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Xenobiotica
the fate of foreign compounds in biological systems
Volume 45, 2015 - Issue 9
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Animal Pharmacokinetics and Metabolism

Co-administration of paroxetine increased the systemic exposure of pravastatin in diabetic rats due to the decrease in liver distribution

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Pages 794-802 | Received 09 Dec 2014, Accepted 25 Jan 2015, Published online: 27 Apr 2015
 

Abstract

1. Liver distribution and systemic exposure of pravastatin were the determinant factors of efficacy and toxicity of pravastatin. Aim of the present study was to investigate the effect of paroxetine on the liver distribution and systemic exposure of pravastatin in diabetic rats induced by combining high fat diet (HFD) and low-dose streptozotocin (STZ).

2. Plasma concentrations and liver distribution of pravastatin were measured in the presence of paroxetine. Effect of paroxetine on pravastatin excretion via bile, intestine, feces and urine, as well as pravastatin absorption via intestine was documented. Freshly isolated hepatocytes and Caco-2 cells were used to investigate the effect of paroxetine on pravastatin transport.

3. Paroxetine increased the systemic exposure of pravastatin and decreased hepatic distribution of pravastatin in diabetic rats. In vitro, paroxetine inhibited the hepatic uptake of pravastatin and promoted the efflux of pravastatin in freshly isolated hepatocytes, which may partly explain the decreased hepatic distribution of pravastatin by paroxetine. It was also observed that paroxetine promoted the absorption of pravastatin via jejunum and the uptake of pravastatin in Caco-2 cells.

4. We concluded that paroxetine increased the systemic exposure of pravastatin partly via promoting absorption via jejunum and inhibiting hepatic uptake of pravastatin.

Declaration of interest

This work was supported by funding for National Science Foundation of China (No. 81373482, No. 81473273 and No. 81102503), the Fundamental Research Funds for the Central Universities (ZD2014YX0026, PT2014YX0057) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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