Identification of the metabolites of a new oxazolidinone MAO-A inhibitor in rat.
1. Six metabolites present in rat urine after the oral administration of E2011 ((5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-meth oxymethyl-2- oxazolidinone) were isolated with an Amberlite XAD-4 column and hplc, and termed HPM-1, HPM-2, HPM-31, HPM-32, HPM-33 and HPM-4. 2. To determine the correspondence of the findings of the metabolites between tlc (which was used in our previous study) and hplc, the six metabolites were isolated from rat urine after the administration of 14C-labelled E2011 with an Amberlite XAD-4 column and hplc, and then analysed by tlc. HPM-1, HPM-2, HPM-31, HPM-32, HPM-33 and HPM-4 were identified as IM7, IM3, IM4, IM2, IM1 and E2011, respectively. 3. The structures of the metabolites were identified with nmr and mass spectrometry. One of the compounds identified, HPM-4, was the unchanged drug, E2011, and HPM-2 was O-desmethyl-E2011. Another metabolite (HPM-33), the main metabolite in the urine, was identified as (4S)-hydroxy-E2011, and the others were (4S)-hydroxy-O-desmethyl-E2011 (HPM-1), 2"-hydroxy-E2011 (HPM-31) and (4R)-hydroxy-E2011 (HPM-32). 4. In conclusion, the main metabolic pathway of E2011 in the rat consisted of O-demethylation and hydroxylation.
Naitoh
T
T
Tsukuba Research Laboratories, Eisai Co., Ltd, Ibaraki, Japan.
Kakiki
M
M
Kozaki
T
T
Mishima
M
M
Yuzuriha
T
T
Horie
T
T
D000818:Animals; D052160:Benzothiazoles; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008745:Methylation; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism*; D023303:Oxazolidinones; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013844:Thiazoles / Q000378:metabolism*
D052160:Benzothiazoles; D002250:Carbon Radioisotopes; C091708:E 2011; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D013844:Thiazoles; D008995:Monoamine Oxidase