Eriksson_2012_J.Pharm.Pharmacol_64_1667

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 microM. 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.