title: Paraoxon has only a minimal effect on pralidoxime brain concentration in rats.
abstract: Clinical experience with oximes, cholinesterase reactivators used in organophosphorus poisoning, has been disappointing. Their major anatomic site of therapeutic action and their ability to pass the blood-brain barrier (BBB) are controversial. Although their physico-chemical properties do not favour BBB penetration, access of oximes to the brain may be facilitated by organophosphates. The effect of the organophosphate paraoxon (POX) on pralidoxime (2-PAM) brain entry was therefore determined. Rats either received 50 micromol 2-PAM only (G(1)) or additionally 1 micromol POX ( approximately LD(75)) (G(2)). Three animals each were killed after 5, 15, 30, 60, 90, 120, 180, 240, 360, 480 min, and 2-PAM concentrations in the brain and plasma were measured using HPLC. Moreover, the effect of brain perfusion with isotonic saline on subsequent 2-PAM measurements was assessed. The maximal 2-PAM concentration (C(max)) in G(1) brain was 6% of plasma C(max), while in G(2) brains it was 8%. Similarly, the ratio of the area under the curve (AUC) brain to plasma was 8% in G(1) and 12% in G(2). Brain t(max) (15 min) was slightly higher than plasma t(max) (5 min). The AUC of plasma 2-PAM did not differ between G(1) and G(2). However, in G(1), AUC brain was significantly lower than in G(2), the differences probably being clinically irrelevant. In perfused brains, 2-PAM concentrations were very close to those of non-perfused brains. The results indicate that brain penetration of 2-PAM is poor and that organophosphates only have a modest effect on 2-PAM BBB penetration. Brain perfusion does not significantly alter 2-PAM measurements and is therefore considered unnecessary.
authors.affiliation: Department of Pharmacology and Therapeutics, FMHS, United Arab Emirates University, Al Ain, United Arab Emirates. georg.petroianu@uaeu.ac.ae
authors.forename: G A
authors.initials: GA
authors.lastname: Petroianu
authors.forename: D E
authors.initials: DE
authors.lastname: Lorke
authors.forename: M Y
authors.initials: MY
authors.lastname: Hasan
authors.forename: A
authors.initials: A
authors.lastname: Adem
authors.forename: R
authors.initials: R
authors.lastname: Sheen
authors.forename: S M
authors.initials: SM
authors.lastname: Nurulain
authors.forename: H
authors.initials: H
authors.lastname: Kalasz
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000008:administration & dosage / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D008297:Male; D015394:Molecular Structure; D010261:Paraoxon / Q000008:administration & dosage / Q000494:pharmacology*; D010477:Perfusion; D011220:Pralidoxime Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014664:Vasodilation / Q000187:drug effects
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D011220:Pralidoxime Compounds; C028797:pralidoxime; D010261:Paraoxon