Present address: DMPK and Safety, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
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In-vitro evaluation of the P-glycoprotein interactions of a series of potentially CNS-active Amaryllidaceae alkaloids
Article first published online: 4 JUN 2012
DOI: 10.1111/j.2042-7158.2012.01536.x
© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society
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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
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Present address: DMPK and Safety, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
Publication History
- Issue published online: 12 OCT 2012
- Article first published online: 4 JUN 2012
- Received September 2, 2011; Accepted April 15, 2012
- Abstract
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Keywords:
- alkaloids;
- amaryllidaceae;
- calcein-AM, MDCK(II)-MDR1;
- P-glycoprotein
Abstract
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.