Liquid chromatography-tandem mass spectrometry identification of metabolites of two 5-HT1A antagonists, N-[2-[4-(2-methoxylphenyl)piperazino]ethyl]-N-(2-pyridyl) trans- and cis-4-fluorocyclohexanecarboxamide, produced by human and rat hepatocytes.
Two 5-HT1A antagonists, t-FCWAY and c-FCWAY, were developed as imaging agents for positron emission tomography (PET). In order to evaluate these compounds, hepatocytes from both human and rat were utilized to produce metabolites and LC-MS-MS was used to identify metabolites. These in vitro metabolism studies indicate that hydrolysis of the amide linkage is the major metabolism pathway for humans, whereas aromatic ring-oxidation is the major metabolism pathway for rat. The rat hepatocyte results correlate well with in vivo rat metabolism studies. Based on the structures of the metabolites, we have developed an extraction procedure to determine the concentration of the parent compound in plasma.
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PET Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. ym45j@nih.gov
Lang
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Kiesewetter
D O
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Jagoda
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Sassaman
M B
MB
Der
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Eckelman
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WC
D000818:Animals; D002457:Cell Extracts / Q000737:chemistry; D002478:Cells, Cultured; D002853:Chromatography, Liquid / Q000379:methods*; D005462:Fluorine Radioisotopes; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods*; D008956:Models, Chemical; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013237:Stereoisomerism; D014055:Tomography, Emission-Computed / Q000379:methods
D002457:Cell Extracts; D005462:Fluorine Radioisotopes; C435829:N-(2-(4-(2-methoxyphenyl)piperazino)ethyl)-N-2-(pyridyl)-4-fluorocyclohexanecarboxamide; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists