The effects of a series of
pharmaceutical excipients, including
Span 80,
Brij 30,
Tween 20,
Tween 80, Myrj 52, and
sodium lauryl sulfate (with increasing hydrophilic-lipophilic balance (HLB) values) on the intracellular accumulation, transport kinetics, and intestinal absorption of
epirubicin were investigated in both the human
colon adenocarcinoma (Caco-2) cell line and the everted gut sacs of rat jejunum and ileum. The possible use of these
excipients as multidrug resistance (MDR) reversing agents also was examined.
Epirubicin uptake experiments using a flow cytometer showed that these selected
excipients markedly enhanced the intracellular accumulation of
epirubicin in Caco-2 cells in a dose-dependent manner. The optimal effect on the
epirubicin uptake was characteristic of
excipients with intermediate HLB values ranging from 10 to 17. Moreover, the optimal net efficacy was observed for
excipients with
polyoxyethylene chains and intermediate chain length of
fatty acid and
fatty alcohol (monolaurate for
Tween 20, monooleate for
Tween 80, monostearate for Myrj 52, and
lauryl alcohol for
Brij 30). These
excipients significantly increased apical to basolateral absorption and substantially reduced basolateral to apical efflux of
epirubicin across Caco-2 monolayers. Furthermore, the addition of
Tween 20,
Tween 80, Myrj 52, and
Brij 30 markedly enhanced mucosal to serosal absorption of
epirubicin in the rat jejunum and ileum. This study suggests that inhibition of intestinal
P-glycoprotein (P-gp),
multidrug resistance associated protein family (MRPs), or other transporter
proteins by
pharmaceutical excipients may improve oral absorption of drugs in MDR spectrum. The optimal HLB values of
surfactant systems with suitable
hydrocarbon chains and polar groups are an important factor in designing promising
epirubicin formulations for reversing MDR. In conclusion, therapeutic efficacy of
epirubicin may be enhanced by the use of such low toxicity
excipients as absorption enhancers and MDR modulators in formulations. This provides a potential strategy for improving bioavailability in the optimization of formulations for drugs performing intestinal absorption and secretion.