Diazepam pharmacokinetics after nasal drop and atomized nasal administration in dogs

Abstract

The standard of care for emergency therapy of seizures in veterinary patients is intravenous (i.v.) administration of benzodiazepines, although rectal administration of diazepam is often recommended for out-of-hospital situations, or when i.v. access has not been established. However, both of these routes have potential limitations. This study investigated the pharmacokinetics of diazepam following i.v., intranasal (i.n.) drop and atomized nasal administration in dogs. Six dogs were administered diazepam (0.5 mg/kg) via all three routes following a randomized block design. Plasma samples were collected and concentrations of diazepam and its active metabolites, oxazepam and desmethyldiazepam were quantified with high-performance liquid chromatography (HPLC). Mean diazepam concentrations >300 ng/mL were reached within 5 min in both i.n. groups. Diazepam was converted into its metabolites within 5 and 10 min, respectively, after i.v. and i.n. administration. The half lives of the metabolites were longer than that of the parent drug after both routes of administration. The bioavailability of diazepam after i.n. drop and atomized nasal administration was 42% and 41%, respectively. These values exceed previously published bioavailability data for rectal administration of diazepam in dogs. This study confirms that i.n. administration of diazepam yields rapid anticonvulsant concentrations of diazepam in the dog before a hepatic first-pass effect.

Pharmacokinetics of the cytochrome P‐450 substrates phenytoin, theophylline, and diazepam in healthy Greyhound dogs

“…The pharmacokinetics of IV diazepam has been previously reported in dogs (Löscher & Frey, 1981; Papich & Alcorn, 1995; Musulin et al. , 2011).…”

“…, 2011). The range of the terminal half‐life of diazepam in non‐Greyhound dogs has been 0.25–5.5 h (Löscher & Frey, 1981; Papich & Alcorn, 1995; Musulin et al. , 2011).…”

“…, 2011). The reported plasma clearance of diazepam in non‐Greyhound dogs ranged from 11.5 to 60 mL·min/kg (Papich & Alcorn, 1995; Musulin et al. , 2011).…”

Benzodiazepines

“…6,7 Midazolam can be given as a CRI through a peripheral vein. However, midazolam is poorly bioavailable when given per rectum to dogs, so this route of administration is not recommended.…”

Comparative Veterinary Pharmacokinetics

“…Another example is diazepam, a frequently applied anticonvulsive benzodiazepine. Nasal bioavailability of diazepam is 41-42% in dogs (Musulin et al, 2011), providing an alternative route next to rectal administration in status epilepticus.…”