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

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.

Statin-Induced Chronic Cholesterol Depletion Switches GPCR Endocytosis and Trafficking: Insights from the Serotonin1A Receptor

“…Endocytosis as a mechanism of desensitization of the serotonin 1A receptor has been implicated in the therapeutic action of popular antidepressants (SSRIs) such as fluoxetine. , Interestingly, recent cohort studies suggest that the combination of SSRIs and statins could have superior antidepressant effects relative to SSRI treatment alone. , In another study, the simultaneous administration of fluoxetine and statin has been suggested to enhance the levels of serotonin in rat brain . In this backdrop, our results on a cholesterol-induced switch in the endocytic and intracellular trafficking pathway of the serotonin 1A receptor assume significance.…”

Clinically relevant drug interactions between statins and antidepressants

“…Whereas the potential interaction between fluoxetine and statins has not been investigated in humans, experimental evidence in animal models found that the combination of simvastatin with fluoxetine may result in a potentiation of the anxiolytic and antidepressant properties and produce convergent effects on different neurotransmitter systems or signalling targets in the brain . Based on these findings, Al‐Asmari and colleagues evaluated the PK and PD consequences of the combined administration of simvastatin and fluoxetine in experimental animals. Co‐administration of simvastatin with fluoxetine resulted in a significant increase in the bioavailability of simvastatin in the plasma (41.8%) and brain (68.7%) compared to administration of simvastatin alone ( P < .05).…”

Statins in Depression: An Evidence-Based Overview of Mechanisms and Clinical Studies

“…In this context, statins increase hippocampal serotonin levels ( 43 ), and induce serotonergic-dependent antidepressant-like effect that are counteracted by 5HT 1A and 5HT2 A/C receptor antagonists ( 63 ) and upregulate pre-frontal dopamine receptors expression ( 64 ) in animal models of depression. Moreover, statins seem to directly potentiate the serotonergic effects of some antidepressants in animals ( 65 – 67 ) and possibly in human trials ( 68 ). Non-monoaminergic pathways have also been explored in animal models of depression, showing that statins may elicit antidepressant action via opioid- ( 69 ) and endocannabinoid-mediated ( 70 ) neurotransmission.…”