Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic.
Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic
Antimicrob Agents Chemother. 2017 Aug 24;61(9). doi: 10.1128/AAC.00837-17. Print 2017 Sep.
Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters and assess its importance for pharmacokinetics Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.
利匹韦林（TMC278）是一种高效的非核苷类逆转录酶抑制剂（NNRTI），是治疗 HIV 阳性患者的联合抗逆转录病毒治疗（cART）的有效成分之一。许多常用于 cART 的抗逆转录病毒药物是三磷酸腺苷结合盒（ABC）和/或溶质载体（SLC）药物转运体的底物，因此容易发生药代动力学药物相互作用（DDI）。我们的研究目的是评估利匹韦林与阿巴卡韦和拉米夫定对选定的 ABC 和 SLC 转运体的相互作用，并评估其对药代动力学的重要性。我们使用在过表达选定的 ABC 或 SLC 药物转运体的 MDCK 细胞中进行的积累测定法，发现利匹韦林是 MDR1 和 BCRP 的有效抑制剂，但不是 MRP2、OCT1、OCT2 或 MATE1。随后在 MDCKII-MDR1、MDCKII-BCRP 和 Caco-2 细胞单层上进行的转运实验表明，利匹韦林抑制 MDR1 和 BCRP 介导的阿巴卡韦外排，并增加其跨膜转运。在雄性 Wistar 大鼠中的实验证实了利匹韦林在小肠中抑制 MDR1/BCRP，导致阿巴卡韦的口服生物利用度显著增加。总之，利匹韦林抑制 MDR1 和 BCRP 转运体，并可能影响同时给予这些转运体底物的药代动力学行为，如阿巴卡韦。
