Al-Asmari Abdulrahman K, Ullah Zabih, Al Masoudi Aqeel Salman, Ahmad Ishtiaque
Department of Research, Prince Sultan Military Medical City, Riyadh.
Department of Research and Education, King Abdulaziz Airbase Armed Forces Hospital, Dhahran, Saudi Arabia.
J Exp Pharmacol. 2017 Apr 11;9:47-57. doi: 10.2147/JEP.S128696. eCollection 2017.
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 (<0.05). The maximum drug concentration () of STT was also found to be increased significantly in the plasma and brain compared to that achieved after monotherapy (<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 (<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.
辛伐他汀（STT）是一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，被广泛用于治疗血脂异常，而氟西汀（FLX）是治疗抑郁症和焦虑症的首选药物。最近的一份报告表明，选择性5-羟色胺再摄取抑制剂可与细胞色素P450 3A4底物相互作用，另一份报告则表明STT可增强FLX的抗抑郁活性。然而，数据尚无定论。本研究旨在探讨在实验动物中联合使用STT和FLX的药代动力学和药效学后果。为此，将体重250±10 g的Wistar大鼠分为四组，分别为对照组、STT组（40 mg/kg/天）、FLX组（20 mg/kg/天）和STT+FLX组。给药4周后，处死动物，采集血液和脑样本，用于分析STT、辛伐他汀酸（STA）、FLX、总胆固醇、甘油三酯、高密度脂蛋白（HDL）、5-羟色胺、多巴胺和羟基吲哚乙酸。结果发现，与单独给予STT相比，联合给药导致血浆（41.8%）和脑（68.7%）中STT的生物利用度显著增加（<0.05）。与单药治疗后相比，血浆和脑中STT的最大药物浓度（）也显著增加（<0.05）。然而，STT未能在显著水平上改善FLX的药代动力学。本研究结果表明，与STT单药治疗相比，联合用药方案显著降低了胆固醇和甘油三酯水平，提高了HDL水平。此外，STT与FLX联合给药导致脑中神经递质水平升高（<0.05）。FLX增加了血浆和脑中STT的浓度。这些药物的联合给药还导致脂质谱改善。然而，从长远来看，这种相互作用可能具有重要的临床意义，因为STT水平的升高可能导致与他汀类药物相关的危及生命的副作用。
