Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.
Article Details
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Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW
Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.
J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37.
- PubMed ID
- 12438524 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Bromocriptine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Buspirone P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Carbamazepine P-glycoprotein 1 Protein Humans UnknownInducerDetails Chlorprothixene P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Clomipramine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Desipramine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Doxepin P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Flurazepam P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Fluvoxamine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Haloperidol P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Imipramine P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Naloxone P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Selegiline P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Sumatriptan P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Zimelidine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails