Prodrugs that liberate pivalate (trimethylacetic acid) after hydrolysis have been developed to improve the bioavailability of therapeutic candidates. Catabolism of pivalate released by activation of a prodrug is limited in mammalian tissues. Pivalate can be activated to a coenzyme A thioester in cells. In humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination. Because the total body carnitine pool is limited and can only slowly be replenished through normal diet or biosynthesis, treatment with large doses of pivalate prodrugs may deplete tissue carnitine content. Animal models and long-term treatment of patients with pivalate prodrugs have resulted in toxicity consistent with carnitine depletion. However, low plasma carnitine concentrations after pivalate prodrug exposure may not reflect tissue carnitine content and, thus, cannot be used as a surrogate for potential toxicity. The extent of tissue carnitine depletion will be dependent on the dose of pivalate, because carnitine losses may approximate the pivalate exposure on a stoichiometric basis. These concepts, combined with estimates of carnitine dietary intake and biosynthetic rates, can be used to estimate the impact of pivalate exposure on carnitine homeostasis. Thus, even in populations with altered carnitine homeostasis due to underlying conditions, the use of pivalate prodrugs for short periods of time is unlikely to result in clinically significant carnitine depletion. In contrast, long-term treatment with substantial doses of pivalate prodrugs may require administration of carnitine supplementation to avoid carnitine depletion.

中文翻译：

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人体内产生新戊酸酯的前药和肉碱稳态。

已经开发出在水解后释放新戊酸酯（三甲基乙酸）的前药以改善治疗候选物的生物利用度。通过前药活化释放的新戊酸酯的分解代谢在哺乳动物组织中受到限制。新戊酸酯可以在细胞中活化为辅酶A硫酯。在人类中，由新戊酰辅酶A生成的新戊酰肉碱的形成和尿液排泄是新戊酸酯清除的主要途径。由于全身的肉碱含量有限，只能通过正常饮食或生物合成缓慢补充，因此，使用大剂量新戊酸酯前药治疗可能会耗尽组织中的肉碱含量。动物模型和新戊酸酯前药的长期治疗导致毒性与肉碱消耗一致。然而，新戊酸酯前体药物暴露后血浆肉碱浓度低可能无法反映组织肉碱含量，因此不能用作潜在毒性的替代物。组织肉碱消耗的程度将取决于新戊酸酯的剂量，因为在化学计量的基础上，肉碱的损失可能接近新戊酸酯的暴露量。这些概念，结合肉碱饮食摄入量和生物合成速率的估算，可用于估算新戊酸暴露对肉碱稳态的影响。因此，即使在由于基础条件导致肉碱稳态改变的人群中，短时间内使用新戊酸前药也不太可能导致临床上肉碱的大量消耗。相反，