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抗 HIV 和抗丙型肝炎病毒药物抑制 Caco-2 细胞和精密切割大鼠及人肠切片中的 P-糖蛋白外排活性。

Anti-HIV and Anti-Hepatitis C Virus Drugs Inhibit P-Glycoprotein Efflux Activity in Caco-2 Cells and Precision-Cut Rat and Human Intestinal Slices.

机构信息

Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.

Department of Surgery, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.

出版信息

Antimicrob Agents Chemother. 2019 Oct 22;63(11). doi: 10.1128/AAC.00910-19. Print 2019 Nov.

Abstract

P-glycoprotein (ABCB1), an ATP-binding-cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions (DDIs). ABCB1 has been suggested to interact with many antivirals used to treat HIV and/or chronic hepatitis C virus (HCV) infections. Using bidirectional transport experiments in Caco-2 cells and a recently established model of accumulation in precision-cut intestinal slices (PCIS) prepared from rat ileum or human jejunum, we evaluated the potential of anti-HIV and anti-HCV antivirals to inhibit intestinal ABCB1. Lopinavir, ritonavir, saquinavir, atazanavir, maraviroc, ledipasvir, and daclatasvir inhibited the efflux of a model ABCB1 substrate, rhodamine 123 (RHD123), in Caco-2 cells and rat-derived PCIS. Lopinavir, ritonavir, saquinavir, and atazanavir also significantly inhibited RHD123 efflux in human-derived PCIS, while possible interindividual variability was observed in the inhibition of intestinal ABCB1 by maraviroc, ledipasvir, and daclatasvir. Abacavir, zidovudine, tenofovir disoproxil fumarate, etravirine, and rilpivirine did not inhibit intestinal ABCB1. In conclusion, using recently established methods for measuring drug accumulation in rat- and human-derived PCIS, we have demonstrated that some antivirals have a high potential for DDIs on intestinal ABCB1. Our data help clarify the molecular mechanisms responsible for reported increases in the bioavailability of ABCB1 substrates, including antivirals and drugs prescribed to treat comorbidity. These results could help guide the selection of combination pharmacotherapies and/or suitable dosing schemes for patients infected with HIV and/or HCV.

摘要

P-糖蛋白(ABCB1),一种 ATP 结合盒外排转运体,限制了其底物的肠道吸收,是药物-药物相互作用(DDI)的常见部位。ABCB1 已被认为与许多用于治疗 HIV 和/或慢性丙型肝炎病毒(HCV)感染的抗病毒药物相互作用。我们使用 Caco-2 细胞中的双向转运实验和最近建立的从大鼠回肠或人空肠制备的精密切割肠切片(PCIS)中积累模型,评估了抗 HIV 和抗 HCV 抗病毒药物抑制肠道 ABCB1 的潜力。洛匹那韦、利托那韦、沙奎那韦、阿扎那韦、马拉维若、来迪派韦和达卡他韦抑制了 rhodamine 123(RHD123)作为模型 ABCB1 底物在 Caco-2 细胞和大鼠来源的 PCIS 中的外排。洛匹那韦、利托那韦、沙奎那韦和阿扎那韦也显著抑制了人源 PCIS 中 RHD123 的外排,而马拉维若、来迪派韦和达卡他韦对肠道 ABCB1 的抑制作用存在个体间差异。阿巴卡韦、齐多夫定、富马酸替诺福韦二吡呋酯、依曲韦林和利匹韦林均不抑制肠道 ABCB1。总之,使用最近建立的用于测量大鼠和人源 PCIS 中药物积累的方法,我们已经证明,一些抗病毒药物对肠道 ABCB1 的 DDI 具有很高的潜力。我们的数据有助于阐明导致报道的 ABCB1 底物生物利用度增加的分子机制,包括抗病毒药物和用于治疗合并症的药物。这些结果可以帮助指导感染 HIV 和/或 HCV 的患者的联合药物治疗选择和/或合适的剂量方案。

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