Randomly Methylated β-Cyclodextrin Derivatives Enhance Taxol Permeability Through Human Intestinal Epithelial Caco-2 Cell Monolayer

Intestinal absorption and bioavailability of taxol are limited by its low solubility and P-glycoprotein (Pgp) activity. Methylated beta-cyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated beta-cyclodextrin (RAMEB) is cytotoxic in high concentrations. Second-generation 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 Caco-2 model. Taxol permeability was not changed by 30-min pretreatment with CDs. In co-treatment with beta-cyclodextrins, 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 co-treatment 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, second-generation derivatives of methyl-beta-cyclodextrin, especially MaRAMEB, enhanced taxol permeability across Caco-2 cells with less toxicity and similar effectiveness as RAMEB. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4734-4744, 2011