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• W2110344582 endingPage "2282" @default.
• W2110344582 startingPage "2275" @default.
• W2110344582 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." @default.
• W2110344582 created "2016-06-24" @default.
• W2110344582 creator A5017208135 @default.
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• W2110344582 creator A5033133140 @default.
• W2110344582 creator A5077172862 @default.
• W2110344582 date "2011-09-08" @default.
• W2110344582 modified "2023-10-10" @default.
• W2110344582 title "Systemic and Direct Nose-to-Brain Transport Pharmacokinetic Model for Remoxipride after Intravenous and Intranasal Administration" @default.
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• W2110344582 doi "https://doi.org/10.1124/dmd.111.040782" @default.
• W2110344582 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21903866" @default.
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