Effect of poisoning by soman (pinacolyl methylphosphonofluoridate) 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.