Investigation of the species-dependent in vitro metabolism of BAL30630 by stable isotope labeling and isotope exchange experiments analyzed by capillary liquid chromatography coupled to mass spectrometry

The in vitro metabolic profile of BAL30630, an antifungal piperazine propanol derivative, which inhibits the 1,3-beta- d-glucansynthase, was investigated by incubation with microsomes of several species and with rat hepatocytes. For the spotting of the metabolites, mixtures of BAL30630 with a stable...

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Published in:	Journal of Chromatography A Vol. 1216; no. 18; pp. 3946 - 3953
Main Authors:	Wind, Mathias, Grunwald, Helge, Gebhardt, Klaus, Illig, Klaus, Spickermann, Jochen, Nuoffer, Claude, Roussel, Patrick, Klauer, Dominique, Fullhardt, Pascal, Schmitt-Hoffmann, Anne, Schleimer, Michael
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier B.V 01-05-2009 Amsterdam; New York: Elsevier Elsevier
Subjects:	1-Propanol - chemistry 1-Propanol - pharmacokinetics Accurate mass Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antifungal agents Antifungal Agents - chemistry Antifungal Agents - pharmacokinetics Biological and medical sciences Chromatography, Liquid - methods Deuterium - chemistry Deuterium - metabolism Dogs Guinea Pigs Haplorhini Hepatocytes - chemistry Hepatocytes - metabolism Humans Isotope exchange Isotope Labeling Mass spectrometry Mass Spectrometry - methods Medical sciences Metabolism Mice Microsomes, Liver - chemistry Microsomes, Liver - metabolism Pharmacology. Drug treatments Rabbits Rats Stable isotope labeling Stable isotope labeling Metabolism Mass spectrometry Isotope exchange Accurate mass Capillary column Deuterium Tandem mass spectrometry Chemical analysis Isotope labelling Metabolite Liver Glycosyltransferases HPLC chromatography Microsome Electrospray Antifungal agent Hepatocyte Mass measurement Enzyme Coupled method Transferases Interspecific comparison Enzyme inhibitor 1,3-β-Glucan synthase Hydrogen Isotopes Benzothiazole derivatives In vitro Animal Hexosyltransferases Fluorine Organic compounds Piperazine derivatives Measurement accuracy
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Summary:	The in vitro metabolic profile of BAL30630, an antifungal piperazine propanol derivative, which inhibits the 1,3-beta- d-glucansynthase, was investigated by incubation with microsomes of several species and with rat hepatocytes. For the spotting of the metabolites, mixtures of BAL30630 with a stable isotope (deuterium) labeled analogue were incubated. The metabolic pattern comprises several oxidized metabolites. Based on isotope exchange experiments, their structures could be assigned to epoxide- and hydroxylated metabolites. In hepatocyte incubations, several glucuronides formed from these oxidized metabolites could be observed. From the analysis of the metabolic pattern in microsomes, products of carbamate hydrolysis were characterized. This hydrolysis was highly species dependent. In activated incubations and in rat hepatocytes, those metabolites were further oxidized. In incubations without NADPH activation, the resulting hydrolytic metabolites could be enriched without the subsequent oxidation. Final structural elucidation of the metabolites was performed using accurate mass determination and isotope exchange experiments, in which incubations were analyzed by deuterium exchange and capillary HPLC–QTof-MS and MS/MS. The use of non-radioactive, stabile isotope labeled drug analogues in combination with isotope exchange studies was essential in particular for a defined assignment of the functional groups in the structures of the investigated metabolites.
Bibliography:	http://dx.doi.org/10.1016/j.chroma.2009.03.022 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9673 1873-3778
DOI:	10.1016/j.chroma.2009.03.022