Small Animal Clinical Sciences, University of Florida, Gainesville, FL, 32610, USA.
J Biochem Mol Toxicol. 2013 Dec;27(12):522-5. doi: 10.1002/jbt.21518. Epub 2013 Sep 13.
We characterized the pharmacokinetics and dynamics of dichloroacetate (DCA), an investigational drug for mitochondrial diseases, pulmonary arterial hypertension, and cancer. Adult Beagle dogs were orally administered 6.25 mg/kg q12h DCA for 4 weeks. Plasma kinetics was determined after 1, 14, and 28 days. The activity and expression of glutathione transferase zeta 1 (GSTZ1), which biotransforms DCA to glyoxylate, were determined from liver biopsies at baseline and after 27 days. Dogs demonstrate much slower clearance and greater inhibition of DCA metabolism and GSTZ1 activity and expression than rodents and most humans. Indeed, the plasma kinetics of DCA in dogs is similar to humans with GSTZ1 polymorphisms that confer exceptionally slow plasma clearance. Dogs may be a useful model to further investigate the toxicokinetics and therapeutic potential of DCA.
我们描述了二氯乙酸（DCA）的药代动力学和药效动力学，DCA 是一种用于治疗线粒体疾病、肺动脉高压和癌症的研究药物。成年比格犬经口给予 DCA 6.25mg/kg，q12h，共 4 周。在第 1、14 和 28 天分别检测血浆动力学。在基线和第 27 天，通过肝活检检测谷胱甘肽 S-转移酶 ζ 1（GSTZ1）的活性和表达，GSTZ1 将 DCA 生物转化为乙醛酸。狗比啮齿动物和大多数人类清除速度慢，且 DCA 代谢和 GSTZ1 活性及表达的抑制作用更强。事实上，狗体内 DCA 的血浆动力学与 GSTZ1 多态性导致的异常缓慢的血浆清除率相似，GSTZ1 多态性赋予了人类异常缓慢的血浆清除率。狗可能是进一步研究 DCA 毒代动力学和治疗潜力的有用模型。
