CHDI Management/CHDI Foundation, Princeton, NJ, USA.
Covance Laboratories Inc, Madison, WI, USA.
Xenobiotica. 2021 Oct;51(10):1155-1180. doi: 10.1080/00498254.2021.1977868. Epub 2021 Sep 15.
The disposition of a novel kynurenine monooxygenase inhibitor, CHDI-340246, was investigated and in animals., there was minimal metabolic turnover of CHDI-340246 in all species. The protein binding was higher in human plasma (99.7%) relative to other species.In all species, blood clearance was low (<20% of liver blood flow) and volume of distribution was small (<0.5 L/kg). The terminal half-life was longer in monkeys (9 hr) than in mice, rats, or dogs (1-2 hr). CHDI-340246 was orally bioavailable (>60%) in all species.In rats, [C]CHDI-340246 showed wide distribution of radioactivity in all tissues except brain and testes. In rats, the parent drug was the major circulating moiety with minor amounts of a sulphate conjugate of an -dealkylated metabolite. The elimination occurred via the urinary route and to a lesser extent by biliary route, but mostly as metabolites. In cynomolgus monkeys, the parent drug predominated in plasma with only trace amounts of metabolites detected.Acyl glucuronide conjugate of CHDI-340246 was not detected in plasma of rats or monkeys.Overall, the ADME profile of CHDI-340246 was favourable in rats and monkeys for potential evaluation of KMO inhibition in humans.
研究了新型犬尿氨酸单加氧酶抑制剂 CHDI-340246 的处置情况，在动物体内，所有物种中 CHDI-340246 的代谢转化都很少。与其他物种相比，人血浆中的蛋白结合更高（99.7%）。在所有物种中，血液清除率都很低（<20%的肝血流量），分布体积也很小（<0.5 L/kg）。猴子（9 小时）的半衰期比小鼠、大鼠或狗（1-2 小时）长。CHDI-340246 在所有物种中均具有较高的口服生物利用度（>60%）。在大鼠中，[C]CHDI-340246 在除大脑和睾丸以外的所有组织中均具有广泛的放射性分布。在大鼠中，主要循环部分是母体药物，带有少量 -去烷基化代谢物的硫酸盐轭合物。消除主要通过尿途径，其次是胆汁途径，但主要以代谢物的形式。在食蟹猴中，母体药物在血浆中占主导地位，仅检测到痕量的代谢物。未在大鼠或猴子的血浆中检测到 CHDI-340246 的酰基葡萄糖醛酸轭合物。总体而言，CHDI-340246 在大鼠和猴子中的 ADME 特征有利于在人类中评估 KMO 抑制作用。
