Effect of poisoning by soman (pinacolyl methylphosphono‐fluoridate) on the serum half‐life of the cholinesterase reactivator hi‐6 in mice

Abstract

The effect of fasting, atropine, and poisoning by an organophosphate anticholinesterase soman (pinacolyl methylphosphonofluoridate) on the pharmacokinetics of the acetylcholinesterase oxime reactivator HI-6 (CAS Reg. No. 34433-31-3; 1-[(4-(aminocarbonyl)pyridinio)methoxy)methyl)-2-(hydroxy imino)methyl) pyridinium dichloride) was investigated. Pharmacokinetic parameters (elimination half-life, volume of distribution, clearance rate) were determined for the following groups: (1) a 20 and 50 mg kg-1 dose of HI-6; (2) a 50 mg kg-1 dose of HI-6 after fasting for 18 h (water ad lib); (3) a 50 mg kg-1 dose of HI-6 at 0, 4, and 24 h after atropine (17.4 mg kg-1, i.p.) and soman (287 micrograms kg-1, s.c.); and (4) a 50 mg kg-1 dose of HI-6 at 0 and 4 h after soman (100 micrograms kg-1, s.c.). Fasting increased significantly (p less than 0.05) the elimination of half-life (t1/2) and tended to increase the volume of distribution (Vd) and decrease the clearance rate (CL). Following soman (287 micrograms kg-1) poisoning the t1/2 of HI-6 increased from 8.6 min to 21.6 min and the Vd increased to 0.731 kg-1. At the lower soman dose (100 micrograms kg-1) no significant effect on HI-6 pharmacokinetics was found. Atropine (17.4 mg kg-1: i.p.) pretreatment increased the t1/2 and CL while having no effect on the Vd. By 24 h the pharmacokinetic parameters of HI-6 in the various treatment groups were not significantly different from the control group. The changes in the pharmacokinetics of HI-6 following soman and atropine are probably the result of haemodynamic changes.

Plasma concentrations of pralidoxime methylsulphate in organophosphorus poisoned patients

“…The increased concentrations at lower grades of intoxication are then attributed to an increased volume of distribution because of an increased blood flow, e. g. to the muscles (Green et al 1985). HI-6 half life also increases in severely soman poisoned mice (Clement et al 1988).…”

Swine models in the design of more effective medical countermeasures against organophosphorus poisoning

“…It is clear that the pharmacokinetics of treatment drugs could be altered during poisoning, depending on the agent dose, and this has been demonstrated previously in OP-poisoned mice treated with the oxime -methoxy)-methyl]-2-[hydroxyiminomethyl]-pyridinium) (Clement et al, 1988). Conversely, Göransson-Nyberg et al (1995b) did not report significant changes in the pharmacokinetics of HI-6 in OP-poisoned swine.…”