Present address: DMPK and Safety, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
In-vitro evaluation of the P-glycoprotein interactions of a series of potentially CNS-active Amaryllidaceae alkaloids
Version of Record online: 4 JUN 2012
© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society
Journal of Pharmacy and Pharmacology
Volume 64, Issue 11, pages 1667–1677, November 2012
How to Cite
Eriksson, A. H., Rønsted, N., Güler, S., Jäger, A. K., Sendra, J. R. and Brodin, B. (2012), In-vitro evaluation of the P-glycoprotein interactions of a series of potentially CNS-active Amaryllidaceae alkaloids. Journal of Pharmacy and Pharmacology, 64: 1667–1677. doi: 10.1111/j.2042-7158.2012.01536.x
- Issue online: 12 OCT 2012
- Version of Record online: 4 JUN 2012
- Received September 2, 2011; Accepted April 15, 2012
- calcein-AM, MDCK(II)-MDR1;
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.