Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes
Abstract
Dan XU1, 2, Feng LI1, Mian ZHANG1, Ji ZHANG1, Can LIU1, Meng-yue HU1, Ze-yu ZHONG1, Ling-ling JIA1, Da-wei WANG2, Jie WU2, Li LIU1, *, Xiao-dong LIU1, *
1Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; 2Jiangsu Provincial Institute of Traditional Chinese Medicine, Nanjing 210028, China
Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes.
Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR.
Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp.
Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.
Keywords: diabetes; hypercholesterolemia; simvastatin; pharmacokinetics; hepatocyte; microsome; Cyp3a; organic anion transporting polypeptide 2; multidrug resistance-associated protein 2; breast cancer resistance protein
This work was supported by National Natural Science Foundation of China (No 81373482 and 81102503), National Basic Research Program of China (973 Program) (2011CB505300 and 2011CB505303), and the Fundamental Research Funds for the Central Universities (ZD2014YX0026 and PT2014YX0057).
* To whom correspondence should be addressed.
E-mail xdliu@cpu.edu.cn (Xiao-dong LIU); liulee@cpu.edu.cn (Li LIU)
Received 2013-12-15 Accepted 2014-03-30
Keywords:
1Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; 2Jiangsu Provincial Institute of Traditional Chinese Medicine, Nanjing 210028, China
Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes.
Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR.
Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp.
Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.
Keywords: diabetes; hypercholesterolemia; simvastatin; pharmacokinetics; hepatocyte; microsome; Cyp3a; organic anion transporting polypeptide 2; multidrug resistance-associated protein 2; breast cancer resistance protein
This work was supported by National Natural Science Foundation of China (No 81373482 and 81102503), National Basic Research Program of China (973 Program) (2011CB505300 and 2011CB505303), and the Fundamental Research Funds for the Central Universities (ZD2014YX0026 and PT2014YX0057).
* To whom correspondence should be addressed.
E-mail xdliu@cpu.edu.cn (Xiao-dong LIU); liulee@cpu.edu.cn (Li LIU)
Received 2013-12-15 Accepted 2014-03-30