Paraoxon has only a minimal effect on pralidoxime brain concentration in rats

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.