Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Int J Antimicrob Agents. 2014 Feb;43(2):184-8. doi: 10.1016/j.ijantimicag.2013.10.003. Epub 2013 Nov 5.
Triple therapy combining the protease inhibitor telaprevir with interferon-α and ribavirin is a promising new option for long-term treatment of hepatitis C. The interaction potential of telaprevir has not yet been fully elucidated. The in vitro potency of telaprevir to inhibit P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) was assessed and its substrate characteristics for P-gp, BCRP and the multidrug resistance-associated proteins (MRPs, ABCCs) 1-3 were evaluated. The inducing properties of telaprevir on important drug-metabolising enzymes and transporters were also assessed and its ability to activate the pregnane X receptor (PXR) was investigated. Using growth inhibition assays, it was confirmed that telaprevir is a substrate of P-gp and it was demonstrated for the first time that it is not transported by BCRP and MRPs. Telaprevir only moderately inhibited P-gp in the calcein assay and did not inhibit BCRP in the pheophorbide A assay. In LS180 cells, telaprevir strongly induced mRNA expression of ABCG2 (4.3-fold at 30 μmol/L) and weakly induced ABCB11, CYP2C19 and UGT1A3. In contrast, telaprevir had no significant influence on mRNA expression of CYP3A4, UGT1A9, ABCB1, ABCC2 and SLCO1B1. In a reporter gene assay, telaprevir did not activate PXR. Thus, it appears unlikely that telaprevir induces CYP3A4 and P-gp in vivo in such a way as to provoke clinically relevant drug interactions. From the numerous perpetrator characteristics, telaprevir's inhibitor properties, especially of CYP3A4 and P-gp, appear to be the most relevant mechanism for drug interactions. The clinical relevance of the strong inducing effects on ABCG2 requires proper assessment.
联合蛋白酶抑制剂特拉匹韦、干扰素-α和利巴韦林的三联疗法是治疗丙型肝炎的一种很有前途的新方法。特拉匹韦的相互作用潜力尚未完全阐明。评估了特拉匹韦抑制 P-糖蛋白（P-gp，ABCB1）和乳腺癌耐药蛋白（BCRP，ABCG2）的体外效力，并评估了其对 P-gp、BCRP 和多药耐药相关蛋白（MRPs，ABCCs）1-3 的底物特性。还评估了特拉匹韦对重要药物代谢酶和转运体的诱导特性及其激活孕烷 X 受体（PXR）的能力。通过生长抑制测定，证实特拉匹韦是 P-gp 的底物，并且首次表明它不由 BCRP 和 MRPs 转运。特拉匹韦在钙黄绿素测定中仅中度抑制 P-gp，在原卟啉 A 测定中不抑制 BCRP。在 LS180 细胞中，特拉匹韦强烈诱导 ABCG2 的 mRNA 表达（在 30 μmol/L 时为 4.3 倍），并弱诱导 ABCB11、CYP2C19 和 UGT1A3。相比之下，特拉匹韦对 CYP3A4、UGT1A9、ABCB1、ABCC2 和 SLCO1B1 的 mRNA 表达没有显著影响。在报告基因测定中，特拉匹韦没有激活 PXR。因此，特拉匹韦不太可能以引起临床相关药物相互作用的方式在体内诱导 CYP3A4 和 P-gp。从众多的致犯特征来看，特拉匹韦的抑制剂特性，特别是对 CYP3A4 和 P-gp 的抑制特性，似乎是药物相互作用的最相关机制。对 ABCG2 的强烈诱导作用的临床相关性需要进行适当评估。
