Application of LC-MS analysis to the characterisation of the in vitro and in vivo metabolite profiles of RGH-1756 in the rat.
RGH-1756, 1-(2-methoxy-phenyl)-4-(4-[4-(6-imidazol[2,1-b] thiazolyl)-phenoxy]-butyl-4-(14)C)-piperazine dimethane is a novel atypical antipsychotic drug candidate of Gedeon Richter Ltd. The metabolic pathways of the compound have been investigated by profiling the metabolites present in plasma, bile, and faeces samples of rats treated with (14)C-RGH-1756. The metabolites formed in vitro by rat liver microsomes have also been analysed. Good separation of the compounds has been achieved by gradient HPLC method on Zorbax/Bonus RP-C18 column. Radiometry and mass spectrometry have been applied to detect and characterise the metabolites. The metabolite formed by oxidative cleavage of the chain at the carbon atom adjacent to the piperazine nitrogen has been identified as the major plasma metabolite. Glucuronide conjugate of hydroxy-RGH-1756 has been found as one of the main metabolites excreted in the bile where the unchanged compound has not been detected.
Gémesi
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Gedeon Richter Ltd., 1103, Budapest Gyömrói út 19-21, Budapest, Hungary. larisza.gemesi@richter.hu
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D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D018492:Dopamine Antagonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D065127:Dopamine D2 Receptor Antagonists; D005243:Feces / Q000737:chemistry; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics*; D011874:Radiometry; D051381:Rats; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3; D013844:Thiazoles / Q000378:metabolism / Q000493:pharmacokinetics*
C427703:1-(2-methoxy-phenyl)-4-(4-(4-(6-imidazol(2,1-b) thiazolyl)-phenoxy)-butyl-4-(14)C)-piperazine dimethane; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493595:Drd3 protein, rat; D010879:Piperazines; D050637:Receptors, Dopamine D3; D013844:Thiazoles