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

Jinno Fumihiro; Kakehi Masaaki; Takeuchi Toshiyuki; Tagawa Yoshihiko; Kondo Takahiro; Asahi Satoru

doi:10.1055/s-0031-1296228

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2011; 61(8): 458-471
DOI: 10.1055/s-0031-1296228

Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs

Editio Cantor Verlag Aulendorf (Germany)

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

Jinno Fumihiro

¹Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan

,

Kakehi Masaaki

¹Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan

,

Takeuchi Toshiyuki

¹Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan

,

Tagawa Yoshihiko

¹Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan

,

Kondo Takahiro

¹Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan

,

Asahi Satoru

¹Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan

› Author Affiliations

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

Full Text

References

References
1 Yamada M, Ichikawa T, Ii M, Sunamoto M, Itoh K, Tamura N et al. Discovery of novel and potent small-molecule inhibitors of no and cytokine production as antisepsis agents: synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate. J Med Chem. 2005; 48 (23) 7457-67
2 Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003; 29: 530-8
3 Parrillo JE. Pathogenic mechanism of septic shock. N Engl J Med. 1993; 328 (20) 1471-8
4 Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T et al. A novel cyclohexene derivative, ethyl (6r)-6-[n-(2-chrolo-4-fluorophenyl)sulfamoyl]cyclohe-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. >Mol Pharmacol. 2006; 69 (4) 1288-95
5 Hong SK, Rankin GO. Biotransformation of 2-chloroaniline in the Fischer 344 rat: identification of urinary metabolites. Xenobiotica. 1998; 28 (10) 985-94
6 Rietjens IM, Vervoort J. Bioactivation of 4-fluorinated anilines to benzoquinoneimines as primary reaction products. Chem Biol Interact. 1991; 77: 263-81
7 Cnubben NM, Vervoort J, Boersma MG, Rietjens IM. The effect of varying halogen substituent patterns on the cytochrome P450 catalysed dehalogenation of 4-halogenated anilines to 4-aminophenol metabolites. Biochem Pharmacol. 1995; 49 (9) 1235-48
8 Scarfe GB, Tugnait M, Wilson ID, Nicholson JK. Studies on the metabolism of 4-fluoroaniline and 4-fluoroactanilide in rat: formation of 4-acetamidophenol (paracetamol) and its metabolites via defluorination and N-acetylation. Xenobiotica. 1999; 29 (2) 205-16
9 Baldwin MK, Hutson DH. The metabolism of 3-chloro-4-fluoro-aniline in dog and rat. Xenobiotica. 1980; 10 (2) 135-44
10 Caron N, Kramp R. Measurement of changes in glomerular filtration rate induced by atrial natriuretic peptide in the rat kidney. Exp Physiol. 1999; 84 (4) 689-96
11 Nassar AE, Lopez-Anaya A. Strategies for dealing with reactive intermediates in drug discovery and development. Curr Opin Drug Discov Devel. 2004; 7: 126-36
12 Park BK, Pirmonhamed M, Kitteringham NR. Role of Drug Disposition in Drug Hypersensitivity: A chemical, molecular, and clinical perspective. Chem Res Toxicol. 1998; 11: 969-88