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

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-μm 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.