title: Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ze-Yu
authors.initials: ZY
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Jia
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Meng-Yue
authors.initials: MY
authors.lastname: Hu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liu
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis*; D002460:Cell Line; D003863:Depression / Q000150:complications / Q000188:drug therapy*; D048909:Diabetes Complications / Q000097:blood / Q000188:drug therapy*; D003920:Diabetes Mellitus / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications; D004347:Drug Interactions; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D008297:Male; D017374:Paroxetine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017035:Pravastatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D018687:Antidepressive Agents, Second-Generation; D001786:Blood Glucose; D007328:Insulin; D012701:Serotonin; D017374:Paroxetine; D017035:Pravastatin