ABSTRACT
An isocratic liquid chromatographic method for direct sample injection has been developed for the quantitation of felbamate and four metabolites in rat cerebrospinal fluid. The method uses 0.050- or 0.025-ml aliquots of cerebrospinal fluid diluted with equal volumes of internal standard. Chromatography is performed on a 150 mm x 4.6 mm I.D. Spherisorb ODS2, 3-microns HPLC column eluted with a phosphate buffer-acetonitrile-methanol (820:120:60, v/v/v) mobile phase and ultraviolet absorbance detection at 210 nm. The linear quantitation ranges are: felbamate and the 2-hydroxy metabolite 0.195-200 micrograms/ml, the propionic acid metabolite 0.195-50.0 micrograms/ml, the p-hydroxy metabolite 0.781 to 50.0 micrograms/ml, and the monocarbamate metabolite 0.098-50.0 micrograms/ml.
Subject(s)
Anticonvulsants/cerebrospinal fluid , Propylene Glycols/cerebrospinal fluid , Animals , Anticonvulsants/pharmacokinetics , Biotransformation , Chromatography, High Pressure Liquid , Felbamate , Phenylcarbamates , Propylene Glycols/pharmacokinetics , Rats , Spectrophotometry, UltravioletABSTRACT
The concentrations of felbamate (FBM) and its three metabolites were determined in plasma, cerebrospinal fluid (CSF), and brain tissue of adult and neonatal rats that received single oral doses of FBM at amounts varying from 250 to 2000 mg/kg for adults and from 100 to 500 mg/kg for neonates. The increase in plasma Cmax and AUC0-24 with the dose was less than proportional in both age groups. The highest plasma Cmax in adults dosed with 2000 mg/kg was 140.3 micrograms/ml; in neonates dosed with 500 mg/kg it was 257.0 micrograms/ml. The maximum brain concentrations for these dosages were 90.9 and 220.4 micrograms/g, respectively. The average brain/plasma, CSF/plasma, and brain/CSF partition coefficients for the drug were 0.64, 0.55, and 1.16 for adults and 0.83, 0.67, and 1.23 for neonates, respectively. No statistically significant change of the partition coefficients with time or dose was observed (p < 0.05). Very good linear correlations between FBM plasma concentrations and concentrations in CSF and brain tissue were obtained (r2 > 0.98). Only the 2-hydroxy metabolite was present in considerable amounts in plasma and brain tissue of the high-dose groups of both ages.
Subject(s)
Aging/metabolism , Animals, Newborn/metabolism , Anticonvulsants/cerebrospinal fluid , Anticonvulsants/pharmacokinetics , Brain/metabolism , Propylene Glycols/cerebrospinal fluid , Propylene Glycols/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Blood-Brain Barrier/physiology , Dose-Response Relationship, Drug , Felbamate , Female , Male , Phenylcarbamates , Rats , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
High-resolution proton magnetic resonance spectroscopy was used to analyze human cerebrospinal fluid obtained from patients with several neurological problems. The major metabolites measured included glucose, lactate, glutamine, citrate, inositol, acetate, creatine, creatinine, beta-hydroxybutyrate, alanine, and pyruvate. A drug vehicle, propylene glycol, was also measured. Alterations in the cerebrospinal fluid of these metabolites provided information concerning metabolism of the brain. Magnetic resonance spectroscopy offered a simple and rapid means of assessing these and other exogenous and endogenous compounds in diseases affecting the nervous system.
