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首页> 外文期刊>Journal of biochemical and molecular toxicology >Pharmacokinetics of Oral Dichloroacetate in Dogs
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Pharmacokinetics of Oral Dichloroacetate in Dogs

机译：犬口服二氯乙酸盐的药代动力学

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摘要

We characterized the pharmacokinetics and dynamics of dichloroacetate (DCA), an investiga-tional drug for mitochondrial diseases, pulmonary arterial hypertension, and cancer. Adult Beagle dogs were orally administered 6.25 mg/kg ql2h 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 glyoxy-late, 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 toxicoki-netics and therapeutic potential of DCA.
机译：我们表征了二氯乙酸酯（DCA）的药代动力学和动力学，这是一种用于线粒体疾病，肺动脉高压和癌症的研究药物。成年比格犬口服6.25 mg / kg ql2h DCA，持续4周。在1,14和28天后测定血浆动力学。从基线时和第27天后的肝活检中确定了将DCA生物转化为乙醛酸的谷胱甘肽转移酶zeta 1（GSTZ1）的活性和表达。与啮齿动物和大多数人相比，狗表现出的清除速度慢得多，对DCA代谢以及GSTZ1活性和表达的抑制作用更大。实际上，狗中DCA的血浆动力学与具有GSTZ1多态性的人相似，后者具有异常缓慢的血浆清除率。狗可能是进一步研究DCA的毒性动力学和治疗潜力的有用模型。

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