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Determination of new 2,3-benzodiazepines in rat plasma using high-performance liquid chromatography with ultraviolet detection.

Abstract
A method for the analysis of [1-(4-aminophenyl)-3,5-dihydro-7, 8-dimethoxy-4H-2,3-benzodiazepin-4-one] (CFM-2) and its analogues CFM-3, CFM-4 and CFM-5 in rat plasma was developed. The 2,3-benzodiazepines (2,3-BZs) were extracted by liquid-liquid extraction and analyzed using high-performance liquid chromatography (HPLC) with ultraviolet detection (UV) at 240 nm. The method exhibited a large linear range from 0.05 to 2 micrograms/ml with an intra-assay accuracy for all studied compounds ranging from 92 to 105.5%; whereas the intra-assay precision ranged from 0.59 to 8.16% in rat plasma. The inter-assay accuracy of CFM-2, CFM-4 and their 3-methyl derivatives, CFM-3 and CFM-5 ranged from 92.2 to 107% and the inter-assay precision ranged from 2.17 to 11.9% in rat plasma. The lower limit of detection was 5.5 ng/ml for CFM-2, 6.5 ng/ml for CFM-3, 7 ng/ml for CFM-4 and 8.5 ng/ml for CFM-5 in rat plasma. The pharmacokinetic study demonstrated that 2,3-BZs achieved a peak plasma concentration between 45 and 75 min after drug administration. Moreover, we observed that plasma chromatograms of rats treated with CFM-3, CFM-4 and CFM-5, respectively, showed a peak consistent with CFM-2. Our study suggests that CFM-4, CFM-5 and CFM-3 are prodrugs of CFM-2, in which they are biotransformed in vivo via different metabolic pathways. In particular, CFM-2 has been proven to possess anticonvulsant activity in various models of seizures, acting as alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor antagonist.
AuthorsM Rizzo, G De Sarro, M Zappalà, A Chimirri
JournalJournal of chromatography. B, Biomedical sciences and applications (J Chromatogr B Biomed Sci Appl) Vol. 731 Issue 2 Pg. 207-15 (Aug 20 1999) ISSN: 1387-2273 [Print] Netherlands
PMID10510773 (Publication Type: Journal Article)
Chemical References
  • Benzodiazepines
Topics
  • Animals
  • Benzodiazepines (blood, pharmacokinetics)
  • Biotransformation
  • Calibration
  • Chromatography, High Pressure Liquid (methods)
  • Rats
  • Rats, Sprague-Dawley
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Spectrophotometry, Ultraviolet

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