title: Identification and quantitation of an oxidative metabolite of labetalol in sheep: pharmacokinetic and metabolic implications.
abstract: A sensitive and selective assay has been developed for the identification and quantitation of 3-amino-1-phenyl butane (3-APB), a metabolite of labetalol, in biological fluids using electron impact gas chromatography/mass-selective detection. Samples were extracted with n-hexane, derivatized with heptafluorobutyric anhydride and chromatographed on a cross-linked fused-silica capillary column. A positive EI spectrum was obtained using a mass-selective detector. Identification of the metabolite was accomplished using an authentic standard; quantitation was performed in the selected ion monitoring mode using ions m/z 345 (M+) and 132. The assay was linear over the calibration range of 0.5-1000 ng of the analyte and the intra-sample coefficients of variation were less than 12% in all cases. The absolute recovery of 3-APB following extraction from urine and bile was found to be 102.9 +/- 4.9% and 98.3 +/- 1.45% (mean +/- SEM) respectively. The minimum quantitation limit of the assay was 0.5 ng ml-1 (approximately 2 pg injected). Application of the assay in a pharmacokinetic-pharmacodynamic study of labetalol in sheep is demonstrated. The metabolite was detected in urine and bile samples obtained from adult non-pregnant sheep following labetalol administration. The cumulative amount of 3-APB excreted in urine over 24 h was found to be 71.55 micrograms in one animal following a 100 mg dose of labetalol. Evidence for biliary excretion, glucuronidation and sulfation of 3-APB was also found.
authors.affiliation: Division of Pharmaceutics and Biopharmaceutics, Faculties of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Yeleswaram
authors.forename: D W
authors.initials: DW
authors.lastname: Rurak
authors.forename: E
authors.initials: E
authors.lastname: Kwan
authors.forename: C
authors.initials: C
authors.lastname: Hall
authors.forename: F S
authors.initials: FS
authors.lastname: Abbott
authors.forename: J E
authors.initials: JE
authors.lastname: Axelson
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry; D002082:Butylamines / Q000032:analysis* / Q000652:urine; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D007741:Labetalol / Q000378:metabolism* / Q000493:pharmacokinetics; D012756:Sheep
chemical_list: D002082:Butylamines; C058063:3-amino-1-phenylbutane; D007741:Labetalol