Colchicine effect on P-glycoprotein expression and activity: in silico and in vitro studies.
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Silva R, Carmo H, Vilas-Boas V, Barbosa DJ, Palmeira A, Sousa E, Carvalho F, Bastos Mde L, Remiao F
Colchicine effect on P-glycoprotein expression and activity: in silico and in vitro studies.
Chem Biol Interact. 2014 Jul 25;218:50-62. doi: 10.1016/j.cbi.2014.04.009. Epub 2014 Apr 20.
- PubMed ID
- 24759273 [ View in PubMed]
- Abstract
Colchicine is a P-glycoprotein (P-gp) substrate that induces its expression, thus increasing the risk for unexpected pharmacokinetic interactions with this drug. Because increased P-gp expression does not always correlate with increased activity of this efflux pump, we evaluated the changes in both P-gp expression and activity induced by colchicine using an in vitro model. Caco-2 cells were incubated with 0.1-100 muM colchicine up to 96 h. Cytotoxicity was evaluated by the MTT and LDH leakage assays, P-gp expression and activity were evaluated by flow cytometry and P-gp ATPase activity was measured in MDR1-Sf9 membrane vesicles. Furthermore, colchicine fitting in P-gp induction and competitive inhibition pharmacophore hypothesis, and docking studies evaluating the interaction between colchicine and P-gp drug binding pocket were tested in silico. Significant cytotoxicity was noted after 48 h. At 24 h a significant increase in P-gp expression was observed, which was not accompanied by an increase in transport activity. Moreover, colchicine significantly increased P-gp ATPase activity, demonstrating to be actively transported by the pump. New pharmacophores were constructed to predict P-gp modulatory activity. Colchicine fitted both the P-gp induction and competitive inhibition models. In silico, colchicine was predicted to bind to the P-gp drug-binding pocket suggesting a competitive mechanism of transport. These results show that colchicine induced P-gp expression in Caco-2 cells but the activity of the protein remained unchanged, highlighting the need to simultaneously evaluate P-gp expression and activity. With the newly constructed pharmacophores, new drugs can be initially screened in silico to predict such potential pharmacokinetic interactions.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Colchicine P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareColchicineCarfilzomib The serum concentration of Colchicine can be increased when it is combined with Carfilzomib. ColchicineVoclosporin The serum concentration of Colchicine can be increased when it is combined with Voclosporin. ColchicineSildenafil The serum concentration of Colchicine can be increased when it is combined with Sildenafil. ColchicineReserpine The serum concentration of Colchicine can be increased when it is combined with Reserpine. ColchicineLoxapine The serum concentration of Colchicine can be increased when it is combined with Loxapine.