Investigation of the unique metabolic fate of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242) in rats and dogs using two types of ¹⁴C-labeled compounds having different labeled positions

Abstract

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 formM-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 formcysteine 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 metabolismand excretion kinetics and the cyclohexene ring moiety of TAK-242 showed potential for covalent binding to endogenous components such as plasma proteins.

Key words

Anti-sepsis drug - Covalent binding - Metabolism - Pharmacokinetics - Species difference - TAK-242

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