Alam Novera, Angeli Mia G, Greenblatt David J
Graduate Program in Pharmacology and Drug Development, Sackler School of Graduate Biomedical Sciences, Boston, MA, USA.
Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.
J Pharm Pharmacol. 2017 Dec;69(12):1794-1801. doi: 10.1111/jphp.12821. Epub 2017 Oct 9.
The direct-acting protease inhibitor paritaprevir is a new pharmaco-logic option available for treatment of chronic hepatitis C (HCV). Paritaprevir is reported to inhibit human UGT 1A1, but the mechanism of inhibition and its possible clinical consequences are not established. Our objective was to evaluate the in-vitro metabolic interaction between paritaprevir and the oral contraceptive steroid ethinyl estradiol (EE), a UGT 1A1 substrate.
Enzyme kinetic parameters were determined using human liver microsomes for the biotransformation of EE to its glucuronide metabolites, and the potency and mechanism of inhibition by paritaprevir. Probenecid was used as a reference inhibitor for purposes of assay validation.
The underlying pattern of EE kinetics was complex, with evidence of substrate inhibition. The in-vitro inhibition constant (K ) value for paritaprevir vs EE on average was 20 μm and was consistent with a competitive inhibition mechanism. The ratio of in-vivo maximum plasma concentration of paritaprevir to in-vitro K was <0.1.
Paritaprevir is an in-vitro inhibitor of UGT 1A1. However, the in-vitro K value relative to maximum clinical plasma concentrations is below the threshold to trigger a recommendation for pharmacokinetic drug interaction studies.
直接作用蛋白酶抑制剂帕立瑞韦是治疗慢性丙型肝炎（HCV）的一种新的药理学选择。据报道，帕立瑞韦可抑制人尿苷二磷酸葡萄糖醛酸基转移酶1A1（UGT 1A1），但其抑制机制及其可能的临床后果尚未明确。我们的目的是评估帕立瑞韦与口服避孕药甾体炔雌醇（EE，一种UGT 1A1底物）之间的体外代谢相互作用。
使用人肝微粒体确定EE转化为其葡萄糖醛酸代谢物的酶动力学参数，以及帕立瑞韦的抑制效力和机制。丙磺舒用作测定验证的参考抑制剂。
EE动力学的基本模式很复杂，有底物抑制的证据。帕立瑞韦对EE的体外抑制常数（Ki）值平均为20μm，与竞争性抑制机制一致。帕立瑞韦体内最大血浆浓度与体外Ki的比值<0.1。
帕立瑞韦是UGT 1A1的体外抑制剂。然而，相对于临床最大血浆浓度的体外Ki值低于触发药代动力学药物相互作用研究建议的阈值。
