Jinno Fumihiro, Kakehi Masaaki, Takeuchi Toshiyuki, Tagawa Yoshihiko, Kondo Takahiro, Asahi Satoru
Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Arzneimittelforschung. 2011;61(8):458-71. doi: 10.1055/s-0031-1296228.
The pharmacokinetics of TAK-242 (ethyl (6R)-6- [N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate, CAS 243984-11-4) and its metabolites were investigated in rats and dogs after intravenous (i.v.) dosing of TAK-242 using two types of radiolabeled TAK-242: [phenyl ring-U-14C]TAK-242 and [cyclohexene ring-U-14C]TAK-242. The phenyl ring moiety of TAK-242 yielded 2-chloro-4-fluoroaniline, M-I, and M-I was further acetylated and conjugated to form M-II and the glucuronide (M-I-G), respectively. M-I was also converted to M-III and M-IV by hydroxylation and subsequent sulfate conjugation. Meanwhile, the cyclohexene ring moiety of TAK-242 was metabolized to glutathione conjugate, M-SG, followed by further metabolism of M-SG to form cysteine conjugate (M-Cys) and mercapturic acid conjugate (M-Mer). After i.v. injection of [phenyl ring-U-14C]TAK-242 to rats and dogs, the 14C concentrations in dogs declined slowly with a half-life of about 1 week although that in rats was about 6 h. The predominant components in the plasma of rats and dogs were M-I-G and M-III, respectively. After i.v. injection of [cyclohexene ring-U-14C]TAK-242 to rats and dogs, 14C-components unextractable by organic solvents were observed in the plasma. These results indicated two unique metabolic fates of TAK-242. The phenyl ring moiety of TAK-242 showed species differences between rats and dogs in the metabolism and excretion kinetics and the cyclohexene ring moiety of TAK-242 showed potential for covalent binding to endogenous components such as plasma proteins.
使用两种放射性标记的TAK-242（[苯环-U-¹⁴C]TAK-242和[环己烯环-U-¹⁴C]TAK-242）对TAK-242（乙基(6R)-6-[N-(2-氯-4-氟苯基)氨磺酰基]环己-1-烯-1-羧酸酯，CAS 243984-11-4）及其代谢产物在大鼠和犬静脉注射给药后进行了药代动力学研究。TAK-242的苯环部分产生2-氯-4-氟苯胺（M-I），M-I进一步乙酰化并分别结合形成M-II和葡糖醛酸苷（M-I-G）。M-I还通过羟基化和随后的硫酸结合转化为M-III和M-IV。同时，TAK-242的环己烯环部分代谢为谷胱甘肽结合物（M-SG），随后M-SG进一步代谢形成半胱氨酸结合物（M-Cys）和巯基尿酸结合物（M-Mer）。对大鼠和犬静脉注射[苯环-U-¹⁴C]TAK-242后，犬体内的¹⁴C浓度下降缓慢，半衰期约为1周，而大鼠体内的半衰期约为6小时。大鼠和犬血浆中的主要成分分别为M-I-G和M-III。对大鼠和犬静脉注射[环己烯环-U-¹⁴C]TAK-242后，血浆中观察到有机溶剂无法提取的¹⁴C成分。这些结果表明TAK-242有两种独特的代谢归宿。TAK-242的苯环部分在代谢和排泄动力学方面在大鼠和犬之间表现出种属差异，TAK-242的环己烯环部分显示出与内源性成分如血浆蛋白共价结合的潜力。
