In-vitro evaluation of the P-glycoprotein interactions of a series of potentially CNS-active Amaryllidaceae alkaloids

J Pharm Pharmacol. 2012 Nov;64(11):1667-77. doi: 10.1111/j.2042-7158.2012.01536.x. Epub 2012 Jun 4.


Objectives: Drug compounds interacting with the blood-brain barrier efflux transporter P-glycoprotein (P-gp) might have limited access to brain tissue. The aim of the present study was to evaluate whether nine potentially CNS-active Amaryllidaceae alkaloids of the crinine, lycorine and galanthamine types interact with P-gp.

Methods: Alkaloids with inhibitory activity towards either the serotonin reuptake transporter or acetylcholinesterase, or both, were investigated using the calcein-AM efflux assay in Madin-Darby canine kidney cells transfected with human multidrug resistance transporter 1.

Key findings: Powelline and 6-hydroxycrinamine showed an interaction with P-gp, with IC50 values between 300 and 500 µM. 3-O-Acetylhamayne showed a weaker interaction, with an IC50 value above 3 mM. Epibuphanisine, lycorine, 1-epi-deacetylbowdenisine, papyramine and galanthamine all showed weak or no interaction with P-gp. There was no observed correlation between alkaloid type and P-gp interaction.

Conclusions: Structurally similar compounds such as crinine and epibuphanisine showed very different P-gp interactions, highlighting the difficulty in predicting P-gp interactions. Epibuphanisine has previously shown activity in the serotonin reuptake transporter assay and may therefore serve as a lead for serotonin reuptake transporter active compounds. The most potent compound in the acetylcholinesterase assay, the marketed drug compound galanthamine (Reminyl), showed no interaction with P-gp.

Publication types

  • Historical Article
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Amaryllidaceae Alkaloids / administration & dosage
  • Amaryllidaceae Alkaloids / pharmacology*
  • Animals
  • Blood-Brain Barrier / metabolism
  • Dogs
  • Dose-Response Relationship, Drug
  • Fluoresceins / metabolism*
  • Fluorescent Dyes / metabolism*
  • History, Ancient
  • Humans
  • Inhibitory Concentration 50
  • Transfection


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amaryllidaceae Alkaloids
  • Fluoresceins
  • Fluorescent Dyes
  • calcein AM