Inhibition of human efflux transporter ABCC2 (MRP2) by self-emulsifying drug delivery system: Influences of concentration and combination of excipients

Purpose: This study investigated influences of concentration and combination of excipients, commonly used in self-emulsifying drug delivery systems (SEDDS), on inhibition of human efflux transporter ABCC2 (MRP2). Methods: Ten commonly used excipients of SEDDS with inhibitory effect on MRP2 including Cremophor® EL, Cremophor® RH, Pluronic® F127, Maisine® 35-1, β-cyclodextrin, Labrasol®, Pluronic® F68, PEG 2000, PEG 400 and Transcutol® were studied with the Caco-2 cell model. Six excipients with inhibitory effect including Cremophor® EL, Cremophor® RH, Pluronic® F127, PEG 2000, PEG 400 and Transcutol® were further analyzed using the MRP2 vesicle assay and ATPase activity assay. Ultra-performance liquid-chromatography tandem mass spectrometry was used to measure scutellarin as the MRP2 substrate. Results: In studying concentration-dependent effects, five excipients including Cremophor® EL, Cremophor® RH, Pluronic® F127, Maisine® 35-1 and β-cyclodextrin showed concentration-dependent decrease in efflux ratio of scutellarin. The other five excipients did not show such phenomenon, and their inhibitory effects were restricted to be above to certain critical or minimum concentrations. In studying combined effects, PEG 2000 and Pluronic® F127 both showed combined effect with Cremophor® EL on inhibiting MRP2. However, some combinations of excipients such as PEG 400　and Transcutol® with Cremophor® EL increased the scutellarin efflux ratio and decreased the transport of scutellarin and ATPase activity, compared to Cremophor® EL alone. Conclusion: The above results suggest that appropriate choice of excipients according to their concentration-dependent and combined effects on MRP2 inhibition can facilitate formulation of SEDDS for improving the bioavailability of drugs that are MRP2 substrates.