PT  - JOURNAL ARTICLE
AU  - HaiYan Liu
AU  - Li Liu
AU  - Jia Li
AU  - Dan Mei
AU  - Ru Duan
AU  - Nan Hu
AU  - HaiFang Guo
AU  - ZeYu Zhong
AU  - XiaoDong Liu
TI  - Combined Contributions of Impaired Hepatic CYP2C11 and Intestinal Bcrp Activities and Expressions to Increased Exposure of Oral Glibenclamide in Streptozotocin-induced Diabetic Rats
AID  - 10.1124/dmd.111.043513
DP  - 2012 Mar 05
TA  - Drug Metabolism and Disposition
PG  - dmd.111.043513
4099  - http://dmd.aspetjournals.org/content/early/2012/03/05/dmd.111.043513.short
4100  - http://dmd.aspetjournals.org/content/early/2012/03/05/dmd.111.043513.full
AB  - The purpose of the study was to evaluate the contribution of the impaired cytochrome P450s (CYP450s) and breast cancer resistance protein (Bcrp) activity and expression to drug pharmacokinetics under diabetic states. Diabetic rats were induced by intraperitoneal administration of streptozocin (STZ). Glibenclamide (GLB), a substrate of Bcrp, was served as a model drug. The pharmacokinetics of oral GLB (10 mg/kg) was studied. The results showed that diabetes mellitus significantly increased exposure (AUC and Cmax) of GLB following an oral administration. Data from hepatic microsomes suggested impairment of GLB metabolism in diabetic rats. GLB metabolism in hepatic microsomes was significantly inhibited by a selective inhibitor (sulfaphenazole, SUL) of CYP2C11 and CYP2C11 antibody. Western blot further showed the contribution of impaired CYP2C11 expression to the impairment of GLB metabolism. Data from excretion showed that approximately 72% of oral dose was excreted via feces of normal rats, indicating an important role of intestinal Bcrp. Diabetes significantly decreased recovery from feces, which was only 40% of oral dose. Results from in situ single-pass intestine perfusion revealed that diabetes significantly increased the apparent permeability coefficient (Peff) and decreased efflux of GLB via intestine, inferring impairment of intestinal Bcrp function, which may play a role in the increased exposure of oral GLB in diabetic rats. Insulin treatment partly or completely reversed the changes in diabetic rats. All results gave the conclusion that both the impaired hepatic CYP2C11 and intestinal Bcrp expression and activity induced by diabetes contributed to the increased exposure of oral GLB.