1 0.061 mu M.min(-1)). The appearance of tenofovir [(mono)ester] in intestinal perfusate was similar in control rats upon co-administering probenecid or when using MRP2-deficient rats. In conclusion, MRP2 appeared to have no modulatory effect on the intestinal disposition of tenofovir and tenofovir (mono)ester. However, inhibition (probenecid) or the total absence of MRP2 (MRP2-deficient rats) significantly reduced hepatobiliary elimination, which was accompanied by increased systemic exposure.