Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

Abstract

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.

Clinically relevant drug interactions between statins and antidepressants

“…The synergistic effect on blood glucose was limited to paroxetine and pravastatin and was not a class action between SSRIs and statins. A subsequent experimental study in diabetic rats was performed to verify the deregulation of glucose homeostasis by comedication of paroxetine and pravastatin and to identify the possible mechanism via PK analysis . In line with findings of clinical reports, although paroxetine itself produced a trend towards impaired glycaemic control and insulin secretion in diabetic rats, comedication with paroxetine and pravastatin further deteriorated glucose homeostasis.…”

Contribution of Hepatic Retinaldehyde Dehydrogenase Induction to Impairment of Glucose Metabolism by High‐Fat‐Diet Feeding in C57BL/6J Mice

“…Isolation of rat primary hepatocytes and drug treatment. Primary rat hepatocytes were isolated according to a technique described previously [26]. Cell viability was identified to be more than 80% as measured by trypan blue dye exclusion.…”

Apa yang Terjadi Ketika Mengkombinasikan Beberapa Obat ?

“…Ini juga menurunkan nilai rata-rata perkiraan laju filtrasi glomerulus (eGFR) dari 43 menjadi 37 mL / menit / 1,73 m3 dan kadar CO2 dalam darah dari 24,8 menjadi 23,9 mEq / L. Temuan ini menunjukkan bahwa ko-medikasi pravastatin dan paroxetine mungkin memiliki dampak signifikan pada anti-koagulasi darah, fungsi ginjal, dan homeostasis glukosa. Paroxetine menghambat sekresi insulin melalui penurunan 5-HT intraseluler dan biosintesis insulin dihasilkan dari supresi mRNA Tph-1 dan Insulin-2 (Li et al, 2014).…”