title: Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration.
abstract: Intranasal (IN) administration could be an attractive mode of delivery for drugs targeting the central nervous system, potentially providing a high bioavailability because of avoidance of a hepatic first-pass effect and rapid onset of action. However, controversy remains whether a direct transport route from the nasal cavity into the brain exists. Pharmacokinetic modeling is proposed to identify the existence of direct nose-to-brain transport in a quantitative manner. The selective dopamine-D2 receptor antagonist remoxipride was administered at different dosages, in freely moving rats, by the IN and intravenous (IV) route. Plasma and brain extracellular fluid (ECF) concentration-time profiles were obtained and simultaneously analyzed using nonlinear mixed-effects modeling. Brain ECF/plasma area under the curve ratios were 0.28 and 0.19 after IN and IV administration, respectively. A multicompartment pharmacokinetic model with two absorption compartments (nose-to-systemic and nose-to-brain) was found to best describe the observed pharmacokinetic data. Absorption was described in terms of bioavailability and rate. Total bioavailability after IN administration was 89%, of which 75% was attributed to direct nose-to brain transport. Direct nose-to-brain absorption rate was slow, explaining prolonged brain ECF exposure after IN compared with IV administration. These studies explicitly provide separation and quantitation of systemic and direct nose-to-brain transport after IN administration of remoxipride in the rat. Describing remoxipride pharmacokinetics at the target site (brain ECF) in a semiphysiology-based manner would allow for better prediction of pharmacodynamic effects.
authors: Division of Pharmacology, Leiden-Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors: Jasper
authors: J
authors: Stevens
authors: Bart A
authors: BA
authors: Ploeger
authors: Piet H
authors: PH
authors: van der Graaf
authors: Meindert
authors: M
authors: Danhof
authors: Elizabeth C M
authors: EC
authors: de Lange
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017330:Remoxipride / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D018492:Dopamine Antagonists; D017330:Remoxipride