Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2486173 | Journal of Pharmaceutical Sciences | 2011 | 11 Pages |
Abstract
Intestinal absorption and bioavailability of taxol are limited by its low solubility and Pâglycoprotein (Pgp) activity. Methylated βâcyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated βâcyclodextrin (RAMEB) is cytotoxic in high concentrations. Secondâgeneration derivatives containing monoamino (MaRAMEB) and succinylated (SuRAMEB) ionic substituents with similar inclusion capacity but less toxicity could be promising alternatives of RAMEB. Our aim was to examine and compare the efficacy of MaRAMEB and SuRAMEB with the parental RAMEB on taxol bidirectional permeability using the Cacoâ2 model. Taxol permeability was not changed by 30âmin pretreatment with CDs. In coâtreatment with βâcyclodextrins, the apical to basolateral taxol flux was 4 to 6 times greater than in untreated monolayers and it was also higher than in cells treated with Pgp inhibitor cyclosporin A. No decrease in basolateral to apical taxol flux was observed in pretreatment or coâtreatment with CDs, suggesting no Pgp inhibition. All three CDs showed similar effects on taxol permeability but RAMEB altered tight junction protein distribution and significantly decreased transepithelial electrical resistance. None of the CDs modified paracellular permeability to mannitol and polyethylene glycol 4000. In conclusion, secondâgeneration derivatives of methylâβâcyclodextrin, especially MaRAMEB, enhanced taxol permeability across Cacoâ2 cells with less toxicity and similar effectiveness as RAMEB. © 2011 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 100:4734-4744, 2011
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Authors
Ferenc Fenyvesi, TÃmea Kiss, Ãva Fenyvesi, Lajos Szente, Szilvia Veszelka, Mária A. Deli, Judit Váradi, Pálma Fehér, Zoltán Ujhelyi, Árpád Tósaki, Miklós Vecsernyés, Ildikó Bácskay,