Intramuscular diazepam pharmacokinetics in soman-exposed guinea pigs

Intramuscular (i.m.) diazepam is included by the US military as an anticonvulsant in the standard therapeutic regimen for organophosphorus nerve agent intoxication. In this study we investigated the pharmacokinetics of diazepam after i.m. administration while monitoring pharmacodynamic (electroencephalogram, EEG) data in soman-exposed guinea pigs. Prior to experiments the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered pyridostigmine (0.026 mg x kg(-1) i.m.) 30 min prior to soman (56 microg x kg(-1), 2 x LD50; subcutaneously, s.c.), which was followed in 1 min by atropine sulfate (2 mg x kg(-1) i.m.) and pralidoxime chloride (25 mg x kg(-1) i.m.). All animals receiving this regimen developed seizure activity. Diazepam (10 mg x kg(-1) i.m.) was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure terminated or not terminated at 30 min after diazepam. Serial blood samples were obtained from each animal. Diazepam (10 mg x kg(-1) i.m.) terminated seizure activity in 52% of the animals within 30 min. The pharmacokinetics were characterized by a one-compartment model with first-order absorption and elimination. The maximum plasma concentrations (Cmax) were 991 and 839 ng x ml(-1) for seizure terminated and not terminated, respectively. Mean plasma concentrations of diazepam were significantly different (P < 0.05) for seizure terminated vs not terminated groups at 30 min. The plasma Cmax in seizure-terminated animals in this study is similar to the minimum range of plasma diazepam (200-800 ng x ml(-1)) reported to suppress seizure activity in humans. It has been reported in an earlier study that the minimum effective i.m. dose (0.1 mg x kg(-1)) required to prevent soman-induced convulsions in Rhesus monkeys produces a mean Cmax of 50 ng x ml(-1) for diazepam. The data from our current study suggest that a higher dose (and corresponding Cmax) is necessary to terminate ongoing seizure activity.