Ceckova Martina, Reznicek Josef, Ptackova Zuzana, Cerveny Lukas, Müller Fabian, Kacerovsky Marian, Fromm Martin F, Glazier Jocelyn D, Staud Frantisek
Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic.
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Antimicrob Agents Chemother. 2016 Aug 22;60(9):5563-72. doi: 10.1128/AAC.00648-16. Print 2016 Sep.
Lamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employed in vitro accumulation and transport experiments on MDCK cells overexpressing drug efflux transporters, in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparent Km of 4.21 mM and Vmax of 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent with in vitro transport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.
拉米夫定是预防HIV阳性女性母婴传播（MTCT）的首选抗逆转录病毒药物之一。在本研究中，我们调查了药物外排转运体P-糖蛋白（P-gp）（MDR1[ABCB1]）、乳腺癌耐药蛋白（BCRP）（ABCG2）、多药耐药相关蛋白2（MRP2）（ABCC2）和多药及毒素排出蛋白1（MATE1）（SLC47A1）对拉米夫定跨膜转运和经胎盘转运的相关性。我们在过表达药物外排转运体的MDCK细胞上进行了体外蓄积和转运实验、原位灌注的足月大鼠胎盘实验，以及从人足月胎盘中分离的微绒毛质膜（MVM）囊泡中的囊泡摄取实验。MATE1显著加速了在表达MATE1的MDCK细胞中拉米夫定的转运，而在MDCK-MDR1、MDCK-MRP2和MDCK-BCRP单层细胞中未观察到转运体驱动的拉米夫定外排。MATE1介导的拉米夫定外排似乎是一个低亲和力过程（在MDCK-MATE1细胞中，表观Km为4.21 mM，Vmax为5.18 nmol/mg蛋白/分钟）。与体外转运研究一致，拉米夫定的经胎盘清除不受P-gp、BCRP或MRP2的影响。然而，拉米夫定跨双灌注大鼠胎盘的转运以及拉米夫定进入人胎盘MVM囊泡的摄取显示出pH依赖性，表明MATE1可能参与了药物从胎儿到母体的外排。总之，拉米夫定的胎盘转运似乎不受P-gp、MRP2或BCRP的影响，但一种pH依赖性机制介导了拉米夫定在胎儿到母体方向的转运。我们认为MATE1可能至少部分负责这种转运。
