title: In vivo investigation of brain and systemic ketobemidone metabolism.
abstract: Ketobemidone metabolites have previously been identified in urine and plasma; here we show, for the first time, that norketobemidone and ketobemidone N-oxide are present in in vivo microdialysate from rat brain (striatum) after reverse microdialysis, suggesting striatal metabolism of ketobemidone. Ketobemidone metabolites were also identified in in vivo microdialysate samples from brain and blood, as well as in urine from rats, after subcutaneous administration of ketobemidone. Three Phase I metabolites (norketobemidone, ketobemidone N-oxide and hydroxymethoxyketobemidone) and three Phase II metabolites (glucuronic acid conjugates of ketobemidone, norketobemidone and hydroxymethoxyketobemidone) were identified in the microdialysates after subcutaneous administration. Coupled capillary liquid chromatography tandem mass spectrometry (LC-MS/MS) and SPE (boronate)-MS/MS were utilized for the analysis of the biological samples. The Phase I metabolites were identified by comparing the retention times and tandem mass spectra of the microdialysates with synthetic standards. The Phase II metabolites were identified by determination of exact masses and by comparing the tandem mass spectra of the microdialysates with those of synthetic standards for the aglycones. Hydroxyketobemidone, a catechol-type Phase I metabolite, was selectively isolated by solid-phase boronate-complexation but identified in urine alone. This work demonstrated that the in vivo microdialysis technique in combination with LC-MS/MS can be used to study the local metabolism of a drug in the brain.
authors.affiliation: Department of Pharmaceutical Biosciences, Medical Mass Spectrometry, Uppsala University, Biomedical Centre, Box 583, SE-75123 Uppsala, Sweden.
authors.forename: Ingela
authors.initials: I
authors.lastname: Sundström
authors.forename: Joris
authors.initials: J
authors.lastname: Arts
authors.forename: Douglas
authors.initials: D
authors.lastname: Westerlund
authors.forename: Per E
authors.initials: PE
authors.lastname: Andrén
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D008297:Male; D008614:Meperidine / Q000031:analogs & derivatives* / Q000378:metabolism; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008614:Meperidine; C012394:ketobemidone