Blank Antje, Meier Katrin, Urban Stephan, Haefeli Walter Emil, Weiss Johanna
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany.
Antivir Ther. 2018;23(3):267-275. doi: 10.3851/IMP3206.
Myrcludex B is a first-in-class virus entry inhibitor for patients with chronic hepatitis B or B/D infections. In patients it will be coadministered with drugs needed for the disease or comorbidities. We aimed to define the risk of drug-drug interactions by characterizing the influence of myrcludex B on relevant drug transporting and metabolizing enzymes in vitro.
Inhibition of P-glycoprotein (P-gp; ABCB1), breast cancer resistance protein (BCRP/ABCG2), and the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3) was measured in cells over-expressing the respective transporter using fluorogenic substrates. Inhibition of cytochrome P450 enzymes (CYPs) was assessed with commercially available kits. mRNA induction of drug transporting and metabolizing enzymes was measured in LS180 cells after 4 days of treatment by quantitative real-time PCR. Pregnane X receptor (PXR) activation was assessed using a reporter-gene assay.
Whereas activities of P-gp and BCRP were not influenced by myrcludex B, OATP1B1 and OATP1B3 were specifically inhibited with a 50% inhibitory concentration (IC) of 0.5 and 8.7 µM, respectively. Myrcludex B weakly inhibited all CYPs tested at concentrations ≥10 µM except CYP2D6, which was not inhibited at concentrations up to 2 µM. Myrcludex B had no influence on mRNA expression of CYP1A1, CYP3A4, UGT1A3, ABCB1, ABCC2 and ABCG2, and on PXR activity.
Our in vitro study suggests that myrcludex B is not at major risk of acting as a perpetrator drug. A potential inhibition of the uptake transporters OATP1B1 and OATP1B3 and a previous clinical finding of potential CYP3A inhibition, requires further evaluation and should be carefully addressed in future trials.
Myrcludex B是用于慢性乙型肝炎或B/D型感染患者的一流病毒进入抑制剂。在患者中，它将与治疗该疾病或合并症所需的药物联合使用。我们旨在通过在体外表征Myrcludex B对相关药物转运和代谢酶的影响来确定药物相互作用的风险。
使用荧光底物在过表达相应转运蛋白的细胞中测量对P-糖蛋白（P-gp；ABCB1）、乳腺癌耐药蛋白（BCRP/ABCG2）以及有机阴离子转运多肽1B1和1B3（OATP1B1/SLCO1B1和OATP1B3/SLCO1B3）的抑制作用。使用市售试剂盒评估细胞色素P450酶（CYPs）的抑制作用。通过定量实时PCR在处理4天后的LS180细胞中测量药物转运和代谢酶的mRNA诱导。使用报告基因测定评估孕烷X受体（PXR）的激活。
虽然P-gp和BCRP的活性不受Myrcludex B的影响，但OATP1B1和OATP1B3分别被特异性抑制，50%抑制浓度（IC）分别为0.5和8.7μM。Myrcludex B在浓度≥10μM时对所有测试的CYPs有微弱抑制作用，但对CYP2D6除外，其在浓度高达2μM时未被抑制。Myrcludex B对CYP1A1、CYP3A4、UGT1A3、ABCB1、ABCC2和ABCG2的mRNA表达以及PXR活性没有影响。
我们的体外研究表明，Myrcludex B作为肇事药物的风险不大。对摄取转运蛋白OATP1B1和OATP1B3的潜在抑制以及先前关于潜在CYP3A抑制的临床发现，需要进一步评估，并且在未来试验中应谨慎处理。
