Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits

The purpose of this study was to investigate the plasma pharmacokinetics and brain uptake of a lipophilic benzodiazepine anticonvulsant, diazepam in New Zealand white rabbits and Sprague–Dawley rats to evaluate the possible absorption pathways after intravenous and intranasal administration. The intranasal formulation was prepared by dissolving DZ and 1% sodium glycocholate into microemulsion system composed of 15% ethyl laurate, 25% Labrasol®, 37.5% Transcutol®P, 12.5% ethanol, and 10% water. Diazepam was administered intravenously (1 mg/kg) or intranasally (2 mg/kg) to rats and rabbits. Drug concentrations in the plasma and six different regions of the brain tissues, i.e., olfactory bulb, olfactory tract, anterior, middle, and posterior segments of cerebrum and cerebellum were analyzed by LC/MS method after solid phase extraction. After IN administration, DZ was rapidly absorbed into the systemic circulation, and readily and homogenously distributed into the different regions of brain tissues with a tmax of 5 and 10 min in rats and rabbits, respectively. The bioavailability of DZ in rat plasma (68.4%) and brain (67.7%) were 32–47% higher than those observed in rabbit plasma (51.6%) and brain (45.9%). The AUCbrain/AUCplasma ratios in rabbits after IN administration (3.77 ± 0.17) were slightly lower than from IV administration (4.23 ± 0.08). However, in rats the AUCbrain/AUCplasma ratios after IV (3.03 ± 0.07) and IN (3.00 ± 0.32) administration were nearly identical. The plasma pharmacokinetic and distribution studies in the two animal models clearly showed that lipophilic DZ molecules reached the brain predominantly from the blood by crossing the blood–brain barrier after IN administration with no significant direct nose-to-brain transport via olfactory epithelium.