Colchicine effect on P-glycoprotein expression and activity: In silico and in vitro studies

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Renata Silva (Author) Other; Helena Carmo (Author) FFUP; Vania Viras Boas (Author) Other; Daniel Jose Barbosa (Author) Other; Andreia Palmeira (Author) Other; Emilia Sousa (Author) FFUP; Felix Carvalho (Author) FFUP; Maria de Lourdes Bastos (Author) FFUP; Fernando Remiao (Author) FFUP

Journal

Title: Chemico-Biological Interactions

Vol. 218

Pages: 50-62

ISSN: 0009-2797

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 25 Citations

ISI Web of Science

Scopus - 26 Citations

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences > Basic medicine

CORDIS: Health sciences > Pharmacological sciences > Toicology

Other information

Authenticus ID: P-009-DQG

DOI: 10.1016/j.cbi.2014.04.009

Abstract (EN): 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 mu M colchicine up to 96 h. Cytotoxicity was evaluated by the MIT 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 silica. 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 silica, 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 silica to predict such potential pharmacokinetic interactions.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13