title: Brain distribution of ribavirin after intranasal administration.
abstract: Ribavirin has proved to be effective in vitro against several RNA viruses responsible for encephalitis in humans and animals. However, the in vivo efficacy towards the cerebral viral load seems to be limited by the blood-brain barrier. Since the nose-to-brain pathway has been indicated for delivering drugs to the brain, we investigated here the distribution of ribavirin in the central nervous system (CNS) after intranasal administration. We first tested in vitro ribavirin diffusion from an aqueous solution across a biological membrane, using Franz cells and rabbit nasal mucosa. About 35% of ribavirin permeated in 4 h across the mucosa, after reaching steady-state flux in less than 30 min. In the first in vivo experiment, ribavirin aqueous solution was administered intranasally to Sprague Dawley rats (10 mg/kg). Animals were sacrificed at 10, 20 or 30 min after administration to collect brain areas (cerebellum, olfactory bulb, cerebral cortex, basal ganglia and hippocampus) and biological fluids (cerebrospinal fluid and plasma). Ribavirin, quantified by LC-MS/MS spectrometry, was detected at each time point in all compartments with the highest concentration in olfactory bulb and decreasing in rostro-caudal direction. Two subsequent in vivo experiments compared the nasal route (ribavirin solution) with the intravenous one and the nasal administration of ribavirin solution with ribavirin powder (10 mg/kg). It was found that 20 min after administration, ribavirin concentration in olfactory bulb was similar after intravenous or nasal administration of the ribavirin solution, whereas the powder led to significantly higher levels. Ribavirin was also present in deeper compartments, such as basal ganglia and hippocampus. Even if the mechanisms involved in ribavirin nose-to-brain transport are not clear, these results suggest a rapid extracellular diffusive flux from the nasal epithelium to the olfactory bulb and different CNS areas.
authors: Department of Pharmaceutical Sciences, University of Ferrara, Italy.
authors: Gaia
authors: G
authors: Colombo
authors: Luca
authors: L
authors: Lorenzini
authors: Elisa
authors: E
authors: Zironi
authors: Viola
authors: V
authors: Galligioni
authors: Fabio
authors: F
authors: Sonvico
authors: Anna Giulia
authors: AG
authors: Balducci
authors: Giampiero
authors: G
authors: Pagliuca
authors: Alessandro
authors: A
authors: Giuliani
authors: Laura
authors: L
authors: Calzà
authors: Alessandra
authors: A
authors: Scagliarini
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D010539:Permeability; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin