Quantitative evaluation of the function of small intestinal P-glycoprotein: comparative studies between in situ and in vitro.

PURPOSE

The extent of intestinal absorption of MDR1 P-glycoprotein (P-gp) substrate drugs may be affected by interindividual differences in the expression level of P-gp, and/or by simultaneously administered P-gp substrates/inhibitors. The purpose of the present study is to examine whether the extent to which the intestinal absorption is affected by P-gp can be predicted from in vitro experiments.

METHODS

The in situ intestinal perfusion experiments were performed for 12 compounds in mdrla/lb (-/-) and normal mice to determine the permeability-surface area (PS) product. Thus determined intestinal P-gp function was compared with the in vitro P-gp function, which was determined by comparing the transcellular transport across human P-gp expressing and parental LLC-PK1 monolayers.

RESULTS

In situ experimental results revealed that the extent to which the intestinal absorption is affected by P-gp was in the following order: quinidine > ritonavir > loperamide, verapamil, daunomycin > digoxin, cyclosporin A > dexamethasone, and vinblastine. A significant correlation was observed between P-gp function determined in the intestinal perfusion and that in LLC-PKI monolayers.

CONCLUSION

The in vitro transcellular transport across P-gp expressing monolayers may be used to predict the extent to which the intestinal absorption is affected by P-gp.