Velpatasvir is a novel inhibitor of hepatitis C virus nonstructural protein 5A that received US Food and Drug Administration approval for the treatment of patients with chronic hepatitis C virus genotypes 1–6. In the present study, a sensitive bioanalytical method for velpatasvir was developed using high-performance liquid chromatography coupled with a fluorescence detector system, which was applied to elucidate the factors determining the oral bioavailability and disposition of velpatasvir. This method offered sufficient sensitivity, with a lower limit of quantification of 0.5 ng/mL, which is comparable to previously reported methods using liquid chromatography coupled with tandem mass spectrometry. Velpatasvir exhibited low oral bioavailability, moderate intestinal permeability, and significant biliary excretion in rats. It was also found to be significantly metabolized in the liver, with a low-to-moderate extraction ratio; however, its intestinal metabolism and enterohepatic circulation did not occur. Thus, our present results demonstrate that the oral bioavailability of velpatasvir is primarily dependent on gut absorption and hepatic first-pass metabolism. The fractions of velpatasvir dose unabsorbed from the gut and eliminated by the liver before reaching the systemic circulation following oral administration were estimated to be 32.8%–58.6% and 4.74%–30.54% of the oral dose, respectively. To our knowledge, this is the first systematic study to investigate the contributory roles of biopharmaceutical and pharmacokinetic factors on the oral bioavailability of velpatasvir, together with a new bioanalytical method for velpatasvir.

Velpatasvir 是一种新型丙型肝炎病毒非结构蛋白 5A 抑制剂，已获得美国食品和药物管理局批准用于治疗慢性丙型肝炎病毒基因型 1-6 的患者。在本研究中，使用高效液相色谱结合荧光检测器系统开发了一种敏感的维帕他韦生物分析方法，用于阐明决定维帕他韦口服生物利用度和处置的因素。该方法提供了足够的灵敏度，定量下限为 0.5 ng/mL，这与之前报道的使用液相色谱与串联质谱联用的方法相当。Velpatasvir 在大鼠中表现出低口服生物利用度、中等肠道通透性和显着胆汁排泄。还发现它在肝脏中显着代谢，提取率低至中等；然而，其肠道代谢和肠肝循环并未发生。因此，我们目前的结果表明，维帕他韦的口服生物利用度主要取决于肠道吸收和肝脏首过代谢。口服给药后未从肠道吸收并被肝脏消除的维帕他韦剂量比例分别估计为口服剂量的 32.8%–58.6% 和 4.74%–30.54%。据我们所知，这是第一项研究生物药学和药代动力学因素对维帕他韦口服生物利用度的贡献作用的系统研究，以及维帕他韦的新生物分析方法。