Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs
Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs
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DOI：
10.1097/00002030-200211220-00009
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发表时间：
2002-11-22
期刊：
影响因子：
3.8
通讯作者：
Schinkel, AH
中科院分区：
文献类型：
--
作者：
Huisman, MT;Smit, JW;Schinkel, AH
背景资料：ATP结合盒（ABC）家族的各种药物转运蛋白限制了底物药物的口服生物利用度和细胞、脑、睾丸、脑脊液和胎儿渗透。MDR 1 P-糖蛋白（P-gp）已被证明转运大多数HIV蛋白酶抑制剂（HPI），并降低其口服生物利用度和淋巴细胞、脑、睾丸和胎儿渗透，可能导致对这些药物的治疗效果的主要限制作用。目的：为了研究ABC转运蛋白MRP 1、MRP 2、MRP 3、MRP 5和乳腺癌耐药蛋白1（Bcrp 1）是否是HPI沙奎那韦的有效转运蛋白，方法：用人或鼠的互补DNA（cDNA）转导极化的非人（犬）上皮细胞系，研究HPI的跨上皮转运。亚磺酰脲也能够增强MRP 2介导的沙奎那韦转运。与此相反，MRP 1，MRP 3，MRP 5，或Bcrp 1没有有效地运输HPI tested.Conclusions：人MRP 2积极运输几个HPI，并可能根据其已知的和假定的组织分布，因此降低HPI口服生物利用度。它还可能限制这些药物的脑和胎儿渗透，并增加其肝胆、肠和肾清除率。MRP 2的功能和增强其活性可能会对HPI的治疗效果产生不利影响，包括药理学保护区渗透。因此，体内抑制MRP 2功能可能会改善HIV/AIDS治疗。(C)2002年利平科特威廉姆斯威尔金斯。
Background: Various drug transporters of the ATP-binding cassette (ABC) family restrict the oral bioavailability and cellular, brain, testis, cerebrospinal fluid and fetal penetration of substrate drugs. MDR1 P-glycoprotein (P-gp) has been demonstrated to transport most HIV protease inhibitors (HPI) and to reduce their oral bioavailability and lymphocyte, brain, testis and fetal penetration, possibly resulting in major limiting effects on the therapeutic efficacy of these drugs.Objectives: To investigate whether the ABC transporters MRP1, MRP2, MRP3, MRP5 and breast cancer resistance protein 1 (Bcrp1) are efficient transporters of the HPI saquinavir, ritonavir and indinavir.Methods: Polarized epithelial non-human (canine) cell lines transduced with human or murine complementary DNA (cDNA) for each of the transporters were used to study transepithelial transport of the HPI.Results: MRP2 efficiently transported saquinavir, ritonavir and indinavir and this transport could be enhanced by probenecid. Sulfinpyrazone was also able to enhance MRP2-mediated saquinavir transport. In contrast, MRP1, MRP3, MRP5, or Bcrp1 did not efficiently transport the HPI tested.Conclusions: Human MRP2 actively transports several HPI and could, based on its known and assumed tissue distribution, therefore reduce HPI oral bioavailability. It may also limit brain and fetal penetration of these drugs and increase their hepatobiliary, intestinal and renal clearance. MRP2 function and enhancement of its activity could adversely affect the therapeutic efficacy, including the pharmacological sanctuary penetration, of HPI. In vivo inhibition of MRP2 function might, therefore, improve HIV/AIDS therapy. (C) 2002 Lippincott Williams Wilkins.