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 Table of Contents  
Year : 2018  |  Volume : 5  |  Issue : 1  |  Page : 26-32

Effect of food and antacid on simvastatin bioavailability on healthy adult volunteers

1 Department of Clinical Pharmacy, School of Pharmacy, University Sains Malaysia, Penang, Malaysia; Department of Clinical Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia; Department of Pharmacy, Medical School in Thamar University, Dhamar, Republic of Yemen
2 Department of Clinical Pharmacy, King Khalid University, Abha, Kingdom of Saudi Arabia

Date of Submission23-Mar-2017
Date of Acceptance22-Dec-2017
Date of Web Publication30-Apr-2018

Correspondence Address:
Dr. Easwaran Vigneshwaran
Department of Clinical Pharmacy, King Khalid University, Abha
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jhrr.jhrr_36_17

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Aims: The current research work was framed to identify and estimate the changes in pharmacokinetic data for oral simvastatin 40 mg in healthy adult volunteers during fasting condition and with simultaneous administration of food and antacids at a frequent interval. Materials and Methods: Nine healthy Malaysian male adult volunteers recruited into the present study. If study participants had a history of any major disease, they were excluded from the study. This study comprised of three groups with a crossover design in three blocks. Prior and after intake of drug, the blood samples (10 ml) were withdrawn and transferred to labeled glass tubes at a frequent interval. The blood sample was processed and the obtained serum was quantified by liquid chromatography–mass spectrometry/mass spectrometry method. Results: The pharmacokinetic data such as AUC0–24, Tmax, and Cmaxvalues were increased when the drug is administered along with drug or antacid. The elimination rate constant and volume of distribution do not found to have difference among the three groups. The t1/2of simvastatin was decreased when the drug is taken along with food but not with antacid or on empty stomach. The clearance of the drug is limited when the drug is administered along with antacid. Both antacid and food had the similar effect on simvastatin on various pharmacokinetic parameters such as AUC0–24, Cmax, Ke, Tmax, Cl, and Vd. Conclusion: The prolonged gastric residence time of simvastatin was produced by food and antacid by delaying gastric emptying which is offset by increased pH of the gastrointestinal tract. Thus, it leads to increased stability of lactone form of simvastatin and its absorption.

Keywords: Bioavailability, lactone stability, simvastatin

How to cite this article:
Alakhali KM, Vigneshwaran E, Shaik MA. Effect of food and antacid on simvastatin bioavailability on healthy adult volunteers. J Health Res Rev 2018;5:26-32

How to cite this URL:
Alakhali KM, Vigneshwaran E, Shaik MA. Effect of food and antacid on simvastatin bioavailability on healthy adult volunteers. J Health Res Rev [serial online] 2018 [cited 2020 Aug 14];5:26-32. Available from: http://www.jhrr.org/text.asp?2018/5/1/26/231532

  Introduction Top

Simvastatin is considered as lipid-lowering agent and reduces the blood cholesterol level by inhibiting the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme. It reduces atherosclerotic plaques through by which reduces morbidity and mortality of cardiovascular events.[1],[2] The active form of the drug (hydroxyl acid) is produced when lactone moiety of simvastatin gets hydrolyzed in vitro.[3],[4] There are drugs, in which their pharmacokinetic parameters are altered when they are taken simultaneously with food.[5],[6] The same concept is applicable even for the drugs which are taken along with antacids.[7],[8],[9] The interaction between drug and another substance (drugs, foods, and dietary supplement) that modify the action of drug is known as drug interaction. Drug–food interaction is common and it is very well known that adverse drug reactions may occur when statins are consumed simultaneously with food. It is reported that foods could interfere with statins' bioavailability and other pharmacokinetic parameters.[10] The bioavailability is getting enhanced when the statins are administered along with liquid antacids. Even though a lot of literature reported about the deviation of pharmacokinetic parameters, when the drug is administered with food or antacids, the relative evidence is very scarce with regard to statins and in particularly to simvastatin. Thus, the current research work was framed to identify and estimate the changes in pharmacokinetic data of oral simvastatin (40 mg) in healthy adult volunteers during fasting condition and with simultaneous administration of food and antacids at a frequent interval.

  Materials and Methods Top

Study design and study subjects

The current study procedure followed guidelines of the Helsinki Declaration of 1975 and its amendments. Further, the study protocol was approved by the Ethics Committee of the Joint Pinang Hospital/School of Pharmaceutical Sciences, Universiti Sains Malaysia Committee on Bioavailability Studies. All the study participants were informed about study procedure, and the informed written consent was obtained from all of them. Further, they also informed that they could withdraw from the study at any point of the study period. The study protocol was approved by the ethics committee of the Joint Pinang hospital/School of pharmaceutical sciences, Universiti Sains Malaysia committee on bioavailability studies (JPH/23032017).

It is a prospective analysis conducted for the period of 3 months. Nine healthy Malaysian male adult volunteers recruited into the present study with an age ranges from 22 to 49 years (all nonsmokers). To avoid patient selection bias, all the study participants underwent a medical examination to ensure they are healthy. Volunteers were eligible if they were 18 years of age or older and were in good health as assessed by detailed medical examination including blood and serum examination and 12-lead electrocardiogram. They were also included when body mass index of the volunteers ranges from 18 to 30 kg/m 2.

The volunteers were ensured for abstinence from any medication for the past 2 weeks before and throughout the study period as well. Study participants if they had any history of major disease were also excluded from the study.

Volunteers were excluded if they had any disease or disorder preferably in the gastrointestinal tract that affects absorption of any drugs or history of adverse reaction to simvastatin. Volunteers who fall sick during the study and volunteers who do not satisfy the inclusion criteria were excluded from the study. Volunteers agreed to abstain from taking additional prescription or nonprescription drugs (including nutritional supplements) and alcohol throughout the study period.

This study consisted of nine participants with three groups with a crossover design in three blocks. The three groups were on fasting conditions during the initiation of a study to estimate interindividual variability with food and with an antacid. The study participants were invited and their fasting status was maintained and monitored before the administration of simvastatin. One-week interval was given between the three study groups to allow drug-free days during the research period [Table 1].
Table 1: Classification and description of study groups

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About 10 ml of blood samples was withdrawn from study participants and transferred to prelabeled glass tubes which contained an anticoagulant. The time of withdrawal of blood sample is just before the administration of simvastatin and after administration of simvastatin (at frequent time interval up to 24 h). Anticoagulant was added to the sample and left for half an hour to ensure appropriate mixing. The centrifugation was done for 15 min at 3000 rpm. The plasma was isolated from whole blood by centrifugation at 3000 rpm and then transferred into a glass tube. The glass tube was placed in a freezer at −20°C until it gets frozen; further, it was stored in a −85°C freezer until analysis.

Sample analysis

Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Ethyl acetate and hexane were used to extract simvastatin from serum sample (90/10%, v/v). Lovastatin was used as internal standard. A mixture of acetonitrile and 3 mM formic acid (75/25%, v/v) was used as mobile phase, and the flow rate was 500 μL/min. C18 columns were used as stationary phase. The daughter ions m/z 325 for simvastatin and m/z 285 for lovastatin were used in positive ion mode for estimating in the selective reaction monitoring. Parent ions in positive ion mode were m/z 441.3 for simvastatin and m/z 405.1 for lovastatin. The lower limit of quantitation of 0.25 ng/mL was achieved. The coefficient of variation on the same was lesser than 14.00%, and 90.00% and 109.33% of accuracy were achieved. The coefficients of variation for day to day were <10.00%, and 97.70% and 106.60% of accuracy were achieved.

Pharmacokinetic analysis

The first occurrence of concentration at the maximum (Cmax) and the time to maximum concentration (Tmax) were recorded. The linear trapezoidal rule for each incremental trapezoid was used to estimate area under the curve (AUC) from initial time to final estimated plasma concentration. The apparent terminal elimination rate constant Ke was derived. From the log-linear disposition phase of the concentration-time curve, the apparent terminal elimination rate constant was obtained. Visual inspection ratio and least squares regression were used to estimate Ke but not less than four points. t1/2, Vd, and clearance were also calculated in the present study.

Statistical analysis

Except for Tmax, all other remaining data re-expressed as a mean ± standard deviation. Tmax is expressed as median along with range. The analysis of variance and a posteriori testing with the Tukey test were used for statistical analysis of pharmacokinetic data obtained except Tmax. Wilcoxon test was used to analyze Tmax. The Statistical Package for the Social Sciences program, version 11.5, was used for analysis. This program was developed by SPSS Inc., Chicago, United States of America.

  Results Top

The characteristics of study participants were detailed in [Table 2]. The mean plasma concentration of oral simvastatin (40 mg) versus time profiles of volunteers for all the three groups is shown in [Figure 1]. Pharmacokinetic parameters derived from the current study listed in [Table 3]. The extent of drug absorption was derived as AUC0–24, the rate of drug absorption was derived as Tmax, and both rate and extent of drug absorption were calculated as Cmax.
Table 2: Demographic characteristics of nine healthy volunteers

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Figure 1: The mean plasma concentration versus time plot for simvastatin with fasting, food, and antacid. Mean ± standard deviation, n = 9

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Table 3: Pharmacokinetic parameters of simvastatin in nine volunteers after 40 mg oral simvastatin in fasting, food, and antacid conditions

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In each volunteer, the administration of simvastatin with meal resulted in significantly higher AUC0–24 and Cmax values for simvastatin. To the Groups I and II, the intersubject difference was significant with regard to AUC0–24 value. The AUC0–24 was ranged from 6.20 to 15.86 ng/mL h and from 12.56 to 23.86 ng/mL h for fasting and food state, respectively, for simvastatin. The AUC0–24 is increased up to 50% more in Group II than Group I (P< 0.05 at 95% confidence interval).

In both fasting and food situations, the interindividual variation was significant with regard to Cmax. The Cmax ranged from 0.93 to 4.96 ng/mL and from 3.12 to 6.34 ng/mL during fasting and food state for simvastatin. The peak concentration was increased to around 85% to Group II than Group I. We found that the maximum concentration was higher in three out of nine volunteers in fed state.

The observed Tmax mean for simvastatin with food is significantly higher than the fasting state. However, food intake reduced the absorption of simvastatin which is evident by delayed time to reach maximum concentration (Tmax) in most study participants. The observed Tmax mean is increased for simvastatin up to 90% higher in Group I than Group II (P< 0.05 at 95% confidence interval).

The present study results revealed that t1/2 of simvastatin is not affected by food. The mean observed t1/2 determined is 3.16 ± 1.68 and 2.49 ± 0.80 h for the Group I and Group II, respectively (P > 0.05 at 95% confidence interval). Similarly, the elimination rate constant (Ke), Vd, and clearance value (Cl) did not show any statistical difference between Group I and Group II (P > 0.05 at 95% confidence interval). The mean observed value with standard deviation was shown in [Table 3].

While we compare the kinetic data between Group I and Group III, the interindividual difference was significant with respect to peak concentrations and AUC0–24 values. AUC0–24 values are range from 6.20 to 15.86 ng/mL h in the fasting situations and from 11.75 to 38.04 ng/mL h in the antacid condition. In each volunteer, the AUC0–24 value was larger (95%) when simvastatin gave along with an antacid except one volunteer, to whom the AUC0–24h value is equal in both Group I and Group III.

The peak concentrations are range from 0.93 to 4.96 ng/mL in Group I and from 1.72 to 5.84 ng/mL in Group III. The mean Cmax of the simvastatin was increased from 2.61 ± 1.42 in fasting state to 3.30 ± 1.53 ng/mL in the antacid state (P > 0.05 at 95% confidence interval).

Co-administration of simvastatin with multiple doses of antacid was produced a higher effect on the Tmax. The observed Tmax mean for simvastatin with antacid is significantly higher than when it is administered on an empty stomach with water (P< 0.05 at 95% confidence interval).

The half-life of simvastatin was not influenced by the antacid. However, it does not show a significant difference between antacid and fasting states: 3.16 ± 1.68 and 4.38 ± 1.43 h, respectively (P > 0.05 at 95% confidence interval). Like Group II, even the Group III does not show a significant difference on elimination rate constant, the volume of distribution, and clearance value while it is in comparison with Group I (P > 0.05 at 95% confidence interval). The detailed values are mentioned in [Table 3].

Unlike the results of comparison between Group I and Group II and between Group I and Group III, we could not be able to record a statistical difference among Group II and Group III with respect to pharmacokinetic data. It includes all the pharmacokinetic parameters included in the present study [Table 3].

  Discussion Top

Physiologic changes such as gastric emptying and altered gastric secretions and increased bile production are important factors for poor water-soluble drugs as it results in facilitated dissolution process through substantial concentrations of bile salts and lecithin.[11]

Various lipophilic drugs were shown to be dissolute in this way, and rate of absorption rate was increased.[12],[13] However, a similar mechanism may be explained here in the present study for increased absorption of simvastatin after intake of 30.70 g fat-containing food.

The current study is providing an evidence that systemic exposure (Cmax and AUC) of simvastatin is high when it is administered with food. With regard to AUC, the current study results are similar to previously published studies; they provided an important note that food increases drug absorption due to change in hepatic flow.[14],[15],[16]

Simvastatin has a high degree of first-pass metabolism.[17] Food may noticeably diminish presystemic clearance of (certain) lipophilic basic drugs, which is not noticed in our study.

The delayed gastric emptying and gastrointestinal motility might be due to food which contains carbohydrate or protein or fat or when there is an alteration in pH.[5],[6],[18] Our study is adding an additional evidence to this concept, by showing the variations in Tmax in food and fasting conditions for the simvastatin that is longer gastric residence time of simvastatin.

Our results are consistent with the concept of other researchers that food may induce the absorption of lipophilic drugs by stimulating the dissolution rate and delayed gastric emptying.[19],[20],[21]

In our study, the plasma concentration of Simvastatin was increased when it is administered after food. This can be considered as an additional evidence on effect of food on Statins. However, it needs to be explained whether it is because of pH change of gastrointestinal tract or by food.

Altered gastric pH and food can diminish the bioavailability of few acid-labile drugs.[22] Our results are differing from previous studies conducted on acid-labile compounds (for example, erythromycin).[23] One possible explanation for this discrepancy could be the critical pH value. For example, in the case of erythromycin, the unsteadiness was noted under pH 5, and for simvastatin, it is about 2 (in vitro).[22],[24]

It is already known that all acid-labile compounds will not behave, similarly, while they are administered with food. Our study results are may consider as an additional evidence along with that.[22],[25]

The absolute bioavailability of simvastatin along with food is higher than on empty stomach. There is 50% increase in AUC with food versus fasting conditions. Furthermore, the Cmax is greater and Tmax is longer in Group II than Group I. These results are displaying similar pharmacokinetic profile of prodrug esters in the presence of food as conducted by previous studies like Sommers et al., Hughes et al., and Crauste-Manciet et al.[26],[27],[28]

The stability of drugs is based on gastric pH and susceptibility to an enzymatic breakdown in gastric fluids. If degradation is extensive, it may lead to poor bioavailability.[28],[29]

Lactone hydrolysis reactions are increased by general acid catalysis; it is expected that strong acidic environment is required for the conversion of lactone form into its hydroxyl acid form.[24],[30] In our study, we observed increased plasma concentration of simvastatin when it is given along with food. This might be due to increased pH which increased the stability of lactone form of the simvastatin in gastrointestinal tract.

No research literature is available to explain the mechanism of absorption of simvastatin when it is given along with food in healthy adult volunteers. Only one research was conducted by Schaefer et al. that too in elderly patients with coronary heart disease. However, that study is not enough to finalize the pharmacokinetic profile of simvastatin in food and fasting conditions. They reported better bioavailability to simvastatin when it is administered along with food. Similar kind of results was observed in the current study also.[31]

Antacid, based on its action on gastrointestinal pH, has been projected to decrease the absorption of the weakly acidic simvastatin drug. Unfortunately, we could not able to identify a research data, which demonstrate this effect of antacids on simvastatin absorption, which would increase AUC and plasma levels of the simvastatin.

The area under the curve shows larger area when Simvastatin is administered after the antacid administration, which implies the increased absorption of simvastatin.

The higher plasma levels and AUC of simvastatin after administration with antacid were not because of chelation between drugs and metal ions, which is supported by Fleisher et al. Clinically, fluoroquinolone loses its antibacterial efficiency, due to interactions with metal ions in food and antacids, which decreases absorption of fluoroquinolone.[18],[32]

The current study as well as reported by Fleisher et al. did not support the study done by Ambre and Fischer where they concluded that antacids may chelate anticoagulants when it is administered along with antacid and thus leads to higher level of plasma drug concentration.[7],[18]

Most drugs are either weak bases or weak acids. They are usually better absorbed through the lipid membranes if they are lipid soluble, i.e., unionized. According to the pH-partition theory,[33] a change in pH may have quite opposite effects on the solubility of lipids and rate of dissolution of a drug.

Our study in vivo agrees with previous studies in vitro conducted by Garrett and Won, Kaufman, and Serajuddin et al. With the current study, we observed the higher plasma concentration of simvastatin after administration of liquid antacid. This effect may be a result of decreased pH of the gastrointestinal tract caused by the liquid antacid. It will lead to increased stability of lactone form of simvastatin in the gastrointestinal tract and improve drug dissolution by prolonging residence time in the gastric area. Similar results were also obtained when simvastatin is administered along with food.[24],[30],[34]

Based on the current study results, the oral simvastatin (40 mg) with food and liquid antacid produced greater values for AUC, Cmax, and Tmax than simvastatin single dose 40 mg with fasting. Therefore, the present study strongly recommends that the food and liquid antacid increase simvastatin bioavailability and enhance the absorption of simvastatin by increasing the stability of lactone form and by increasing the pH of the gastrointestinal tract.

Previous studies conducted by Crauste-Manciet et al. reported that food and antacid could block cholinesterase action by lowering gastric pH. They also reported that they tend to produce a protective effect against hydrolysis if drugs in the intestinal lumen.[28] In our study, simvastatin is prodrug lactone form, and the results obtained by us were similar to that of it.[33]

The present study has a major limitation that we have not calculated a power analysis, and the present study comprises relatively low number of samples.

  Conclusion Top

Food and antacid influenced the increasing pH of the gastrointestinal tract which leads to increased stability of simvastatin in its lactone form and rate of drug dissolution. The study can be concluded, food and antacid increase the absorption of simvastatin due to the stability of lactone form by enhancing the pH of the gastrointestinal tract, and this revealed that simvastatin is pH dependent.

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There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3]

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