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 (C_max) 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: bioavailability; drug interaction; fluoxetine; lipid levels; neurotransmitters; simvastatin.

Figure 1

Mean plasma levels of STT, STA, and FLX after single and combined administration of STT and FLX. Time course for (A) STT plasma levels, (B) STA plasma levels, and (C) FLX plasma levels after single administration of STT at a dose of 40 mg/kg b.w. and FLX at a dose of 20 mg/kg b.w. and combined administration of STT with FLX for a period of 4 weeks. Results are expressed as mean±SD; n=3 (three animals per time points). FLX administered simultaneously with STT was able to increase the plasma concentration of STT. Significant difference at the C_max level was observed with combined treatment. *p<0.05, compared to STT alone. Abbreviations: STT, simvastatin; STA, simvastatin acid; FLX, fluoxetine; b.w., body weight; SD, standard deviation; C_max, maximum plasma drug level.

Figure 2

Brain concentration–time profile of (A) STT, (B) STA, and (C) FLX obtained after oral administration of FLX and STT, alone and in combination, to Wistar rats for a period of 4 weeks. The data are represented as mean±SD; n=3. Combined administration of STT with FLX led to a significant increase in the level of STT in brain in comparison to STT monotherapy (p<0.05). However, STT did not alter the brain concentration of FLX up to a significant level. *p<0.05, compared to STT alone. Abbreviations: STT, simvastatin; STA, simvastatin acid; FLX, fluoxetine; SD, standard deviation.

Figure 3

Bar graph of cholesterol, triglyceride, and HDL plasma concentrations in Wistar rats after the treatment with FLX and STT alone and their combination for a period of 4 weeks. The data are presented as mean±SD; n=6. Significant differences were observed between the lipid control and the other experimental groups. There was a significant decrease in cholesterol levels in the animals treated with FLX alone. Significant improvement in lipid profile was observed when STT was administered along with FLX. FLX alone did not affect the level of triglyceride or HDL, but in combination with STT, exerted a synergistic effect in reducing cholesterol and triglyceride level. *p<0.05, compared to lipid control; ^#p<0.05, compared to STT alone. Abbreviations: HDL, high-density lipoprotein; FLX, fluoxetine; STT, simvastatin; SD, standard deviation.

Figure 4

Levels of neurotransmitters in Wistar rat brain after the combined and separate treatment with FLX and STT for 4 weeks. STT significantly increased 5HT level in the brain when administered alone and produced a synergistic effect in combination with FLX, whereas it did not alter the level of dopamine up to a significant level. Furthermore, FLX produced significant increases in the brain level of dopamine and 5HT after 4-week systemic administrations. In addition, both of these drugs failed to alter the concentration of HIAA up to a significant level. The data are presented as mean±SD; n=6. *p<0.05, compared to lipid control; ^#p<0.05, compared to FLX alone. Abbreviations: FLX, fluoxetine; STT, simvastatin; 5HT, 5-hydroxytryptamine; HIAA, hydroxy indole acetic acid; SD, standard deviation.