Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure
Abstract
Feng LI, Mian ZHANG, Dan XU, Can LIU, Ze-yu ZHONG, Ling-ling JIA, Meng-yue HU, Yang YANG, Li LIU*, Xiao-dong LIU*
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
Aim: Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms.
Methods: Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine (10 mg/kg) and pravastatin (10 mg/d) or both the drugs daily for 28 d. The pharmacokinetics of paroxetine and pravastatin were examined on d 1 and d 28. Biochemical parameters including serum insulin, glucose and lipids were monitored during the treatments. An insulin-secreting cell line (INS-1) was used for measuring insulin secretion.
Results: In diabetic rats, co-administration of paroxetine and pravastatin markedly increased the concentrations of both the drugs compared with administration of each drug alone. Furthermore, co-administration severely impaired glucose homeostasis in diabetic rats, as demonstrated by significantly increased serum glucose level, decreased serum and pancreatic insulin levels, and decreased pancreatic Insulin-2 mRNA and tryptophan hydroxylase-1 (Tph-1) mRNA levels. Treatment of INS-1 cells with paroxetine (5 and 10 μmol/L) significantly inhibited insulin secretion, decreased the intracellular insulin, 5-HT, Insulin-2 mRNA and Tph-1 mRNA levels. Treatment of the cells with pravastatin (10 μmol/L) significantly stimulated insulin secretion, which was weakened by co-treatment with paroxetine.
Conclusion: Paroxetine inhibits insulin secretion at least via decreasing intracellular 5-HT and insulin biosynthesis. The deregulation of glucose homeostasis by co-administration of paroxetine and pravastatin in diabetic rats can be attributed to enhanced paroxetine exposure.
Keywords: diabetes mellitus; paroxetine, pravastatin; drug-drug interaction; pharmacokinetics; insulin; 5-HT; tryptophan hydroxylase
This work was supported by funding from the Graduate Student Research and Innovation Program of Jiangsu Province (No CXZZ12 0325, 2012) and funding for National Natural Science Foundation of China (No 81373482), National Youth Science Foundation of China (No 81102503), and the Fundamental Research Funds for the Central Universities (ZD2014YX0026).
* To whom correspondence should be addressed.
E-mail liulee@yeah.net (Li LIU); xdliu@cpu.edu.cn (Xiao-dong LIU)
Received 2014-02-06 Accepted 2014-03-21
Keywords:
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
Aim: Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms.
Methods: Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine (10 mg/kg) and pravastatin (10 mg/d) or both the drugs daily for 28 d. The pharmacokinetics of paroxetine and pravastatin were examined on d 1 and d 28. Biochemical parameters including serum insulin, glucose and lipids were monitored during the treatments. An insulin-secreting cell line (INS-1) was used for measuring insulin secretion.
Results: In diabetic rats, co-administration of paroxetine and pravastatin markedly increased the concentrations of both the drugs compared with administration of each drug alone. Furthermore, co-administration severely impaired glucose homeostasis in diabetic rats, as demonstrated by significantly increased serum glucose level, decreased serum and pancreatic insulin levels, and decreased pancreatic Insulin-2 mRNA and tryptophan hydroxylase-1 (Tph-1) mRNA levels. Treatment of INS-1 cells with paroxetine (5 and 10 μmol/L) significantly inhibited insulin secretion, decreased the intracellular insulin, 5-HT, Insulin-2 mRNA and Tph-1 mRNA levels. Treatment of the cells with pravastatin (10 μmol/L) significantly stimulated insulin secretion, which was weakened by co-treatment with paroxetine.
Conclusion: Paroxetine inhibits insulin secretion at least via decreasing intracellular 5-HT and insulin biosynthesis. The deregulation of glucose homeostasis by co-administration of paroxetine and pravastatin in diabetic rats can be attributed to enhanced paroxetine exposure.
Keywords: diabetes mellitus; paroxetine, pravastatin; drug-drug interaction; pharmacokinetics; insulin; 5-HT; tryptophan hydroxylase
This work was supported by funding from the Graduate Student Research and Innovation Program of Jiangsu Province (No CXZZ12 0325, 2012) and funding for National Natural Science Foundation of China (No 81373482), National Youth Science Foundation of China (No 81102503), and the Fundamental Research Funds for the Central Universities (ZD2014YX0026).
* To whom correspondence should be addressed.
E-mail liulee@yeah.net (Li LIU); xdliu@cpu.edu.cn (Xiao-dong LIU)
Received 2014-02-06 Accepted 2014-03-21