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Simultaneous administration of fluoxetine and simvastatin ameliorates lipid profile, improves brain level of neurotransmitters, and increases bioavailability of simvastatin

Authors Al-Asmari AK, Ullah Z, Al Masoudi AS, Ahmad I

Received 25 November 2016

Accepted for publication 28 February 2017

Published 11 April 2017 Volume 2017:9 Pages 47—57


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 2

Editor who approved publication: Professor Bal Lokeshwar

Abdulrahman K Al-Asmari,1 Zabih Ullah,1 Aqeel Salman Al Masoudi,2 Ishtiaque Ahmad1

1Department of Research, Prince Sultan Military Medical City, Riyadh, 2Department of Research and Education, King Abdulaziz Airbase Armed Forces Hospital, Dhahran, Saudi Arabia

Abstract: Simvastatin (STT), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is widely prescribed for dyslipidemia, whereas fluoxetine (FLX) is the first-choice drug for the treatment of depression and anxiety. A recent report suggests that selective serotonin reuptake inhibitors can interact with the cytochrome P450 3A4 substrate, and another one suggests that STT enhances the antidepressant activity of FLX. However, the data are inconclusive. The present study was designed to explore the pharmacokinetic and pharmacodynamic consequences of coadministration of STT and FLX in experimental animals. For this, Wistar rats weighing 250±10 g were divided into four groups, including control, STT (40 mg/kg/day), FLX (20 mg/kg/day), and STT+FLX group, respectively. After the dosing period of 4 weeks, the animals were sacrificed, and the blood and brain samples were collected for the analysis of STT, simvastatin acid (STA), FLX, total cholesterol, triglyceride, high-density lipoprotein (HDL), 5-hydroxytryptamine, dopamine, and hydroxy indole acetic acid. It was found that the coadministration resulted in a significant increase in the bioavailability of STT in the plasma (41.8%) and brain (68.7%) compared to administration of STT alone (p<0.05). The maximum drug concentration (Cmax) of STT was also found to be increased significantly in the plasma and brain compared to that achieved after monotherapy (p<0.05). However, STT failed to improve the pharmacokinetics of FLX up to a significant level. The results of this study showed that the combined regimen significantly reduced the level of cholesterol and triglyceride and increased the level of HDL when compared to STT monotherapy. Furthermore, the coadministration of STT with FLX led to an elevated level of neurotransmitters in the brain (p<0.05). FLX increased the concentration of STT in the plasma and brain. The coadministration of these drugs also led to an improved lipid profile. However, in the long-term, this interaction may have a vital clinical importance because the increase in STT level may lead to life-threatening side effects associated with statins.

Keywords: fluoxetine, simvastatin, lipid levels, neurotransmitters, bioavailability, drug interaction

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