Pharmacokinetic interaction profile of riociguat, a new soluble guanylate cyclase stimulator, in vitro

摘要: Abstract Riociguat is a new soluble guanylate cyclase stimulator under development for pulmonary arterial hypertension and chronic thromboembolic hypertension. So far, the interaction potential of riociguat with other drugs nearly unknown. Therefore, we assessed in vitro potency to inhibit important drug metabolising enzymes (cytochrome P450 (CYP) 3A4, CYP2C19, CYP2D6) transporters (P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), organic anion transporting polypeptides (OATP) 1B1 1B3). In addition evaluated its substrate characteristics P-gp, BCRP, multidrug resistance-associated 1 (MRP1/ABCC1). We also riociguat's inducing properties on investigated ability activate pregnane-X-receptor (PXR). was identified as weak moderate inhibitor 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), CYP2C19 (IC50 = 46.1 ± 7.14 μM). Furthermore, it induced mRNA expression BCRP/ABCG2 (3-fold at 20 μM) lesser extent CYP3A4 (2.3-fold 20 μM), UGT1A4, ABCB11. The only were confirmed by activation PXR. Considering systemic concentrations perpetrator seems be low. contrast, our data suggest that might therefore act victim when co-administered strong inductors or inhibitors.