Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs
| Autor: | Lindsey O. Webster, Larry J. Shampine, Kelly M. Mahar Doan, Cosette J. Serabjit-Singh, Joan E. Humphreys, Joseph W. Polli, Stephen A. Wring, Kimberly K. Adkison |
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| Rok vydání: | 2002 |
| Předmět: |
Cell Membrane Permeability
Membrane permeability Central nervous system ATP-binding cassette transporter Pharmacology Permeability Cell Line Dogs Drug Delivery Systems polycyclic compounds medicine Animals ATP Binding Cassette Transporter Subfamily B Member 1 P-glycoprotein biology Chemistry Penetration (firestop) In vitro medicine.anatomical_structure Pharmaceutical Preparations Blood-Brain Barrier Cell culture biology.protein Molecular Medicine Efflux Central Nervous System Agents |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 303:1029-1037 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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 values150 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 (p0.05), 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 permeability150 nm/s and not be a good (B --A/A --B ratio2.5) Pgp substrate. |
| Databáze: | OpenAIRE |
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