title: Entry of two new asymmetric bispyridinium oximes (K-27 and K-48) into the rat brain: comparison with obidoxime.
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.
authors.affiliation: Department of Anatomy, FMHS, UAE University, Al Ain, United Arab Emirates.
authors.forename: D E
authors.initials: DE
authors.lastname: Lorke
authors.forename: M Y
authors.initials: MY
authors.lastname: Hasan
authors.forename: S M
authors.initials: SM
authors.lastname: Nurulain
authors.forename: R
authors.initials: R
authors.lastname: Sheen
authors.forename: K
authors.initials: K
authors.lastname: Kuca
authors.forename: G A
authors.initials: GA
authors.lastname: Petroianu
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D002801:Cholinesterase Reactivators / Q000493:pharmacokinetics*; D008297:Male; D009768:Obidoxime Chloride / Q000493:pharmacokinetics*; D010091:Oximes / Q000493:pharmacokinetics*; D011726:Pyridinium Compounds / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C513728:4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide; D002801:Cholinesterase Reactivators; C520230:K-48 compound; D010091:Oximes; D011726:Pyridinium Compounds; D009768:Obidoxime Chloride