title: Determination of the in vitro metabolism of (+)- and (-)-epibatidine.
abstract: The oxidative in vitro metabolism of epibatidine was investigated using liver microsomes from rat, dog, rhesus monkey and human. Analysis was performed using liquid chromatography-mass spectrometry (LC-MS) using both achiral and chiral stationary phases. Comparison of the metabolism of the (+)- and (-)-enantiomers revealed species differences in the extent of metabolism, with rhesus monkey>dog>rat=human. Furthermore, differences in the routes of metabolism for epibatidine enantiomers were also observed, with mass spectra consistent with hydroxylation of the azabicycle for (-)-epibatidine and with the formation of diastereomeric N-oxides for (+)-epibatidine being obtained. For chiral LC-MS, a volatile ion-pair reagent of heptafluorobutyric acid was used in place of pentanesulphonic acid with no deterioration in chiral selectivity. Analysis of the same samples by chiral LC-MS revealed no evidence for metabolic chiral interconversion and chiral analysis from a metabolic time course of racemic material revealed enantiomers to be metabolised to approximately the same extent. Such findings may be important particularly should epibatidine be investigated in non-rodent species.
authors.affiliation: Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK.
authors.forename: A P
authors.initials: AP
authors.lastname: Watt
authors.forename: L
authors.initials: L
authors.lastname: Hitzel
authors.forename: D
authors.initials: D
authors.lastname: Morrison
authors.forename: K L
authors.initials: KL
authors.lastname: Locker
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004285:Dogs; D006801:Humans; D008253:Macaca mulatta; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D011725:Pyridines; C082748:epibatidine