Abstract
Intranasal (IN) administration could be an attractive mode of delivery for drugs targeting the central nervous system (CNS) potentially providing a high bioavailability due to 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 non-linear mixed effects modeling. Brain ECF/plasma AUC ratios were 0.28 and 0.19 after IN and IV administration, respectively. A multi compartment 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 following 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 to 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 semi-physiology based manner would allow for better prediction of pharmacodynamic effects.
- bioavailability
- blood-brain barrier
- blood-CNS transport
- CNS pharmacokinetics
- drug distribution
- pharmacokinetic modeling
- physiologically-based modeling
- targeted delivery
- Received May 23, 2011.
- Accepted September 8, 2011.
- The American Society for Pharmacology and Experimental Therapeutics