title: Stereoselective disposition of S- and R-licarbazepine in mice.
abstract: The stereoselective disposition of S-licarbazepine (S-Lic) and R-licarbazepine (R-Lic) was investigated in plasma, brain, liver, and kidney tissues after their individual administration (350 mg/kg) to mice by oral gavage. Plasma, brain, liver, and kidney concentrations of licarbazepine enantiomers and their metabolites were determined over the time by a validated chiral HPLC-UV method. The mean concentration data, attained at each time point, were analyzed using a non-compartmental model. S-Lic and R-Lic were rapidly absorbed from gastrointestinal tract of mouse and immediately distributed to tissues supplied with high blood flow rates. Both licarbazepine enantiomers were metabolized to a small extent, each parent compound being mainly responsible for the systemic and tissue drug exposure. The stereoselectivity in the metabolism and distribution of S- and R-Lic was easily identified. An additional metabolite was detected following R-Lic administration and S-Lic showed a particular predisposition for hepatic and renal accumulation. Stereoselective processes were also identified at the blood-brain barrier, with the brain exposure to S-Lic almost twice that of R-Lic. Another finding, reported here for the first time, was the ability of the mouse to perform the chiral inversion of S- and R-Lic, albeit to a small extent.
authors.affiliation: Faculty of Pharmacy, Laboratory of Pharmacology, Coimbra University, Coimbra, Portugal.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Alves
authors.forename: Isabel
authors.initials: I
authors.lastname: Figueiredo
authors.forename: Amílcar
authors.initials: A
authors.lastname: Falcão
authors.forename: Margarida
authors.initials: M
authors.lastname: Castel-Branco
authors.forename: Margarida
authors.initials: M
authors.lastname: Caramona
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-Da-Silva
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003984:Dibenzazepines / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D000078330:Oxcarbazepine; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D000927:Anticonvulsants; D003984:Dibenzazepines; D002220:Carbamazepine; D000078330:Oxcarbazepine; C428744:10,11-dihydro-10-hydroxy-5H-dibenz(b,f)azepine-5-carboxamide