title: Chemical reactivity of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242) in vitro.
abstract: Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242) was metabolized to cyclohexene and phenyl ring moieties in non-clinical pharmacokinetic studies and it was suggested that the cyclohexene ring moiety of TAK-242 is tightly bound to endogenous macromolecules. After incubation of TAK-242 and glutathione (GSH) in phosphate buffer (pH 7.4) at 37 °C, TAK-242 reacted with GSH to produce a glutathione conjugate of the cyclohexene ring moiety of TAK-242, which had been observed as a metabolite (M-SG) in non-clinical pharmacokinetic studies. Formation of M-SG was time dependent with a first order reaction and M-I, a metabolite from the phenyl ring moiety of TAK-242, was also produced in parallel. The formation of M-SG was accelerated with increasing pH, therefore it was indicated that TAK-242 reacted with GSH by a nucleophilic substitution reaction. Because glutathione transferase (GST) enhanced M-SG formation in vitro, it is expected that the conjugation of TAK-242 with GSH is also facilitated by GST in vivo in addition to a spontaneous chemical reaction. When radio-labeled TAK-242 ([cyclohexene ring-U-¹⁴C]TAK-242) was incubated with rat serum albumin (RSA) or human serum albumin (HSA) in vitro, the radioactive material was covalently bound to RSA and HSA, and M-I was generated simultaneously in the reaction mixture. The chemical structure of the TAK-242 adduct covalently bound to HSA was characterized by the accurate mass spectra that cyclohexene ring moiety of TAK-242 was covalently bound to the lysine residue in HSA. The adduct was also detected in the plasma of rats and humans after single i.v. dosing of TAK-242 (in vivo).
authors: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, Osaka, Japan. Jinno_Fumihiro@takeda.co.jp
authors: Fumihiro
authors: F
authors: Jinno
authors: Tomoki
authors: T
authors: Yoneyama
authors: Akio
authors: A
authors: Morohashi
authors: Takahiro
authors: T
authors: Kondo
authors: Satoru
authors: S
authors: Asahi
mesh_terms: D000818:Animals; D005978:Glutathione; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D015394:Molecular Structure; D051381:Rats; D012709:Serum Albumin / Q000737:chemistry; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors
chemical_list: D012709:Serum Albumin; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D005978:Glutathione