title: Telaprevir is a substrate and moderate inhibitor of P-glycoprotein, a strong inductor of ABCG2, but not an activator of PXR in vitro.
abstract: 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.
authors: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Electronic address: johanna.weiss@med.uni-heidelberg.de.
authors: Johanna
authors: J
authors: Weiss
authors: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors: Jonas Philipp
authors: JP
authors: Becker
authors: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors: Walter Emil
authors: WE
authors: Haefeli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009842:Oligopeptides / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism*
chemical_list: C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000998:Antiviral Agents; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins; D009842:Oligopeptides; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C486464:telaprevir
keywords: CYPs; Drug transporters; Interaction; PXR; Telaprevir