Effect of Chronic Hepatitis C on the Activity of the Membrane Transporters P-gp and OATP1B1/BCRP on Patients With Different Stages of Hepatic Fibrosis.

Abstract

The activity of the membrane transporters organic anion-transporting polypeptide 1B1 (OATP1B1) & breast cancer resistance protein (BCRP) (rosuvastatin) and P-glycoprotein (P-gp) (fexofenadine) was evaluated in patients with chronic hepatitis C virus (HCV) infection (n = 28), genotypes 1 and 3, investigated before the treatment with direct-acting antiviral agents (Phase 1) and up to 30 days after the assessment of the virologic response (Phase 2). Participants allocated in Groups 1 (n = 15; F0/F1 and F2, mild to moderate liver fibrosis) and 2 (n = 13; F3 and F4, advanced course of liver fibrosis/cirrhosis) received in both phases fexofenadine (10 mg) and rosuvastatin (2 mg). OATP1B1 & BCRP activity (rosuvastatin area under the plasma concentration-time curve of rosuvastatin from time zero to infinity (AUC0-∞ )) was reduced in Groups 1 and 2, respectively, by 25% (ratio 0.75 (0.53-0.82), P < 0.01) and 31% (ratio 0.69 (0.46-0.85), P < 0.05) in Phase 1 compared with Phase 2. OATP1B1 & BCRP activity was reduced in Phases 1 and 2, respectively, by 49% (median ratio 1.51 (1.17-2.20), P < 0.05) and 61% (ratio 1.39 (1.16-2.02), P < 0.01) in Group 2 compared with Group 1. P-gp activity (fexofenadine AUC0-∞ ) was also reduced in Phase 1 compared with Phase 2 (ratio Phase2/Phase1 0.79 (0.66-0.96) in Group 1 and 0.81 (0.69-0.96) in Group 2) as well as in Group 2 compared with Group 1 in both Phases (ratio Group2/Group1 1.47 (1.08-2.01) in Phase 1 and 1.51 (1.10-2.07) in Phase 2). Thus, clinicians administering OATP1B1 & BCRP and P-gp substrates with low therapeutic indexes should consider the evolution of the treatment and the stage of HCV infection.