title: Pharmacokinetic interaction profile of riociguat, a new soluble guanylate cyclase stimulator, in vitro.
abstract: Riociguat is a new soluble guanylate cyclase stimulator under development for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. So far, the interaction potential of riociguat with other drugs is nearly unknown. Therefore, we assessed in vitro the potency of riociguat to inhibit important drug metabolising enzymes (cytochrome P450 (CYP) 3A4, CYP2C19, and CYP2D6) and drug transporters (P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and organic anion transporting polypeptides (OATP) 1B1 and 1B3). In addition we evaluated its substrate characteristics for P-gp, BCRP, and the multidrug resistance-associated protein 1 (MRP1/ABCC1). We also assessed riociguat's inducing properties on important drug metabolising enzymes and transporters and investigated its ability to activate the pregnane-X-receptor (PXR). Riociguat was identified as a weak to moderate inhibitor of P-gp (f2-value: 11.7 ± 4.8 μM), BCRP (IC50 = 46.2 ± 20.3 μM), OATP1B1 (IC50 = 34.1 ± 3.15 μM), OATP1B3 (IC50 = 50.3 ± 7.5 μM), CYP2D6 (IC50 = 12.4 ± 0.74 μM), and CYP2C19 (IC50 = 46.1 ± 7.14 μM). Furthermore, it induced mRNA expression of BCRP/ABCG2 (3-fold at 20 μM) and to a lesser extent of CYP3A4 (2.3-fold at 20 μM), UGT1A4, and ABCB11. The only weak inducing properties were confirmed by weak activation of PXR. Considering its systemic concentrations its interaction potential as a perpetrator drug seems to be low. In contrast, our data suggest that riociguat is a P-gp substrate and might therefore act as a victim drug when co-administered with strong P-gp inductors or inhibitors.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Rickert
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: johanna.weiss@med.uni-heidelberg.de.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D010599:Pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D006162:Guanylate Cyclase; C542595:riociguat
keywords: Chronic thromboembolic pulmonary hypertension; Drug metabolising enzymes; Drug transporters; Interaction; Pulmonary arterial hypertension; Riociguat