Scholarlink

<p>To develop an LC–MS/MS method for simultaneous quantification of mildronate and L-carnitine, and to investigate the pharmacokinetic profile of mildronate in rats, its effect on L-carnitine homeostasis, as well as the exposure characteristics, underlying mechanisms, and their associations with therapeutic efficacy and toxicity risks. We quantified mildronate using its deuterated analog ([<sup>2</sup>H₃]-mildronate) as an internal standard, while endogenous L-carnitine was relatively quantified using a surrogate matrix. A pharmacokinetic study was conducted in rats following oral administration of mildronate at doses of 40–160&#xa0;mg/kg. Tissue distribution and excretion studies of mildronate were performed at the 80&#xa0;mg/kg dose level. Mildronate exhibited nonlinear pharmacokinetics at 160&#xa0;mg/kg, demonstrated by a greater-than-dose-proportional increase in systemic exposure. It exhibited high distribution and prolonged retention in cardiac and skeletal muscle. The cumulative urinary excretion of the parent drug amounted to only 3.01%. Furthermore, mildronate dose-dependently reduced plasma L-carnitine concentrations, depleted L-carnitine levels in cardiac and skeletal muscle tissues, and increased its urinary excretion. The developed LC–MS/MS method is reliable for simultaneous quantification of mildronate and L-carnitine. The integrated PK-PD findings, including nonlinear exposure, target tissue accumulation, and disruption of L-carnitine homeostasis, collectively elucidate mildronate’s mechanism of action through energy substrate depletion, as well as its intrinsic efficacy-toxicity duality. These findings thus lay a robust scientific foundation for optimizing the drug’s clinical dosing regimens and guiding safety monitoring practices.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The in vivo disposition of mildronate and its regulatory effects on L-carnitine in rats

  • 期刊论文

  • 发表日期：

    2026年1月26日

查看全文
  • Qiannan Zhang,
  • Junwen Hu,
  • Chuyao Yang,
  • Jingtao Wang,
  • Xia Wu,
  • Lingchao Wang,
  • Wenpeng Zhang,
  • Xiaomei Zhuang

摘要

To develop an LC–MS/MS method for simultaneous quantification of mildronate and L-carnitine, and to investigate the pharmacokinetic profile of mildronate in rats, its effect on L-carnitine homeostasis, as well as the exposure characteristics, underlying mechanisms, and their associations with therapeutic efficacy and toxicity risks. We quantified mildronate using its deuterated analog ([2H₃]-mildronate) as an internal standard, while endogenous L-carnitine was relatively quantified using a surrogate matrix. A pharmacokinetic study was conducted in rats following oral administration of mildronate at doses of 40–160 mg/kg. Tissue distribution and excretion studies of mildronate were performed at the 80 mg/kg dose level. Mildronate exhibited nonlinear pharmacokinetics at 160 mg/kg, demonstrated by a greater-than-dose-proportional increase in systemic exposure. It exhibited high distribution and prolonged retention in cardiac and skeletal muscle. The cumulative urinary excretion of the parent drug amounted to only 3.01%. Furthermore, mildronate dose-dependently reduced plasma L-carnitine concentrations, depleted L-carnitine levels in cardiac and skeletal muscle tissues, and increased its urinary excretion. The developed LC–MS/MS method is reliable for simultaneous quantification of mildronate and L-carnitine. The integrated PK-PD findings, including nonlinear exposure, target tissue accumulation, and disruption of L-carnitine homeostasis, collectively elucidate mildronate’s mechanism of action through energy substrate depletion, as well as its intrinsic efficacy-toxicity duality. These findings thus lay a robust scientific foundation for optimizing the drug’s clinical dosing regimens and guiding safety monitoring practices.