The pharmacokinetics of midazolam after intravenous, intramuscular, and rectal administration in healthy dogs

Abstract

Intravenous benzodiazepines are utilized as first-line drugs to treat prolonged epileptic seizures in dogs and alternative routes of administration are required when venous access is limited. This study compared the pharmacokinetics of midazolam after intravenous (IV), intramuscular (IM), and rectal (PR) administration. Six healthy dogs were administered 0.2 mg/kg midazolam IV, IM, or PR in a randomized, 3-way crossover design with a 3-day washout between study periods. Blood samples were collected at baseline and at predetermined intervals until 480 min after administration. Plasma midazolam concentrations were measured by high-pressure liquid chromatography with UV detection. Rectal administration resulted in erratic systemic availability with undetectable to low plasma concentrations. Arithmetic mean values ± SD for midazolam peak plasma concentrations were 0.86 ± 0.36 μg/mL (C0) and 0.20 ± 0.06 μg/mL (Cmax), following IV and IM administration, respectively. Time to peak concentration (Tmax ) after IM administration was 7.8 ± 2.4 min with a bioavailability of 50 ± 16%. Findings suggest that IM midazolam might be useful in treating seizures in dogs when venous access is unavailable, but higher doses may be needed to account for intermediate bioavailability. Rectal administration is likely of limited efficacy for treating seizures in dogs.

Status Epilepticus and Cluster Seizures

“…It should be noted that lorazepam per rectum may not be useful AED therapy because of rapid conversion to inactive metabolites and first pass hepatic metabolism, 29 and that there is erratic systemic availability of midazolam when given per rectum. 30 …”

Intranasal Midazolam versus Rectal Diazepam for the Management of Canine Status Epilepticus: A Multicenter Randomized Parallel‐Group Clinical Trial

“…On the other hand, in 1 clinical trial, R‐DZP was considered effective for treating canine generalized cluster seizures . Pharmacokinetic studies indicate that MDZ, administered via IV and IM routes, might be useful to treat seizures, but that rectal application was unlikely to be effective …”

Pharmacokinetics of midazolam and its major metabolite 1‐hydroxymidazolam in the ball python (Python regius) after intracardiac and intramuscular administrations

“…The t max of IM midazolam was 2.33 ± 0.98 hr, which was much later than reports in dogs (0.13 hr) (Court & Greenblatt, ; Schwartz, Muñana, Nettifee‐Osborne, Messenger, & Papich, ) and sheep (0.46 hr) (Simon et al, ). Maximum sedation has been reported 1 hr postinjection in ball pythons (Larouche et al, ), which appears to be shorter than the t max from the current study.…”