Effects of Zhenyuan capsule on the pharmacokinetics comparison of simvastatin and its active metabolites in rats        
Ye Yuan, Bo Yu, Xueqin Zhang, Yanan Li, Shumei Wang*       
The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China   
 
 
Abstract: The total ginsenosides of ginseng fruit are the main constituents of Zhenyuan capsule, which is mainly used for the treatment of cardiovascular diseases. It has been reported that ginsenoside can affect the activity of CYP450 enzymes. Zhenyuan capsule and simvastatin may interact with each other through CYP3A4 mediation, then affect the efficacy and even produce adverse reactions. However, no studies have investigated the effects of Zhenyuan capsule on the pharmacokinetics of simvastatin and its active metabolites. In this study, liquid chromatography–electrospray ionization–mass spectrometry (LC-MS/MS) was used to detect the pharmacokinetics of simvastatin and its active metabolites-simvastatin acid with or without Zhenyuan capsule in rats. Compared with the simvastatin alone, the pharmacokinetic parameters of simvastatin and simvastatin acid were significantly different in AUC024 and AUC0, and they were decreased in varying degrees (P<0.05). It appeared that the Zhenyuan capsule might increase the activity of CYP3A4 to some extent.                        
Keywords: Zhenyuan capsule; Simvastatin; Simvastatin acid; LC-MS/MS; Pharmacokinetics 
CLC number: R942                Document code: A                 Article ID: 10031057(2020)749410
 
 
1. Introduction
Simvastatin, a reversible competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, is characterized by reduced hepatic lipoprotein production,and it can increase the number of low density lipoprotein (LDL) receptors on cell membrane[1,2]. Accordingly, it is widely used in clinical practice as an lipid lowering agent for the treatment of hyperlipidemia and cardiovasculardiseases[3,4]. Simvastatin is mainly metabolized by CYP3A4 enzyme[5,6], and studies have shown that ginsenoside has certain effects on CYP1A2 and CYP3A4 enzyme activities[7,8]. For this reason, they may be able to interactwith each other through CYP3A4 mediation, affect the blood concentration of simvastatin and its active metabolite simvastatin acid, and then impair the efficacy or even produce adverse reactions.
With more and more in-depth research on ginseng, its preparation has been popularized and applied accordingly. Ginseng contains many types of components,and the ginsenoside are the main components of ginseng extracts. In recent studies, it has been found that ginsenoside has the effects of anti-tumor, cardiac strengthening, hypoglycemic and inhibiting apoptosis of diabetic cardiomyocytes[9–11], as well as the functions of enhancing immunity, anti-aging and bacteriostasis[12,13]. Based on the pharmacological activities of ginsenoside, clinical preparations, such as capsule, tablet and oral liquid, have been developed, and its interaction with Western medicine and other safety issues have gradually attracted our attention.
Zhenyuan capsule is composed of total ginsenosides of ginseng fruit, which is mainly used to treat cardiovasculardiseases. The biologically active compounds in ginsenoside include ginsenoside Rb1, Rb2/RB3, RC, RD, Re, RF, Rg1, Rh1 and other ingredients[14]. Complex ingredients have a wide range of pharmacological effects (Fig. 1). It has been reported that ginsenoside can affect the CYP450 enzyme activity[14,15]. The combination of Zhenyuan capsule and simvastatin may produce drug-druginteraction due to the simultaneous mediation of CYP3A4enzyme, resulting in toxic side effects and adverse drug-drug interaction. In this study, a liquid chromatography-electrospray ionization-mass spectrometry (LC-MS/MS) method was developed and validated to determine the concentration of simvastatin and its active metabolite simvastatin acid, and the pharmacokinetics comparison between them was conducted. It would be important to sufficiently recognize the potential combined effects of the co-administration of Zhenyuan capsule and simvastatin. 
 
 
Figure 1. Chemical structures of simvastatin (a), simvastatin acid (b), lovastatin (c, internal standard) and ticagrelor (d, internal standard).  
2. Experimental
2.1. Medicines and chemicals
Chemical reference substances of simvastatin (99.4% purity), simvastatin acid (98.65% purity) and lovastatin (99.4% purity) were all obtained from Chinese Food and Drug Inspection Institute. Ticagrelor (99.6% purity) was obtained from AK Scientific Inc. Acetonitride (LC/MS grade) was supplied by Fisher Scientific. Formic acid (HPLC grade) was provided by J&K Chemicals. Ammonium acetate was obtained from Aladdin. Watsonsdistilled water was used throughout the study, and methyltert-butyl ether and other reagents were of analytical grade. Simvastatin tablets (40 mg per tablet) were produced by Merck Sharp & Dohme (Australia) Pty. Ltd.
2.2. Equipment and analysis conditions
The LC-MS/MS system was performed on a liquid chromatography system CBM-20A (SHIMADZU, Japan) equipped with a binary gradient pump, a refrigerated autosampler, and a temperature-controlled column compartment, and accompanied with a triple quadrupole tandem mass spectrometer API 4000+ (Applied Biosystems, Foster City, CA, USA) equipped with an electrospray ionization (ESI) source in the positive ion mode.
Chromatographic separation was carried out on a Diamonsil C18 column (150 mm×4.6 mm, 5 μm, Dikma Science, China), which was kept a temperature at 35ie Separation was used with isocratic elution of acetonitrileammonium acetate solution (0.1% formic acid adjusted to pH = 4.5) (75:25, v/v) at a liquid flow rate of 0.8 mL/min. To ensure the mobile phase was clean and pollution was reduced, it was prepared freshly, passed through a Millipore 0.45-μm filter and then degassed prior to use. The sample injection volume was 10 µL, and the autosampler temperature was at 4 ºC. Moreover, the analytical run time was 9 min, including 0–5.8 min in negative ion mode and 5.9–9 min in positive ion mode.
The mass spectrometer was operated in the positive and negative ion switching electrospray ionization (ESI)mode. The operational MS/MS parameters were used for all analytes as follows: the ion spray voltage 5500 V; source temperature 550 ºC gas one 55 psi; gas two 50 psi. Quantification was performed to use multiple reactions monitoring (MRM) method with the ion transitions of m/z 419.3199.1 with declustering potential (DP) 88 V and collision energy (CE) –77 eV for simvastatin, m/z 435.2319.3 with DP 80 V and CE –130 eV for simvastatin acid, m/z 405.3199.0 with DP 17 V and CE –29 eV for lovastatin, and m/z 521.1361.2 with DP17 V and CE 32 eV for ticagrelor. The secondary massspectra of the two analytes and IS are shown in Figure 2. 
 
 
 
Figure 2. Secondary mass spectra of simvastatin (a), simvastatin acid (b), lovastatin (c, internal standard) and ticagrelor (d, internal standard). 
 
2.3. Preparation of standard solutions and quality control samples
The standard stock solutions of simvastatin and simvastatin acid were prepared separately by dissolving in acetonitrile at the concentration of 200 µg/mL. The solutions were then serially diluted with acetonitrile to obtain the series of simvastatin and simvastatin acid working standard solutions at the concentrations of 100, 50, 20, 10, 5, 2, 1 ng/mL and 1000, 500, 200, 100, 50, 20, 10 ng/mL, respectively. The IS working solutions of lovastatin and ticagrelor were prepared at the final concentrations of 100 and 50 µg/mL by diluting its stock solution with acetonitrile. All solutions were stored at 4 ºC. The quality control (QC) samples of simvastatin and simvastatin acid were prepared at the concentrations of 8, 1, 0.2 ng/mL and 80, 10, 2 ng/mL, respectively. 
2.4. Preparation of intragastrical solutions
Sodium carboxymethyl cellulose (CMC) solution: Sodium CMC was weighed at 300 mg and dissolved in about 100 mL distilled water. The solution was prepared by stirring and accelerating the dissolution with glass rod.
2.5. Preparation of plasma sample
Briefly, 200 μL of plasma samples, 20 μL of IS working solutions and 300 μL of ammonium acetate (100 mM) were combined and vortex-mixed for 1 min. Then the mixture was extracted with 2 mL of methyl tert-butyl ether by vortex-shaking for 3 min and centrifuged at 10 900 r/min for 5 min at 4 ºC. The supernatant was evaporated to dryness under a stream of nitrogen in water bath at 40 ºC was dissolved in 100 μL acetonitrilewith vortex-mixing for 1 min and transferred to the autosamplervials, 20 μL solution was injected into the LC-MS/MS system for analysis.
3. Method validation
3.1. Linearity of calibration curves and LLOQ
The lower limit of quantization (LLOQ) was based on a signal-to-noise ratio (S/N) of 10 that was produced by the concentrations of plasma samples, and the lower limit of detection (LLOD) was based on a signal-to-noise ratio (S/N) of 3 that was also produced by the concentrations of plasma samples.
3.1.1. Accuracy and precision
The intra-day accuracies and precisions were evaluated by analyzing three different concentrations (low, medium and high) of QC samples in one day, and each concentrationwere tested with five replicates. The inter-day accuracies and precisions were also evaluated by analyzing the same QC biological samples on five consecutive days, and each concentration was tested with three replicates per day. Mean, standard deviation (SD) and relative standard deviation (RSD) were calculated and used to estimate the intra-day and inter-day precision. Accuracy was the ratio of the concentrations that were calculated from the regression equations and the known concentrations. It is considered to be stable if the precision of the assay values satisfied that the RSD was within±15% and the accuracy was within 85.0%–115.0%.
3.1.2. Recovery and matrix effect
The absolute recoveries of simvastatin and simvastatinacid were evaluated at three concentrations of QC samples by comparing the peak areas of the pretreated QC samples with those of standard solutions at equivalent concentrations.The absolute recovery of IS was evaluated in the same way. The matrix effect was also evaluated by comparing the peak areas of the analyte spiked with extracted blank plasma with those of the same concentration that were dissolved in mobile phase. The matrix effect of IS was evaluated in the same way. All the above effects were tested in five replicates.
3.1.3. Stability
Stability experiments were evaluated by utilizing the QC samples at three concentrations using five replicatesunder the different conditions as follows: the short-term stability (room temperature for 4 h); the freeze/thaw stability (three complete freeze/thaw cycles); and the long-term stability (–80 ºC for 10 d).
3.2. Animal experiment
Adult, male and clean grade Wistar rats weighting 180–200 g were obtained from the Experimental Animal Center of Hebei Medical University, China. All the animals were fed with standard cages and had free access to food and water. They were acclimatized for at least 1 week prior to experimentation. A total of 24 Wistarrats were randomly and evenly divided into two groups,namely control group (3‰ sodium carboxymethylcellulosefor 15 consecutive days) and experimental group (ginsenoside consecutively for 15 consecutive days). After 15 days’ administration, the rats were fasted for 12h, a dose of 5.3 mg/kgsimvastatin was given to all rats on the next morning, and the blood samples were collected from the eye canthus in rats at time points 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12 and 24 h. Blood samples were centrifuged at 10900 r/min for 5 min, and then the supernatant was frozen at –70 ºC prior to further analysis.
3.3. Statistics
The pharmacokinetic parameters were calculated by non-compartmental model using the DAS 2.0 software, and all data were expressed as the mean±SD. Variables between groups were analyzed via SPSS Version 21.0 by an impaired Student’s t-test. P<0.05 was considered as statistically significant. 
4. Results and discussion
4.1. Method validation
4.1.1. Specificity
Figure 3 shows the typical chromatograms. The results indicated that there was no significant interference from endogenous substances at the retention time of simvastatin (7.7 min), simvastatin acid (4.9 min), lovastatin (6.2 min) and ticagrelor (3.3 min). 
 
 
Figure 3. Chromatogram of simvastatin and simvastatin acid in rat plasma: (A) blank plasma; (B) simvastatin; (C) simvastatin acid; (D) lovastatin;(E) ticagrelor; (F) test substance reference substance and internal standard control substance; (G) blank plasma and internal standards; (H) experimental group plasma and internal standards. 1. Simvastatin; 2. simvastatin acid; 3. lovastatin; 4. ticagrelor. 
 
4.1.2. Linearity of calibration curve and LLOQ
The calibration curves of simvastatin and simvastatin acid in plasma samples of rats were liner over the range
 
of 1–100 ng/mL and 10–1000 ng/mL, respectively. The regression equations with weighing factor 1/x2 of simvastatin and simvastatin acid in rats plasma were Y = 0.246X + 0.024 (r = 0.9992) and Y = 0.0565X + 0.00897 (r= 0.9996), respectively. The LLOQ of the two analytes was 1 ng/mLand 10 ng/mL, respectively.
4.1.3. Precision and accuracy
The intra- and inter-day precision of simvastatin and simvastatin acid in plasma ranged from 3.4% to 12.18% and from 2.35% to 14.89%, respectively, while the accuracy ranged from 80% to 99.38% and from 93.51%to 98.77%, respectively. Table 1 summarizes the results of precision and accuracy. 
 
Table 1. Intra-day and inter-day precision and accuracy of simvastatin and simvastatin acid in QC plasma.
  
 
4.1.4. Recovery and matrix effect
The mean absolute recoveries of simvastatin and simvastatin acid were measured from 88.41% to 88.81% and from 72.44% to 85.90%, respectively. The mean matrix effects of simvastatin and simvastatin acid were found to be 97.48% to 102.99% and from 86.85% to 87.64%, respectively. These results indicated that the matrix effects could be ignored under the currentconditions. Table 2 summarizes the mean recoveries and matrix effects of the two analytes. 
 
Table 2. The absolute recoveries and matrix effects of simvastatin and simvastatin acid in QC plasma (n = 5).
  
 
4.1.5. Stability
The stability of simvastatin and simvastatin acid in plasma samples was found to be stable the under conditions of short-term (4 h) at room temperature, three freeze/thaw cycles and the long-term storage at–80 ºC. Table 3 shows the RSD values of stability under the three storage conditions.
 
 
Table 3. Stability of simvastatin and simvastatin acid in QC plasma under various storage conditions (n = 5).
   
 
4.1.6. Pharmacokinetic study
The HPLC-MS/MS method was proved to be reliableand could be successfully applied to the pharmacokineticexperiment. In this study, the average AUC0–24 and Cmaxof simvastatin and simvastatin acid in the control groupwere 17.88 ng·h/mL, 6.76 ng·h/mL and 126.08 ng·h/mL, 56.48 ng·h/mL, respectively. The average AUC0–24 and Cmax of simvastatin and simvastatin acid in the experimental group were 12.96 ng·h/mL, 2.74 ng·h/mL and 102.89 ng·h/mL, 33.62 ng·h/mL, respectively. Compared with the control group, AUC0–24 and Cmax in the experimental group were decreased in varying degrees.The pharmacokinetic parameters (AUC0–24 and Cmax) of simvastatin and simvastatin acid were significantly different (P<0.05). Figure 4 illustrates the mean concentration-time profiles of simvastatin and simvastatinacid in plasma after oral administration. Table 4 summarizesthe data of main pharmacokinetic parameters, which were expressed as the mean±SD.
 
 
 
Figure 4. Average plasma concentration-time curves of simvastatin and simvastatin acid of experiment and control groups in rats.  
 
Table 4. Main pharmacokinetic parameters of simvastatin and simvastatin acid in test and control groups (n = 12).  
  
T1/2: half-life; Tmax: the time of peak concentration; Cmax: the peak or maximum concentration; AUC0: area under a curve extrapolated to infinity; Vz/F: volume of distribution based on the terminal phase. F is the fraction of dose absorbed; CLz/F: CL is the total body clearance, CL = Dose/AUC, F is the fraction of dose absorbed. Compared with the control group, *P<0.05. 
   
5. Discussion
The main component of Zhenyuan capsule is the ginsenosides of ginseng fruit extracted by modern technology. Since ginsenosides possess a wide range of notable medicinal effects, such as anti-cancer, anti-oxidative, antiaging, anti-inflammatory, anti-apoptotic and neuroprotective activities, they are mainly used to treat cardiovascular diseases[9–11]. As a Chinese traditional medicine, Zhenyuan capsule is more and more widely used in clinical practice, and more and more attention has been paid to its interaction with Western medicine. As ginsenoside and simvastatin may interact with each other, and such interaction may affect the blood concentration of simvastatin and simvastatin acid and then impair the efficacy and even produce adverse reactions. It is important to evaluate the potential pharmacokinetic interaction between ginsenoside and simvastatin in animals before the clinical studies. Moreover, the combination of two drugs is widely used in the treatment of cardiovascular diseases. Therefore, it is important and urgent to characterize the profile of the drug inter-actions between the two medications.
In the present study, the pharmacokinetics of simvastatin and its active metabolites-simvastatin acid with or without Zhenyuan capsule in rats were detected by using LC-MS/MS. Compared with simvastatin alone, the pharmacokinetic parameters (AUC0–24and AUC0–) of simvastatin and simvastatin acid were significantly decreased to varying degrees (P<0.05). It has been reported that ginsenoside can affect CYP450 enzyme activity[14,15]. Until now, some studies have investigated the influence of CYP450 enzyme activity, including Henderson’s and Gurley’s studies showing that high concentration of crude extract and total saponins of ginseng (>2000 g/mL) can increase the activity of CYP2C9 and CYP3A4 in vitro[16]. This is consistent with our results.
However, in related studies, ginsenosides may be a mild to moderate CYP3A4 inducer, and their deglycosylatedmetabolites can strongly induce the expression of CYP3A4 at the mRNA level[17]. Ginsenoside Re up-regulates CYP2C11 and CYP2J3 enzyme activities, while ginsenoside RH 2 and ginsenoside compound K, down-regulates CYP3A4 enzyme activities[18]. It is inconsistent with our result. It may be related to intestinal bacteria. It has been reported that deglycosylation reactions in ginseng saponins by intestinal bacteria via the stepwise cleavage of the sugar moieties construct the main metabolic pathways of ginsenosides in vivo[19]. This process may affect the activity of CYP3A4.
In addition, our results showed that the pharmacokinetic parameter CL in the test group was higher compared with the control group. On the one hand, the liver and bile are responsible for systemic clearance of ginseng saponins from the circulation[19,20]. On the other hand, it may be due to interplay between CYP3A4 and the efflux transporter P-glycoprotein, as they have been shown to exhibit coordinated regulation[21].
There are also some limitations and deficiencies in this study, such as the species differences in absorption and metabolism between rats and humans, and the sample size is small. The results of this experiment only provided a theoretical reference for clinical use. Whether Zhenyuan capsule affects the pharmacokinetic parameters of simvastatin in human body needs to be further clarified.
6. Conclusions
 In the present study, an LC-MS/MS method was developed and validated to determine the concentration of simvastatin and its active metabolite simvastatin acid in plasma of rats. Our study suggested that compared with simvastatin alone, the pharmacokinetic parameters of simvastatin and simvastatin acid were significantly different in AUC0–24 and AUC0–∞ (P<0.05). The pharmacokinetics of the test and control group showedthat ginsenoside had a certain effect on simvastatin and its active metabolites-simvastatin acid in rats. It may be important to sufficiently recognize the potential combined effect of the co-administration of Zhenyuan capsule and simvastatin, and more clinical studies are required to confirm our conclusions in future. 
Acknowledgements
This study was supported by the Research Fund Project of health and Family Planning Commission of Hebei Province (Grant No. 20170571).
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振源胶囊对辛伐他汀及其活性代谢物在大鼠体内的药动学影响
袁叶, 于博, 张学琴, 李亚男, 王淑梅*
河北医科大学第二医院河北 石家庄 050000      
摘要: 研究振源胶囊对辛伐他汀及其活性代谢产物辛伐他汀酸在大鼠体内的药动学影响, 为临床两药联合应用提供一定理论依据。将24只雄性Wistar大鼠随机分成对照组与实验组, 每组12, 对照组连续灌胃3‰羧甲基纤维素钠15, 实验组连续灌胃振源胶囊混悬液15天。两组大鼠于16日清晨均灌胃给予等量辛伐他汀5.3 mg/kg。给药后不同时间点进眼内眦静脉丛采血, 离心即得血浆样品。采用HPLC-MS/MS法测定辛伐他汀及辛伐他汀酸的血药浓度。应用DAS 2.1.1件拟合药动学参数, SPSS 25.0软件分析统计学差异。结果发现,联用振源胶囊后, 辛伐他汀酸及辛伐他汀的药动学参数AUC0–24Cmax均显著性减少(P<0.05)。振源胶囊可能对CYP3A4酶有一定促进作用, 可减少辛伐他汀及其代谢产物在大鼠体内的含量。 
关键词: 振源胶囊; 辛伐他汀; 辛伐他汀酸; LC-MS/MS; 药动学
 
      
Received: 2020-03-11; Revised: 2020-04-15; Accepted: 2020-05-10.
Foundation item: Research Fund Project of health and Family Planning Commission of Hebei Province (Grant No. 20170571).
*Corresponding author. Tel.: +86-311-66003762, E-mail: Shumei-wang@163.com          
 
       
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