Department of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Clin Pharmacol Ther. 2023 Jul;114(1):173-181. doi: 10.1002/cpt.2908. Epub 2023 May 16.
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 (AUC )) 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 AUC ) 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.
在接受直接作用抗病毒药物治疗之前（第 1 阶段）和评估病毒学应答后 30 天（第 2 阶段），评估了患有慢性丙型肝炎病毒（HCV）感染（n=28）的患者（基因型 1 和 3）的膜转运蛋白有机阴离子转运多肽 1B1（OATP1B1）和乳腺癌耐药蛋白（BCRP）（瑞舒伐他汀）和 P-糖蛋白（P-gp）（非索非那定）的活性。在第 1 阶段，将参与者分配到第 1 组（n=15；F0/F1 和 F2，轻度至中度肝纤维化）和第 2 组（n=13；F3 和 F4，晚期肝纤维化/肝硬化），分别接受非索非那定（10mg）和瑞舒伐他汀（2mg）。第 1 组和第 2 组的 OATP1B1 和 BCRP 活性（瑞舒伐他汀从时间零到无穷大的血浆浓度-时间曲线下面积瑞舒伐他汀 AUC）分别降低了 25%（比值 0.75（0.53-0.82），P<0.01）和 31%（比值 0.69（0.46-0.85），P<0.05），与第 2 阶段相比。与第 1 组相比，第 1 阶段和第 2 阶段的 OATP1B1 和 BCRP 活性分别降低了 49%（中位数比值 1.51（1.17-2.20），P<0.05）和 61%（比值 1.39（1.16-2.02），P<0.01）。第 1 组和第 2 组的 P-gp 活性（非索非那定 AUC）也分别低于第 1 阶段（第 1 组比值 Phase2/Phase1 0.79（0.66-0.96），第 2 组比值 0.81（0.69-0.96））与第 2 阶段（第 1 组比值 Group2/Group1 1.47（1.08-2.01），第 2 组比值 1.51（1.10-2.07））。因此，给具有低治疗指数的 OATP1B1 和 BCRP 和 P-gp 底物的患者进行治疗的临床医生应考虑治疗的进展和 HCV 感染的阶段。
