Entry of two new asymmetric bispyridinium oximes (K-27 and K-48) into the rat brain: Comparison with obidoxime

D. E. Lorke, M. Y. Hasan, S. M. Nurulain, R. Sheen, K. Kuča, Georg A. Petroianu

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67 Citations (Scopus)

Abstract

In the search for new oximes with higher reactivation potency and a broader spectrum, K-27 and K-48, have recently been synthesized. To test if their superior efficacy was related to better penetration across the blood-brain barrier, their brain entry was compared with that of obidoxime, when administered either alone or after the organophosphate paraoxon (POX). Rats received 50 μmol obidoxime, K-27 or K-48, either alone or in addition to 1 μmol POX. Oxime concentrations at various points in time in brain and plasma were measured using HPLC. The obidoxime Cmax in brain was 1.3% of the plasma Cmax when injected alone, and 1.5% when injected following POX. The ratio of the area under the curve (AUC) brain to plasma for obidoxime was around 6%, irrespective of whether it was administered alone or after POX. For K-27, Cmax (brain) was 0.6% of Cmax (plasma) when injected alone, and 0.7% when injected after POX (no significant difference). The AUC (brain) was 2% of AUC (plasma) for both K-27 groups. K-48, when injected alone reached 1.4% of Cmax (plasma) in the brain and 1.2% of C max (plasma), when injected following POX. The AUC (brain) was 5% of the AUC (plasma), both when K-48 was administered alone and in combination with POX. Entry of all three oximes into the brain is minimal and cannot explain the better therapeutic efficacy of K-27 and K-48. As already observed for pralidoxime, injection of POX before oxime administration had no influence upon penetration across the blood-brain barrier.

Original languageEnglish
Pages (from-to)482-490
Number of pages9
JournalJournal of Applied Toxicology
Volume27
Issue number5
DOIs
Publication statusPublished - Sep 2007

Keywords

  • Blood-brain barrier
  • HPLC
  • Obidoxime
  • Organophosphate
  • Oxime
  • Paraoxon

ASJC Scopus subject areas

  • Toxicology

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