title: Decreased exposure of atorvastatin in diabetic rats partly due to induction of hepatic Cyp3a and Oatp2.
abstract: 1. Atorvastatin is frequently prescribed for lowering blood cholesterol and for prevention of events associated with cardiovascular disease. The aim of this study was to investigate the pharmacokinetics of atorvastatin in diabetic rats. 2. Diabetes was induced in rats by combination of high-fat diet and low-dose streptozotocin (35 mg/kg). Plasma concentrations of atorvastatin following oral (10 mg/kg) and intravenous (2 mg/kg) administrations to rats were measured by LC-MS. Metabolism and uptake of atorvastatin in primary hepatocytes of experimental rats were assessed. Protein expressions and activities of hepatic Cyp3a and Oatp2 were further investigated. 3. Clearances of atorvastatin in diabetic rats following oral and intravenous administrations were remarkably increased, leading to marked decreases in area-under-the-plasma concentration-time curve (AUC). The estimated oral and systematic clearances of atorvastatin in diabetic rats were 4.5-fold and 2.0-fold of control rats, respectively. Metabolism and uptake of atorvastatin in primary hepatocytes isolated from diabetic rats were significantly increased, which were consistent with the up-regulated protein expressions and activities of hepatic Cyp3a and Oatp2. 4. All these results demonstrated that the plasma exposure of atorvastatin was significantly decreased in diabetic rats, which was partly due to the up-regulated activities and expressions of both hepatic Cyp3a and Oatp2.
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Nan
authors: N
authors: Shu
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Mengyue
authors: M
authors: Hu
authors: b Department of Biochemistry and Molecular Biology , Miller School of Medicine, University of Miami , Miami , FL , USA , and.
authors: Can
authors: C
authors: Liu
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Mian
authors: M
authors: Zhang
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Zhaoli
authors: Z
authors: Ling
authors: c Department of Pharmacy , the First Affiliated Hospital, Zhengzhou University , Zhengzhou , Henan , China.
authors: Ji
authors: J
authors: Zhang
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Ping
authors: P
authors: Xu
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Zeyu
authors: Z
authors: Zhong
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Yang
authors: Y
authors: Chen
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Li
authors: L
authors: Liu
authors: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , Jiangsu , China .
authors: Xiaodong
authors: X
authors: Liu
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D022781:Hepatocytes; D008099:Liver / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats
chemical_list: D000924:Anticholesteremic Agents; D027361:Organic Anion Transporters; C503597:Slco1a4 protein, rat; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A
keywords: Atorvastatin; Cyp3a; diabetes; organic anion transporting polypeptide 2 (Oatp2); pharmacokinetics; rat