Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Chem Biol Interact. 2021 Apr 1;338:109428. doi: 10.1016/j.cbi.2021.109428. Epub 2021 Feb 27.
Camostat mesylate, a potent inhibitor of the human transmembrane protease, serine 2 (TMPRSS2), is currently under investigation for its effectiveness in COVID-19 patients. For its safe application, the risks of camostat mesylate to induce pharmacokinetic drug-drug interactions with co-administered drugs should be known. We therefore tested in vitro the potential inhibition of important efflux (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2)), and uptake transporters (organic anion transporting polypeptides OATP1B1, OATP1B3, OATP2B1) by camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA). Transporter inhibition was evaluated using fluorescent probe substrates in transporter over-expressing cell lines and compared to the respective parental cell lines. Moreover, possible mRNA induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) was analysed in LS180 cells by quantitative real-time PCR. The results of our study for the first time demonstrated that camostat mesylate and GBPA do not relevantly inhibit P-gp, BCRP, OATP1B1 or OATP1B3. Only OATP2B1 was profoundly inhibited by GBPA with an IC of 11 μM. Induction experiments in LS180 cells excluded induction of PXR-regulated genes such as cytochrome P450 3A4 (CYP3A4) and ABCB1 and AhR-regulated genes such as CYP1A1 and CYP1A2 by camostat mesylate and GBPA. Together with the summary of product characteristics of camostat mesylate indicating no inhibition of CYP1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, our data suggest a low potential of camostat mesylate to act as a perpetrator in pharmacokinetic drug-drug interactions. Only inhibition of OATP2B1 by GBPA warrants further investigation.
甲磺酸卡莫司他是一种有效的人类跨膜丝氨酸 2 蛋白酶（TMPRSS2）抑制剂，目前正在研究其在 COVID-19 患者中的疗效。为了安全应用，应该了解甲磺酸卡莫司他与合用药物发生药代动力学药物相互作用的风险。因此，我们在体外测试了甲磺酸卡莫司他及其活性代谢物 4-(4-胍基苯甲酰氧基)苯乙酸（GBPA）对重要外排转运体（P 糖蛋白（P-gp，ABCB1）、乳腺癌耐药蛋白（BCRP，ABCG2））和摄取转运体（有机阴离子转运多肽 OATP1B1、OATP1B3、OATP2B1）的潜在抑制作用。通过在转运体过表达细胞系中使用荧光探针底物来评估转运体抑制作用，并与相应的亲本细胞系进行比较。此外，通过定量实时 PCR 在 LS180 细胞中分析了受核孕烷 X 受体（PXR）和芳香烃受体（AhR）调节的与药代动力学相关的基因的 mRNA 诱导。我们的研究结果首次表明，甲磺酸卡莫司他和 GBPA 不会显著抑制 P-gp、BCRP、OATP1B1 或 OATP1B3。只有 OATP2B1 被 GBPA 深度抑制，IC 为 11μM。LS180 细胞的诱导实验排除了甲磺酸卡莫司他和 GBPA 对 PXR 调节的基因（如细胞色素 P450 3A4（CYP3A4）和 ABCB1）和 AhR 调节的基因（如 CYP1A1 和 CYP1A2）的诱导。结合甲磺酸卡莫司他产品特性摘要表明，它在体外不会抑制 CYP1A2、2C9、2C19、2D6 和 3A4，我们的数据表明甲磺酸卡莫司他作为药代动力学药物相互作用的主要因素的潜力较低。只有 GBPA 对 OATP2B1 的抑制作用需要进一步研究。
