Pharmacokinetic Studies of Intramuscular Midazolam in Guinea Pigs Challenged with Soman

Abstract

Studies have demonstrated that benzodiazepine compounds are effective at antagonizing seizure activity produced by the organophosphate (OP) cholinesterase inhibitor soman. In this present study we have investigated the pharmacokinetics of midazolam and its associated effects on electroencephalographic (EEG) activity following intramuscular (im) injection to soman‐exposed guinea pigs (Crl:(HA)BR). Prior to experiments, the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered the following pretreatment/OP/treatment regimen. Pyridostigmine bromide (0.026 mg/kg, im) was given 30 min prior to soman (56 µg/kg, 2 × LD50; subcutaneously, sc), followed in one minute by atropine sulfate (2 mg/kg, im) and pralidoxime chloride (25 mg/kg, im). All animals receiving this regimen developed seizure activity. Midazolam 0.8 mg/kg, im, was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure‐terminated or seizure not‐terminated at 30 min following anticonvulsant administration. Serial blood samples were collected for the plasma midazolam analysis; the assay was accomplished with a gas chromatograph/mass spectrometer. The mean time to seizure termination was 8.8 ± 1.6 min. The mean time‐plasma concentration data were fit to standard pharmacokinetic models. The following parameter estimates were determined from the model‐fit for seizure terminated and not‐terminated animals respectively: apparent volumes of distribution (Vd) were 1.4 and 1.7 l/kg; area under the time‐concentration curves (AUC), 15,990 and 15,120 ng · min/ml; times to maximal plasma concentration (Tmax), 1.66 and 2.91 min and maximal plasma concentrations (Cmax) 535.1 and 436.6 ng/ml. These data indicate that im injection of midazolam is effective at terminating ongoing soman‐induced seizure activity. Additionally, the relatively short Tmax and latency to seizure termination demonstrate the rapidity of drug absorption and action respectively.