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Effects of monoglycerides on rhodamine 123 accumulation, estradiol 17 β-D-glucuronide bidirectional transport and MRP2 protein expression within Caco-2 cells Jia, Xi Jessica


Purpose: Oral drug development had been hindered by the bioavailability issue despite vast market popularity. Lipid excipients have shown to enhance bioavailability of several reformulated hydrophobic oral drugs, yet the underlying mechanisms of action by lipids are still unclear. One proposed mechanism is that lipid could facilitate drug uptake by altering the activities of apical membrane intestinal efflux transporters. Thus, this study aimed to investigate the effects of specific monoglycerides on the efflux activity and protein expression of multidrug resistance-associated protein 2 (MRP2) in vitro. Methods: A preliminary study was first conducted to determine the effect of Peceol®, a mono- and di-glyceride mixture, on MPR2 efflux activity. Then, the 24- hour non-cytotoxic ranges of specific monoglycerides (1-monopalmitin, 1- monostearin and 1-monoolein) were determined using MTS and LDH assays in Caco-2 cells. Then, the effects of chosen monoglycerides on the functional activity of MRP2 were assessed via rhodamine 123 (Rh123) accumulation and estradiol 17 β-D-glucuronide(E₂17βG) bidirectional transport studies. The dose responses of Rh123 accumulation with each monoglyceride treatment were also determined. Lastly, Western blotting was used to probe the monoglycerides effect on MRP2 protein expression. Results: In the preliminary study, significant increase in Rh123 accumulation and decrease in E₂17βG efflux ratio were observed in Peceol® treated cells. The non-cytotoxic concentration ranges for 1-monopalmitin, 1-monostearin and 1- monoolein were within 1 mM, 1 mM and 500 μM, respectively. Cells treated with 1 mM 1-monoplamitin, 1 mM 1-monostearin, 500 μM 1-monoolein and 50 μM MK571 (a MRP2 inhibitor) resulted in significant increases in Rh123 accumulation and decreases in E₂17βG efflux ratio compared to the control (medium treated only). The three monoglycerides did not show Rh123 accumulation in a dose-responsive manner. MRP2 protein expressions in 1- monopalmitin and 1-monoolein treated cells were decreased by 19% and 35%, respectively; however, there was no change of MRP2 protein expression in 1- monostearin treated cells. Conclusions: These findings suggested that 1-monoolein, 1-monostearin and 1- monopalmitin could attenuate the activity of MRP2 and possibly other efflux transporters in Caco-2 cells. The reduction of efflux activity of MRP2 by 1- monoolein treatment could be partially explained by the non-specific down regulation of MRP2 protein expression.

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