Kinetic analysis of the toxicity of pharmaceutical excipients cremophor EL and RH40 on endothelial and epithelial cells

Lóránd Kiss, Fruzsina R. Walter, Alexandra Bocsik, Szilvia Veszelka, Béla Ózsvári, László G. Puskás, Piroska Szabó-révész, Mária A. Deli

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60 Citations (Scopus)

Abstract

Cremophor EL and RH40 are widely used excipients in oral and intravenous drug formulations such as Taxol infusion to improve drug dissolution and absorption. Studies indicate that Cremophors, especially EL, have toxic side effects, but few data are available on endothelial and epithelial cells, which form biological barriers and are directly exposed to these molecules. Human hCMEC/D3 brain endothelial and Caco-2 epithelial cells were treated with Cremophor EL and RH40 in the 0.1-50mg/mL concentration range. Cell toxicity was monitored by real-time cell microelectronic sensing and verified by lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and morphological methods. Cremophors caused dose- and time-dependent damage in both cell types. In endothelial cells, 0.1mg/mL and higher concentrations, in epithelial cells, concentrations of 5mg/mL and above were toxic, especially at longer incubations. Cell death was also proven by double fluorescent staining of cell nuclei. Immunostaining for tight junction proteins claudin-4 and -5 showed barrier disruption in cells treated by surfactants at 24h. In conclusion, Cremophor EL and RH40 in concentrations corresponding to clinical doses caused endothelial and epithelial toxicity. Endothelial cells were more sensitive to surfactant treatment than epithelial cells, and Cremophor EL was more toxic than RH40 in both cell types.

Original languageEnglish
Pages (from-to)1173-1181
Number of pages9
JournalJournal of pharmaceutical sciences
Volume102
Issue number4
DOIs
Publication statusPublished - Apr 2013

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Keywords

  • Absorption enhancer
  • Caco-2 cells
  • Cell toxicity
  • Cremophor
  • Endothelial
  • Epithelial
  • Excipient
  • Real-time cell microelectric sensing
  • Surfactant
  • Toxicokinetics

ASJC Scopus subject areas

  • Pharmaceutical Science

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