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

J Appl Toxicol. 2007 Sep-Oct;27(5):482-90. doi: 10.1002/jat.1229.

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 micromol obidoxime, K-27 or K-48, either alone or in addition to 1 micromol POX. Oxime concentrations at various points in time in brain and plasma were measured using HPLC. The obidoxime C(max) in brain was 1.3% of the plasma C(max) 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, C(max) (brain) was 0.6% of C(max) (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 C(max) (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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Area Under Curve
  • Brain / metabolism*
  • Cholinesterase Reactivators / pharmacokinetics*
  • Male
  • Obidoxime Chloride / pharmacokinetics*
  • Oximes / pharmacokinetics*
  • Pyridinium Compounds / pharmacokinetics*
  • Rats
  • Rats, Wistar

Substances

  • 4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide
  • Cholinesterase Reactivators
  • K-48 compound
  • Oximes
  • Pyridinium Compounds
  • Obidoxime Chloride