title: Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.
abstract: Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences are useful criteria in selecting compounds for drug development. Apparent permeability (P(app)) and Pgp substrate profiles for 93 CNS (n = 48) and non-CNS (n = 45) drugs were determined by monolayer efflux. Calcein-AM inhibition assays were used to supplement the efflux results. The CNS set (2 of 48, 4.2%) had a 7-fold lower incidence of passive permeability values <150 nm/s compared with the non-CNS set (13 of 45, 28.9%). The majority of drugs (72.0%, 67 of 93) were not Pgp substrates; however, 49.5% (46 of 93) were positive in the calcein-AM assay when tested at 100 microM. The CNS drug set (n = 7 of 48, 14.6%) had a 3-fold lower incidence of Pgp-mediated efflux than the non-CNS drug set (n = 19 of 45, 42.2%). Analysis of 18 physicochemical properties revealed that the CNS drug set had fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surface area, and reduced flexibility compared with the non-CNS group (p < 0.05), properties that enhance membrane permeability. This study on a large, diverse set of marketed compounds clearly demonstrates that permeability, Pgp-mediated efflux, and certain physicochemical properties are factors that differentiate CNS and non-CNS drugs. For CNS delivery, a drug should ideally have an in vitro passive permeability >150 nm/s and not be a good (B --> A/A --> B ratio <2.5) Pgp substrate.
authors.affiliation: Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Mahar Doan
authors.forename: Joan E
authors.initials: JE
authors.lastname: Humphreys
authors.forename: Lindsey O
authors.initials: LO
authors.lastname: Webster
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Wring
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Shampine
authors.forename: Cosette J
authors.initials: CJ
authors.lastname: Serabjit-Singh
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Adkison
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs; D016503:Drug Delivery Systems / Q000379:methods; D010539:Permeability / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002491:Central Nervous System Agents; D004364:Pharmaceutical Preparations