Combined Contributions of Impaired Hepatic CYP2C11 and Intestinal Breast Cancer Resistance Protein Activities and Expression to Increased Oral Glibenclamide Exposure in Rats with Streptozotocin-Induced Diabetes Mellitus
Combined Contributions of Impaired Hepatic CYP2C11 and Intestinal Breast Cancer Resistance Protein Activities and Expression to Increased Oral Glibenclamide Exposure in Rats with Streptozotocin-Induced Diabetes Mellitus
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肝 CYP2C11 受损和肠乳腺癌抗性蛋白活性和表达对链脲佐菌素诱导的糖尿病大鼠口服格列本脲暴露量增加的综合作用
DOI：
10.1124/dmd.111.043513
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发表时间：
2012-06-01
影响因子：
3.9
通讯作者：
Liu, Xiaodong
中科院分区：
文献类型：
--
作者：
Liu, Haiyan;Liu, Li;Liu, Xiaodong
本研究的目的是评估受损的细胞色素P450和乳腺癌耐药蛋白（BCRP）的活性和表达的糖尿病条件下的药物药代动力学的贡献。腹腔注射链脲佐菌素诱导大鼠糖尿病。格列本脲（GLB）是BCRP的底物，用作模型药物。研究了口服GLB（10 mg/kg）的药代动力学。结果表明，糖尿病显著增加口服给药后GLB的暴露量（曲线下面积和峰浓度）。肝微粒体数据提示糖尿病大鼠GLB代谢受损。肝微粒体中的GLB代谢被CYP 2C 11的选择性抑制剂（磺胺苯吡唑）和抗CYP 2C 11抗体显著抑制。Western blotting进一步表明CYP 2C 11表达受损对GLB代谢受损的贡献。排泄数据显示，正常大鼠经口给药剂量的约72%经粪便排泄，这表明肠道BCRP具有重要作用。糖尿病显著降低了从粪便中的回收率，仅为口服给药剂量的40%。原位、单通道、肠灌注实验的结果显示，糖尿病显著增加了表观有效渗透性，并降低了GLB通过肠道的外排;这表明肠道BCRP功能受损，这可能在糖尿病大鼠口服GLB暴露增加中发挥作用。胰岛素治疗部分或完全逆转糖尿病大鼠的变化。所有结果得出的结论是，糖尿病诱导的肝脏CYP 2C 11和肠道BCRP表达和活性受损导致口服GLB的暴露量增加。
The purpose of this study was to evaluate the contributions of impaired cytochrome P450 and breast cancer resistance protein (BCRP) activity and expression to drug pharmacokinetics under diabetic conditions. Diabetes was induced in rats with the intraperitoneal administration of streptozocin. Glibenclamide (GLB), a substrate of BCRP, served as a model drug. The pharmacokinetics of orally administered GLB (10 mg/kg) were studied. The results showed that diabetes mellitus significantly increased exposure (area under the curve and peak concentration) to GLB after 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) of CYP2C11 and an anti-CYP2C11 antibody. Western blotting further indicated the contribution of impaired CYP2C11 expression to the impairment of GLB metabolism. Excretion data showed that ∼72% of the orally administered dose was excreted in the feces of normal rats, which indicates an important role for intestinal BCRP. Diabetes significantly decreased the recovery from feces, which was only 40% of the orally administered dose. Results from in situ, single-pass, intestinal perfusion experiments revealed that diabetes significantly increased the apparent effective permeability and decreased the efflux of GLB through the intestine; this suggests impairment of intestinal BCRP function, which may play a role in the increased exposure to orally administered GLB in diabetic rats. Insulin treatment partly or completely reversed the changes in diabetic rats. All results yielded the conclusion that impaired hepatic CYP2C11 and intestinal BCRP expression and activity induced by diabetes contributed to the increased exposure of orally administered GLB.