Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849) in rats.
Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849), a novel immunomodulatory agent, in rats was investigated. By co-chromatography with authentic samples, desmethylated (SM-8800) p-hydroxylated (SL-5512) and desmethylated-p-hydroxylated SM-8849 (SL-5515) were detected in the bile. Thermospray mass spectrometry (TSP-MS) analysis of five metabolites isolated from the bile revealed molecular ions of both conjugates (glucuronides and a sulfate) and their aglycones. Aglycone structures were determined by comparison of their product spectra with those of authentic standards. Further analyses of conjugation sites were carried out by 1H-NMR including differential NOE. As a result, the sulfate of SL-5515 (5515-S), the N-glucuronides of SL-5512 and SM-8849 (5512-NG and 8849-NG, respectively), the glucuronide of SL-5512 (5512-G) and the O-glucuronide of 4-hydroxy-3-methoxy-SM-8849 (CatOMe-OG) were identified. In addition, N-methylthiouras was identified in urine by LC/MS/MS.
Yabuki
M
M
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, Osaka, Japan.
Shimakura
J
J
Ito
M
M
Kanamaru
H
H
Iba
K
K
Nakatsuka
I
I
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D005965:Glucuronates / Q000302:isolation & purification / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D014316:Tritium
C107216:4-hydroxy-3-methyl-SM-8849 O-glucuronide; C107219:5515 NG; C107217:8849 NG; D000276:Adjuvants, Immunologic; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D005965:Glucuronates; C107218:SL 5515; D013844:Thiazoles; D014316:Tritium; C072865:4-(1-(2-fluoro-4-biphenyl)ethyl)-2-methylaminothiazole; C002267:N-methylthiourea; D013890:Thiourea