title: Examination of the ability of the nasal administration route to confer a brain exposure advantage for three chemical inhibitors of P-glycoprotein.
abstract: The central nervous system (CNS), efficiently isolated from the systemic circulation by the blood-brain barrier (BBB), represents a challenging therapeutic target. For CNS-targeted agents, augmenting brain exposure by increasing blood drug concentrations often is prohibited by systemic toxicity. Therefore, a means for selectively increasing brain exposure, while minimizing systemic exposure, would be desirable. Limited evidence has indicated that nasally-administered compounds can penetrate into brain, although the selectivity of this approach is unclear. This study demonstrated a distinct, but compound-specific, advantage of the nasal administration route in conferring selective CNS delivery (defined as a brain exposure advantage; BEA). Brain and systemic concentrations of three P-glycoprotein-inhibiting agents were evaluated following single nasal or systemic doses to mice, and the influence of administration route on brain exposure (absolute BEA) and on brain-to-blood partitioning (relative BEA) was calculated. Relative and absolute BEA differed markedly among rifampin, quinidine, and GF120918, with relative BEA ranging between 1.53- and 809-fold and absolute BEA between 0.114- and 9.19-fold. Although substantial increases in brain exposure and partitioning in conjunction with nasal administration were demonstrated, the utility of this approach may be limited by inability to deliver a therapeutically relevant mass of drug to the brain.
authors.affiliation: Curriculum in Toxicology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. jeannie_padowski@unc.edu
authors.forename: Jeannie M
authors.initials: JM
authors.lastname: Padowski
authors.forename: Gary M
authors.initials: GM
authors.lastname: Pollack
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000281:Administration, Intranasal; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D051379:Mice; D011802:Quinidine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044005:Tetrahydroisoquinolines; D011802:Quinidine; C083501:Elacridar; D012293:Rifampin