Hsu Christine C, Bansal Sunil, Cao Hong, Smith Coleman I, He Aiwu Ruth, Gay Martha D, Li Yaoxiang, Cheema Amrita, Smith Jill P
Department of Transplant Surgery, MedStar Georgetown University Hospital, Washington, DC 20007, USA.
Department of Oncology, Georgetown University, Washington, DC 20057, USA.
Pharmaceutics. 2022 Mar 12;14(3):627. doi: 10.3390/pharmaceutics14030627.
Proglumide is an orally administered cholecystokinin receptor antagonist that was found to improve nonalcoholic steatohepatitis, reverse liver fibrosis, and decrease incidence of hepatocellular carcinoma (HCC) in animal models. The current investigation aimed to test the pharmacokinetics and safety of proglumide in subjects with hepatic impairment compared with healthy controls. In this translational study, subjects with confirmed cirrhosis, Child-Pugh stage A or B, or healthy controls were recruited for a single-dosing study. Baseline urine and blood samples were obtained before administration of proglumide and also collected after ingestion up to 24 h. Drug concentrations measured by mass spectroscopy revealed peak plasma concentrations (Cmax) of 7847, 9721, and 10,635 ng/mL at about 1 h (Tmax) for healthy controls, subjects with Child-Pugh A, and B cirrhosis, respectively. The serum elimination half time was 3 h. Maximum urine drug concentration (Cmax = ~411 µg/mL) was observed at 3 h, and urinary drug concentration declined at 5 h. There were no adverse events reported, and follow-up liver panels in cirrhosis subjects were unchanged or improved. This investigation demonstrated that proglumide is safe and has similar pharmacokinetic properties in subjects with cirrhosis as in healthy controls; therefore, it will be safe to test the efficacy of proglumide as a therapeutic agent in those subjects with cirrhosis or HCC.
丙谷胺是一种口服的胆囊收缩素受体拮抗剂，在动物模型中发现它可改善非酒精性脂肪性肝炎、逆转肝纤维化并降低肝细胞癌（HCC）的发病率。当前的研究旨在测试丙谷胺在肝功能损害受试者与健康对照者中的药代动力学和安全性。在这项转化研究中，招募了确诊为肝硬化（Child-Pugh A或B级）的受试者或健康对照者进行单剂量研究。在服用丙谷胺之前采集基线尿液和血液样本，并在摄入后长达24小时内进行收集。通过质谱法测量的药物浓度显示，健康对照者、Child-Pugh A级肝硬化受试者和B级肝硬化受试者在约1小时（达峰时间）时的血浆峰浓度（Cmax）分别为7847、9721和10635 ng/mL。血清消除半衰期为3小时。在3小时时观察到最大尿药浓度（Cmax =约411 µg/mL），尿药浓度在5小时时下降。未报告不良事件，肝硬化受试者的后续肝功能检查结果未改变或有所改善。这项研究表明，丙谷胺在肝硬化受试者中是安全的，并且其药代动力学特性与健康对照者相似；因此，在那些肝硬化或HCC受试者中测试丙谷胺作为治疗药物的疗效将是安全的。
