Randomly methylated β-cyclodextrin derivatives enhance taxol permeability through human intestinal epithelial Caco-2 cell monolayer

Ferenc Fenyvesi, Tímea Kiss, Éva Fenyvesi, Lajos Szente, S. Veszelka, M. Deli, J. Váradi, Pálma Fehér, Zoltán Ujhelyi, A. Tósaki, M. Vecsernyés, I. Bácskay

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Intestinal absorption and bioavailability of taxol are limited by its low solubility and P-glycoprotein (Pgp) activity. Methylated β-cyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated β-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 β-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-β-cyclodextrin, especially MaRAMEB, enhanced taxol permeability across Caco-2 cells with less toxicity and similar effectiveness as RAMEB.

Original languageEnglish
Pages (from-to)4734-4744
Number of pages11
JournalJournal of Pharmaceutical Sciences
Volume100
Issue number11
DOIs
Publication statusPublished - Nov 2011

Fingerprint

Caco-2 Cells
Cyclodextrins
Paclitaxel
Permeability
Epithelial Cells
P-Glycoprotein
Tight Junction Proteins
Intestinal Absorption
Mannitol
Electric Impedance
Solubility
Cyclosporine
Biological Availability

Keywords

  • Caco-2 cells
  • Cyclodextrins
  • Epithelial delivery/permeability
  • P-glycoprotein
  • Taxol
  • Tight junction

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Randomly methylated β-cyclodextrin derivatives enhance taxol permeability through human intestinal epithelial Caco-2 cell monolayer. / Fenyvesi, Ferenc; Kiss, Tímea; Fenyvesi, Éva; Szente, Lajos; Veszelka, S.; Deli, M.; Váradi, J.; Fehér, Pálma; Ujhelyi, Zoltán; Tósaki, A.; Vecsernyés, M.; Bácskay, I.

In: Journal of Pharmaceutical Sciences, Vol. 100, No. 11, 11.2011, p. 4734-4744.

Research output: Contribution to journalArticle

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abstract = "Intestinal absorption and bioavailability of taxol are limited by its low solubility and P-glycoprotein (Pgp) activity. Methylated β-cyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated β-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 β-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-β-cyclodextrin, especially MaRAMEB, enhanced taxol permeability across Caco-2 cells with less toxicity and similar effectiveness as RAMEB.",
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AU - Fenyvesi, Ferenc

AU - Kiss, Tímea

AU - Fenyvesi, Éva

AU - Szente, Lajos

AU - Veszelka, S.

AU - Deli, M.

AU - Váradi, J.

AU - Fehér, Pálma

AU - Ujhelyi, Zoltán

AU - Tósaki, A.

AU - Vecsernyés, M.

AU - Bácskay, I.

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AB - Intestinal absorption and bioavailability of taxol are limited by its low solubility and P-glycoprotein (Pgp) activity. Methylated β-cyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated β-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 β-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-β-cyclodextrin, especially MaRAMEB, enhanced taxol permeability across Caco-2 cells with less toxicity and similar effectiveness as RAMEB.

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