多囊肾病模型中托伐普坦及其部分代谢产物肝肠处置的改变。
Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease.
机构信息
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.J.B., J.B., Y.C., K.L.R.B.); Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan (K.M.); Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland (S.E.R.); and Brock Scientific Consulting, LLC, Montgomery Village, Maryland (W.J.B.).
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.J.B., J.B., Y.C., K.L.R.B.); Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan (K.M.); Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland (S.E.R.); and Brock Scientific Consulting, LLC, Montgomery Village, Maryland (W.J.B.)
出版信息
Drug Metab Dispos. 2019 Feb;47(2):155-163. doi: 10.1124/dmd.118.083907. Epub 2018 Nov 30.
Tolvaptan, a vasopressin V-receptor antagonist, has demonstrated efficacy in slowing kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). In the pivotal clinical trial, the incidence of elevated liver enzymes was higher in patients receiving tolvaptan compared with placebo. Adjudication by a panel of expert hepatologists concluded a causal link of tolvaptan to liver injury in patients with ADPKD. An ex situ isolated perfused liver (IPL) study of tolvaptan disposition was undertaken in a rodent model of ADPKD, the polycystic kidney (PCK) rat ( = 5), and compared with wild-type (WT) Sprague-Dawley rats ( = 6). Livers were perfused with tolvaptan, followed by a tolvaptan-free washout phase. Total recovery (mean ± S.D. percentage of dose; PCK vs. WT) of tolvaptan and two metabolites, DM-4103 and DM-4107, quantified by liquid chromatography-tandem mass spectroscopy, was 58.14% ± 24.72% vs. 43.40% ± 18.11% in liver, 20.10% ± 9.15% vs. 21.17% ± 12.51% in outflow perfusate, and 0.08% ± 0.01% vs. 0.39% ± 0.32% in bile. DM-4103 recovery (mean ± S.D. percentage of dose) was decreased in PCK vs. WT bile (<0.01% ± <0.01% vs. 0.02% ± 0.01%; = 0.0037), and DM-4107 recovery was increased in PCK vs. WT outflow perfusate (1.60% ± 0.57% vs. 0.43% ± 0.29%; = 0.0017). A pharmacokinetic compartmental model assuming first-order processes was developed to describe the rate vs. time profiles of tolvaptan and DM-4103 + DM-4107 in rat IPLs. The model-derived estimate of tolvaptan's biliary clearance was significantly decreased in PCK compared with WT IPLs. The model predicted greater hepatocellular concentrations of tolvaptan and DM-4103 + DM-4107 in PCK compared with WT IPLs. Increased hepatocellular exposure to tolvaptan and metabolites may contribute to the hepatotoxicity in patients with ADPKD treated with tolvaptan.
托伐普坦是一种血管加压素 V 型受体拮抗剂，已被证明可减缓常染色体显性多囊肾病（ADPKD）患者的肾功能下降速度。在关键性临床试验中，与安慰剂相比，接受托伐普坦治疗的患者肝酶升高的发生率更高。一组专家肝病学家的裁决得出结论，托伐普坦与 ADPKD 患者的肝损伤之间存在因果关系。在 ADPKD 模型、多囊肾（PCK）大鼠（n = 5）中进行了托伐普坦处置的离体分离灌流肝脏（IPL）研究，并与野生型（WT）Sprague-Dawley 大鼠（n = 6）进行了比较。用托伐普坦对肝脏进行灌流，然后进行托伐普坦洗脱期。通过液相色谱-串联质谱法定量分析，托伐普坦和两种代谢物 DM-4103 和 DM-4107 的总回收率（平均值 ± S.D. 剂量百分比；PCK 与 WT）分别为 58.14% ± 24.72% 和 43.40% ± 18.11%，在肝脏中为 20.10% ± 9.15% 和 21.17% ± 12.51%，在流出灌流液中为 0.08% ± 0.01% 和 0.39% ± 0.32%，在胆汁中为 0.08% ± 0.01% 和 0.39% ± 0.32%。与 WT 胆汁相比，PCK 中 DM-4103 的回收率（平均值 ± S.D. 剂量百分比）降低（<0.01% ± <0.01% 与 0.02% ± 0.01%； = 0.0037），而 DM-4107 的回收率在 PCK 中流出灌流液中增加（1.60% ± 0.57% 与 0.43% ± 0.29%； = 0.0017）。建立了一个假设为一级过程的药代动力学房室模型，以描述托伐普坦和 DM-4103 + DM-4107 在大鼠 IPL 中的速率与时间曲线。模型衍生的托伐普坦胆汁清除率估计值在 PCK 中明显低于 WT IPLs。该模型预测 PCK 中托伐普坦和 DM-4103 + DM-4107 的肝细胞浓度更高。托伐普坦及其代谢物在肝细胞中的暴露增加可能导致接受托伐普坦治疗的 ADPKD 患者发生肝毒性。
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