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


RESULTS
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.
Bioneer:Pharma, Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
André Huss
AH
Eriksson
Nina
N
Rønsted
Semiha
S
Güler
Anna Katharina
AK
Jäger
Júlia Rodríguez
JR
Sendra
Birger
B
Brodin
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D047151:Amaryllidaceae Alkaloids / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000378:metabolism*; D049690:History, Ancient; D006801:Humans; D020128:Inhibitory Concentration 50; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D047151:Amaryllidaceae Alkaloids; D005452:Fluoresceins; D005456:Fluorescent Dyes; C085925:calcein AM