title: Pharmacokinetics of substrate uptake and distribution in murine brain after nasal instillation.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Candace L
authors.initials: CL
authors.lastname: Graff
authors.forename: Rong
authors.initials: R
authors.lastname: Zhao
authors.forename: Gary M
authors.initials: GM
authors.lastname: Pollack
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008956:Models, Chemical; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: D014700:Verapamil