Pharmacokinetics of substrate uptake and distribution in murine brain after nasal instillation

Abstract

Purpose: This study was conducted to develop a physiologically relevant mathematical model for describing brain uptake and disposition of nasally administered substrates.

Methods: [14C]-antipyrine, [14C]-diazepam, [3H]-sucrose, or [3H]-verapamil was administered nasally to CF-1 mice. P-glycoprotein (P-gp)-deficient mice also received [3H]-verapamil to probe the influence of P-gp on uptake/distribution. Mice were sacrificed at selected intervals, and 20 serial 300-microm coronal brain sections were obtained to determine radioactivity. A series of compartmental pharmacokinetic models was developed and fit to concentration vs. time/distance data.

Results: After nasal instillation, substrate concentration was highest in the olfactory bulb and decreased with distance. In the absence of transport-mediated flux, peak brain exposure occurred at 6 h. A catenary pharmacokinetic model with slice-specific brain-to-blood efflux rate constants and slice-to-slice diffusivity factors was capable of fitting the data. P-gp limited fractional absorption of [3H]-verapamil via efflux from the nasal cavity and olfactory epithelium. P-gp also increased the rate constants associated with [3H]-verapamil efflux 1.5- to 190-fold, depending on brain region. P-gp limited [3H]-verapamil uptake from the nasal cavity into brain and facilitated removal of [3H]-verapamil from brain during rostral-to-caudal distribution.

Conclusions: Taken together, the data and associated modeling provide a comprehensive assessment of the influence of P-gp on brain uptake and disposition of nasally administered substrates.