Our previous study showed a higher exposure of berberine, palmatine, coptisine, epiberberine and jatrorrhizine in 6-week streptozotocin (STZ)-induced diabetic rats, after oral administration of Coptidis Rhizoma extract. The aim of the present study was to investigate whether the function and expression of intestinal P-glycoprotein (P-GP) was downregulated in STZ-induced diabetic rats and if the impairment of P-GP function and expression contributed to the exposure increase of the five protoberberine alkaloids. Plasma concentration-time profiles of the drugs in the portal vein were obtained after oral administration of Coptidis Rhizoma extract. The effective permeability of the drug across duodenum and ileum were measured using in situ single-pass intestine perfusion. P-GP function in the rat intestine was assessed by measuring the absorption of rhodamine 123 (Rho123). P-GP levels were evaluated using Western blots. It was found that the C(max) and AUC(0-8) values of five alkaloids in the portal vein of diabetic rats were significantly higher than those in the control rats. Diabetic rats also exhibitd a higher level of Rho123 in the portal vein, which showed impairment of P-GP function. A higher effective permeability of the tested drug was found in the duodenum of diabetic rats using in situ single-pass intestine perfusion, indicating that berberine and Rho123 transported more easily across the intestinal barrier of diabetic rats. A lower level of P-GP protein was found in the duodenum, jejunum and ileum of the diabetic rats as compared with age-matched control rats. All these results suggested that the function and expression of P-GP were impaired in the intestine of STZ-induced diabetic rats which, at least partly, contributed to the exposure increase of the five protoberberine alkaloids.
Georg Thieme Verlag KG Stuttgart-New York.