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
| العنوان: | 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 |
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| المؤلفون: | Asahi Satoru, Tagawa Yoshihiko, Kondo Takahiro, Jinno Fumihiro, Takeuchi Toshiyuki, Kakehi Masaaki |
| المصدر: | Arzneimittelforschung. 61:458-471 |
| بيانات النشر: | Georg Thieme Verlag KG, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Male, Sulfonamides, Magnetic Resonance Spectroscopy, Stereochemistry, Cyclohexene, Mass Spectrometry, Rats, Hydroxylation, Feces, chemistry.chemical_compound, Dogs, chemistry, Isotope Labeling, Injections, Intravenous, Drug Discovery, Animals, Moiety, Carbon Radioisotopes, Carboxylate, Mercapturic acid, Glucuronide, Biotransformation, Chromatography, High Pressure Liquid, Ene reaction, Conjugate |
| الوصف: | The pharmacokinetics of TAK-242 (ethyl (6 R )-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- 14 C]TAK-242 and [cyclohexene ring-U- 14 C]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- 14 C]TAK-242 to rats and dogs, the 14 C 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- 14 C]TAK-242 to rats and dogs, 14 C-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. |
| تدمد: | 1616-7066 0004-4172 |
| DOI: | 10.1055/s-0031-1296228 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f4e63d7a893978e440b5cde1d5e42a20 https://doi.org/10.1055/s-0031-1296228 |
| رقم الانضمام: | edsair.doi.dedup.....f4e63d7a893978e440b5cde1d5e42a20 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16167066 00044172 |
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| DOI: | 10.1055/s-0031-1296228 |