NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy.
Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy.
Int J Mol Sci. 2022 Sep 2;23(17):10043. doi: 10.3390/ijms231710043.
The most commonly used antiviral treatment against hepatitis C virus is a combination of direct-acting antivirals (DAAs) and ribavirin (RBV), which leads to a shortened duration of therapy and a sustained virologic response until 98%. Nonetheless, several dose-related side effects of RBV could limit its applications. This study aims to measure the urinary concentration of RBV and its main metabolites in order to evaluate the drug metabolism ability of HCV patients and to evaluate the adverse effects, such as anemia, with respect to RBV metabolite levels. RBV and its proactive and inactive metabolites were identified and quantified in the urine of 17 HCV males with severe liver fibrosis using proton nuclear magnetic resonance (H-NMR) at the fourth week (TW4) and at the twelfth week of treatment (EOT). Four prodrug urinary metabolites, including RBV, were identified and three of them were quantified. At both the TW4 and EOT stages, six HCV patients were found to maintain high concentrations of RBV, while another six patients maintained a high level of RBV proactive metabolites, likely due to nucleosidase activity. Furthermore, a negative correlation between the reduction in hemoglobin (Hb) and proactive forms was observed, according to RBV-triphosphate accumulation causing the hemolysis. These findings represent a proof of concept regarding tailoring the drug dose in relation to the specific metabolic ability of the individual, as expected by the precision medicine approach.
目前针对丙型肝炎病毒（HCV）最常用的抗病毒治疗方法是直接作用抗病毒药物（DAA）联合利巴韦林（RBV），这使得治疗时间缩短，持续病毒学应答率达到 98%。然而，RBV 的一些剂量相关的副作用可能会限制其应用。本研究旨在通过质子核磁共振（1H-NMR）检测 HCV 患者在第 4 周（TW4）和治疗结束时（EOT）的尿中 RBV 及其主要代谢物的浓度，以评估其药物代谢能力，并评估 RBV 代谢物水平与贫血等不良反应之间的关系。研究人员在 17 名严重肝纤维化的 HCV 男性患者的尿液中检测到 RBV 及其前体和无活性代谢物，并在第 4 周（TW4）和治疗结束时（EOT）进行了质子核磁共振（1H-NMR）检测。共鉴定出 4 种前体尿代谢产物，其中 3 种可定量。在 TW4 和 EOT 两个阶段，有 6 名患者发现 RBV 浓度较高，而另外 6 名患者则保持较高水平的 RBV 前体代谢物，这可能是由于核酶活性所致。此外，根据 RBV-三磷酸酯的积累导致溶血，还观察到血红蛋白（Hb）下降与前体形式之间存在负相关。这些发现为根据个体的特定代谢能力来调整药物剂量提供了概念验证，这也是精准医学方法所期望的。
