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1. Drug Metab Dispos. 2012 Mar 5. [Epub ahead of print]

Combined Contributions of Impaired Hepatic CYP2C11 and Intestinal Bcrp Activities
and Expressions to Increased Exposure of Oral Glibenclamide in
Streptozotocin-induced Diabetic Rats.

Liu H, Liu L, Li J, Mei D, Duan R, Hu N, Guo H, Zhong Z, Liu X.

China Pharmaceutical University.

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 C(max)) 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

PMID: 22393122 [PubMed - as supplied by publisher]