Stability indicating LC-MS/MS method for estimation of lovastatin in human plasma: application to a bioequivalence study
© Saha et al. 2015
Received: 14 January 2015
Accepted: 21 May 2015
Published: 18 June 2015
Sensitive and selective analytical method is required for the estimation of lovastatin in human plasma as lovastatin has been reported to have high intra-subject variability and is converted to its active metabolite lovastatin hydroxy acid in in vitro system and vice versa. If this inter-conversion is not restricted, it could lead to pseudo estimation of lovastatin in human plasma.
A specific, sensitive, and reproducible high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for determination of lovastatin in human plasma, using lovastatin-d3 as an internal standard. Lovastatin and lovastatin-d3 were extracted from human plasma using solid phase extraction, separated on Luna C18 (2)100A (100 × 4.6 mm, 5 μm) column with mobile phase consisting of acetonitrile and 2 mM ammonium acetate buffer (pH 3.6) in the ratio of 90:10, v/v. Quantification was achieved by monitoring transitions of m/z 422.1 → 285.4 for lovastatin and 425.4 → 285.4 for lovastatin-d3 in multiple reaction monitoring, using turbo ion source in positive polarity.
No matrix effect was observed within the linearity range of 0.121–35.637 ng/mL (r > 0.99). The degree of matrix effect for lovastatin was determined as 2.74 %, and it had no impact on incurred samples analysis with run time of 4.5 min. The intra- and inter-day precision values were within 11.38 and 8.62 % respectively, for lovastatin at the lower limit of quantification level.
Stability data indicated that lovastatin is stable under various handling conditions and with insignificant inter-conversion between lovastatin and lovastatin hydroxy acid. The method was successfully applied for the bioequivalence study of lovastatin after oral administration of 40 mg tablet in healthy volunteer.
KeywordsBioequivalence study Liquid chromatography-mass spectrometry Lovastatin Inter-conversion
Lovastatin is a cholesterol-lowering agent, used in the treatment of hypercholesterolemia. It is a lactone, which hydrolyzes readily in vivo to its β-hydroxy acid form, an inhibitor of 3-hydroxy-3-methylgluteryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which finally converted to cholesterol by subsequent biochemical pathways. Thus, inhibition of the HMG-CoA reductase activity limits the biosynthesis of cholesterol (Hsu et al. 1995; O’Connor et al. 1990). Following an oral dose of lovastatin, only about 30 % of dose reaches the systemic circulation, with elevated plasma concentration in 2.0 h. It has protein binding of about 95 % (Mevacor®, Prescribing Information, 2012). It undergoes extensive first-pass metabolism in the liver, because of which the availability of the drug to the general circulation is low and variable. The metabolites of lovastatin in human plasma are 6′β-hydroxy acid lovastatin, 6′-exomethylene lovastatin, and 3″-hydroxy lovastatin (Jacobsen et al. 1998). Hydroxylation of lovastatin at 6′ position also occurs in ex vivo. Therefore, a sensitive and specific analytical method is required for the estimation of lovastatin in human plasma with optimized conditions, wherein inter-conversion between lactone and hydroxy acid form is controlled.
Although several analytical methods have been reported for the determination of lovastatin, but the sensitivity of published HPLC-UV methods (Islam et al. 2010; Lin et al. 2004; Lily et al. 2000; Mullangi et al. 2006; Strode et al. 1999) are inadequate for pharmacokinetic study and therapeutic drug monitoring. In the reported gas chromatography–mass spectrometric method (Morris et al. 1993), the sensitivity was improved by derivatization, but it is a time-consuming process. LC-MS/MS methods (Dong et al. 2008; Haiyan et al. 2008; Lin et al. 2008; Nageswararao et al. 2012; Ramakrishna et al. 2007; Xiao et al. 2006; Xiu and Chris 2003; Wu et al. 1997) have also been reported with increased sensitivity but the inter-conversion between lovastatin to lovastatin hydroxy acid has not been studied in these methods, which could lead to pseudo estimation of lovastatin in plasma. Although the kinetics of in vitro inter-conversion between lactone and its hydroxy acid form has been reported by Kearney et al. (1993) and Won (1994), its application for the estimation of lovastatin in the bioequivalence study has not been reported till date.
The developed method has numerous advantages over other existing methods. The pros of the developed method includes the following: less aliquot volume compared to methods developed by Xiao et al. (2006), Lin et al. (2008), and Nageswararao et al. (2012); better sensitive compared to methods developed by Lily et al. (2000), Mullangi et al. (2006), and Islam et al. (2010); inhibiting the in vitro inter-conversion between lovastatin and lovastatin hydroxy acid results in accurate estimation of lovastatin in incurred samples and this was not reported by Wu et al. (1997), Lin et al. (2008), and Dong et al. (2008).
Chemicals and materials
LC-MS/MS instrumentation and chromatographic conditions
Chromatographic separation was carried out on a Shimadzu scientific instrument (Shimadzu Corporation; Kyoto, Japan) with a Luna C18 (2) 100A column (100 × 4.6 mm, 5 μm) (Phenomenex). A mobile phase consisting of acetonitrile and 5 mM ammonium acetate buffer (pH 3.6) in the ratio of 90:10, v/v, was delivered at a flow rate of 0.7 mL/min. The total analysis run time for each sample was 4.5 min. The ionization and detection were carried out on a triple quadruple mass spectrometer, MDS Sciex API-4000 (Sciex Division of MDS, Toronto, Ontario, Canada), equipped with electrospray ionization operated in positive polarity using multiple reaction monitoring (+MRM). The compound and source parameters were optimized by infusing individual solution of LS, IS, and LHA into the mass spectrometer. The optimized compound parameters for monitoring LS and IS were set as follows: declustering potential (DP), 38 V; entrance potential (EP), 10 V; collision energy (CE), 20 V; and collision cell exit potential (CXP), 7 V. The optimized compound parameters for monitoring LHA were set as follows: DP 48 V, EP 5 V, CE 20 V, and CXP 8 V. The source parameters of the mass spectrometer were optimized and maintained as follows: collision-activated dissociation (CAD) gas, 6 psi; curtain gas (CUR), 20 psi; nebulizer gas (GS1), 60 psi; heater gas (GS2), 40 psi; turbo ion spray voltage, 4500 V; and source temperature, 450 °C. Quadrupole 1 and quadrupole 3 were both maintained at unit resolution, and dwell time was set at 200 ms for all analytes. The mass transitions were selected as 422.1 → 285.4 for LS, 425.4 → 285.4 for IS, and 423.3 → 303.7 for LHA. The data acquisition and processing were performed by Analyst version 1.4.2 software (MDS Sciex, Toronto, Canada). For quantification, the peak area ratios of the target ions of the analyte to those of the internal standard were compared with weighted 1/X 2 (where X = drug concentration) least squares calibration curves in which the peak area ratios of the calibration standards were plotted versus their concentrations.
Preparation of stock solutions, calibration standards, and quality control samples
Two separate stock solutions of LS were prepared for bulk spiking of calibration standards (CS) and quality control (QC) samples for method validation exercises as well as incurred sample analysis. Stock solution of LS, IS, and LHA were prepared in acetonitrile at concentration of 1 mg/mL. Working solutions for CS and QC samples were prepared by appropriate dilution in acetonitrile-water (50:50, v/v). Blank human K3EDTA plasma was screened prior to spiking to ensure that there is no significant endogenous interference at the retention time (RT) of LS and its IS. An 8-point CS and QC samples at four concentration levels were prepared by spiking the blank plasma with an appropriate amount of LS. CS were made at concentrations of 0.121, 0.328, 1.642, 4.105, 10.264, 17.106, 28.510, and 35.637 ng/mL and QC samples at lower limit of quantification (LOQQC), low-quality control (LQC), medium-quality control (MQC), and high-quality control (HQC) at concentrations of 0.122, 0.359, 14.358, and 28.716 ng/mL, respectively. To prevent inter-conversion between LS and LHA, 3 % formic acid solution (v/v) was added in spiked plasma in the ratio of 5:95 (v/v) during bulk spiking. Spiking was carried out in ice-cold water bath under low light condition, and bulk spiked CS and QC samples were stored below −50 °C and protected from light till use. The working solution of IS (150.0 ng/mL) for routine use was prepared by diluting the IS stock solution in acetonitrile-water (50:50, v/v).
Plasma sample (300 μL) was aliquoted, and 50 μL of IS working solution (150.0 ng/mL of IS) was added in ice-cold water bath and vortexed. To this sample, 500 μL of 100 mM ammonium acetate buffer was added and then samples were vortexed. The pretreated samples were loaded onto the pre-conditioned cartridge (Cleanert PEP-3, 30 mg/1 cc) and spun in centrifugation at 4000 rpm for 1 min at 2–10 °C. The cartridges were washed with 1 mL of 20 % methanol in water (v/v), and analytes were eluted with 1 mL of acetonitrile. The extracted samples were evaporated to dryness at 20 psi and at 40 °C under a stream of dry nitrogen using a Zymark TurboVap LV evaporator (Caliper, Hopkinton, MA, USA). Dried residue was reconstituted with 300 μL of reconstitution solution consisting of acetonitrile and 5 mM ammonium acetate buffer (pH 3.6) in the ratio of 60:40, v/v. The reconstituted samples of 20 μL volume were used for injection in LC–MS/MS system.
Inter-conversion between LS and LHA
Role of temperature
Working solution of LS was spiked into human K3EDTA plasma at LQC and HQC level. The spiked samples were kept at different storage conditions ,i.e., room temperature and ice-cold water bath to study the impact of temperature on conversion of LS to LHA. After 6.0 h, four aliquots of each samples stored at different conditions were processed with freshly spiked CS and were analyzed in LC-MS/MS system by monitoring both mass transitions of LS and LHA in MRM.
Role of pH
Protocol-I (control-normal plasma)
Protocol-II (acidified plasma, pH 6.0 adjusted with formic acid solution)
Protocol-III (acidified plasma, pH 4.0 adjusted with formic acid solution)
Spiked samples were kept in ice-cold water bath and under low light condition, and four aliquots of these samples were processed at time intervals 0.0, 2.0, 4.0, and 6.0 h and were analyzed in LC-MS/MS system by monitoring both mass transitions of LS and LHA in MRM.
A thorough and complete method validation of LS in human K3EDTA plasma was carried out, as per the USFDA/EMEA guidelines (USFDA bioanalytical guideline 2001 and EMEA bioanalytical guideline 2011). The method was validated for selectivity, sensitivity, linearity, precision, accuracy, process efficiency, dilution integrity, matrix effect, re-injection reproducibility, and stability of LS during both short-term sample processing and long-term storage.
Three calibration curves were used to demonstrate the linearity of the method. The ratio of area responses for lovastatin was used for regression analysis. Each calibration curve was analyzed individually by using least square weighted (1/X 2) linear regression (obtained by best fit method). Back calculations were made from these curves to determine the concentration of lovastatin in each calibrator. A correlation coefficient r > 0.99 was desirable for all the calibration curves. The analyte peak of LOQ sample should be identifiable, discrete, and reproducible with a precision (% CV) of <20.0 and accuracy within ±20.0 %. The deviation of standards other than LOQ from the nominal concentration should not be more than ±15.0 %.
The intra- and inter-day precision and accuracy were performed for lovastatin in K3EDTA plasma. The intra-run (within a day) and inter-run (between days) accuracy was determined by replicate analysis of QC samples (n = 6) at LOQQC, LQC, MQC, and HQC. The precision of the method was determined by calculating the coefficient of variation (% CV) for each QC level. The deviation at each concentration level from the nominal concentration was expected to be <15.0 except for the LOQQC, for which it should be <20.0. Similarly, the mean accuracy should be within ±15.0 % except for at the LOQQC, for which it should be ±20.0 % of the nominal concentration.
where AME = 1 indicates no matrix effect, AME < 1 indicates ion-suppression, and AME > 1 indicates ion enhancement. As extraction protocol involved a terminal drying step, hence spiking (addition of reference samples) was carried out in post-extracted blank plasma sample to perform AME. The concentration of LS and IS in reference sample representing the QC concentration (at LQC, MQC, and HQC level). The control sample was a reference solution prepared at appropriate concentration in a reconstitution solution.
Relative matrix effect (RME) was evaluated using six lots of human K3EDTA plasma including one hemolyzed and one lipemic plasma lot, processed in duplicate samples at LOQQC and HQC levels and the area ratio (i.e., peak area response of LS/peak area response of IS) was used to check the acceptability of the result. The standard deviation for each lot was calculated, along with % CV and % bias at each level. The deviation of the standards should not be more than ±15 % of their respective nominal concentration, and at least 90 % of the lots at each QC level should be within the aforementioned criteria.
Where S = mean concentration of stability samples and F = mean concentration of freshly spiked samples.
The bench top stability was determined by stored spiked QC samples for ~6.5 h in ice-cold water bath before processing. The autosampler stability was determined by stored reconstituted QC samples for ~72 h under autosampler condition (at 10 °C) before being analyzed. The freeze-thaw stability was conducted by comparing the stability samples that had been frozen at −50 °C and thawed at room temperature three times, with freshly spiked QC samples. Four aliquots each of LQC and HQC concentration level were used for the freeze-thaw stability evaluation. For long-term stability evaluation, the concentrations obtained after 121 days were compared with initial concentrations. All stability exercises were performed against freshly spiked CS.
The dilution integrity experiment was performed with an aim to validate the dilution test to be carried out on higher analyte concentrations above upper limit of quantification (ULOQ), which may be encountered during real incurred sample analysis. Dilution integrity test was performed by preparing samples at a concentration approximately two times the concentration of 90 % ULOQ. These samples were diluted to two and four times with blank plasma to bring the concentration within calibration curve and then analyzed against fresh CS samples. The acceptance criteria for the diluted QC samples are the same as that of QC samples in precision and accuracy run.
The method was applied to an open-label, balanced, randomized, two-treatment, four-period, two-sequence, single dose, crossover design study of lovastatin in healthy human volunteers under fed condition for the assessment of bioequivalence. A single oral dose of lovastatin 40-mg tablet of Ranbaxy and Medostatin 40-mg tablet of Medochemie Limited, Cyprus, marketed by Kodomedic sdn. Bhd, Malaysia, was given to the human volunteers during the study. The bio-study was carried out in accordance with the principles of Good Clinical Practices defined in the ethical guidelines for Biomedical Research on human participants issued by Indian Council of Medical Research, New Delhi, the ICH E6 Guidance for ‘Guidance on Good Clinical Practice,’ and the principles enunciated in the Declaration of Helsinki on 36 healthy volunteers from whom prior informed consent was taken. The bio-study protocol was approved by the Jamia Hamdard Institutional Review Board, New Delhi, India. Blood samples were collected at 0.500, 1.000, 1.333, 1.667, 2.000, 2.333, 2.66, 3.000, 3.333, 3.667, 4.000, 4.333, 4.667, 5.000, 6.000, 9.000, 12.000, 16.000, 24.000, 36.000, and 48.000 h post dose in each period. All blood samples were collected in K3EDTA vacutainers and processed by centrifugation to collect plasma and stored below −50 °C until analysis.
Results and discussion
Optimization of mass parameters and chromatographic conditions
Lovastatin is reported to be highly variable drug in terms of pharmacokinetics (PK) behavior with low Cmax value. For accurate and reliable characterization of PK profile, it is essential to develop a sensitive method with low LOQ (0.1 ng/mL) for 40 mg strength. In order to develop a method with the desired LOQ, it was necessary to use MS-MS detection.
For the separation of LS and LHA, several C18 and phenyl columns like Poroshell 120 EC-C18, Ascentis express, Sunshell C18, Kinetex C18, Hypurity advance, Zorbax SB-C18, Discovery C18, Unisol C18, Luna C18(2), kinetex PFP, and ACE C18 PFP were tried. Many columns with fused core technology were also evaluated to attain resolution between LS and LHA, but due to high back pressure, these columns could not be used. LS and LHA were chromatographically well separated on Luna C18 (2) 100A (100 × 4.6 mm, 5 μm) column with high S/N ratio for LS. This could be due to lower carbon loading of the column, enabling the selectivity by base material of the column, and lower carbon load reduces RT of analyte and increased high throughput. The use of methanol as an organic phase led to high backpressure, and high aqueous portion in mobile phase suppressed the peak area response of LS. However, the mixture of ammonium acetate buffer and acetonitrile (90:10, v/v) was found optimal, with very low background noise and optimum back pressure. In addition, mobile phase with high organic solvent ratio increased the ionization efficiency of LS. The analytes (i.e., LS and LHA) were chromatographically separated from phospholipids and other endogenous components at pH 3.6, which was attained by the addition of glacial acetic acid in ammonium acetate buffer. The absence of co-eluting peaks as well as interference from matrix ions was minimal with a Luna C18 (2) column in combination with mobile-phase ammonium acetate buffer and acetonitrile (90:10, v/v).
Selection of IS
In LC-MS/MS analysis, selection of IS with similar chromatographic and mass spectrometric behavior to that of analyte is of utmost priority. The best IS is a stable isotope form of the analyte which proves to be helpful when significant matrix effect is possible. Therefore, lovastatin-d3 was selected as an IS.
Role of temperature and pH on inter-conversion
Role of temperature on inter-conversion (n = 4)
LQC (0.359 ng/mL)
84.25 ± 1.86
61.37 ± 0.82
HQC (28.716 ng/mL)
86.07 ± 3.44
68.87 ± 3.40
Role of pH in plasma on inter-conversion (n = 4)
Analysis of LS spiked sample (10.0 ng/mL)
Acidified plasma (pH 6.0)
Acidified plasma (pH 4.0)
Analysis of LHA spiked sample (10.0 ng/mL)
Acidified plasma (pH 6.0)
Acidified plasma (pH 4.0)
The samples pretreated with 100 mM ammonium acetate buffer solution were extracted using SPE cartridge. This extraction procedure gave higher PE and cleaner sample. Due to hydrophobic nature of LS, different polymeric cartridges like Oasis HLB, Bond Elut Plexa, Cleanert PEP-H, and Cleanert PEP-3 were tried during method development. The high PE and consistent results were obtained in sample prepared using Cleanert PEP-3 cartridges. Inconsistency in peak area response of LS and IS was observed during analysis of extracted samples. This could be due to low solubility of LS and IS in the mobile phase that was finalized during chromatographic optimization. Low solubility of LS and IS could be due to the high hydrophobic nature of these compound, which led to suppressed LS and IS peak area response in the extracted samples. Therefore, the reconstitution solution composition was further optimized and it was observed that reconstitution solution consisting acetonitrile 2 mM ammonium acetate (pH 3.6) buffer (60:40, v/v) was suitable for solubility of LS and IS and gave consistent IS peak area throughout the analytical batch of larger sample size.
Intra-and inter-run results
% intra-run accuracya
% inter-run accuracyb
% intra-run precisionc
% inter-run precision
LOQQC (0.122 ng/mL)
LQC (0.359 ng/mL)
MQC (14.358 ng/mL)
HQC (28.716 ng/mL)
Absolute matrix effect and process efficiency of lovastatin
Aa (% CV)b
Bc (% CV)b
Cd (% CV)b
Absolute matrix effect (% AME)e
Process efficiency (%PE)f
Relative matrix effect of lovastatin
LOQQC (0.122 ng/mL)
HQC (28.716 ng/mL
Mean calculated concentrationa (% CV)b
Mean calculated concentrationa (% CV)b
Stability of lovastatin in different storage conditions (n = 4)
Autosampler stability (~76.90 h, 10 °C)
Bench top stability (~8.82 h, in ice-cold water bath)
Freeze-thaw stability (three freeze-thaw cycle)
Long-term stability (121 days, below −50 °C)
Re-injection reproducibility of LS was established by re-injecting QC samples of precision and accuracy batch-3 and quantitated against original analyzed calibration curve of precision and accuracy batch-3. The % differences for all re-injected QC samples are ≤7.45.
Pharmacokinetic parameters of lovastatin, after administration of an oral dose of 40 mg of lovastatin test and reference formulation of 31 healthy human volunteers
(Mean ± SD)
3.12 ± 1.28
2.89 ± 1.26
16.13 ± 7.18
16.68 ± 7.36
81.25 ± 34.53
88.73 ± 37.66
t 1/2 (h)
3.12 ± 1.28
2.89 ± 1.26
In summary, a rapid, selective, specific, reproducible, and high-throughput LC-MS/MS method was developed and validated to estimate lovastatin in human plasma using lovastatin-d3 as an internal standard. The proposed method showed good performance with respect to all the validation parameters tested, demonstrated optimized working conditions for lovastatin in human plasma with minimal inter-conversion, and was successfully employed for a bioequivalence study of lovastatin after oral administration of 40-mg tablet.
All the authors wish to acknowledge the support and facilities received from Ranbaxy Research Laboratories, Gurgaon, India, for carrying out this work.
- Daniel M, Mohammed J, Sabine CP (2000) Quantitative determination of pravastatin and its biotransformation products in human serum by turbo ion spray LC/MS/MS. J Pharm Biomed Anal 23:851–866View ArticleGoogle Scholar
- Dong W, Dongmei W, Feng Q, Lingyun C, Famei L (2008) Determination of lovastatin in human plasma by ultra-performance liquid chromatography/electrospray ionization tandem mass spectrometry. Biomed Chromatogr 22:511–518View ArticleGoogle Scholar
- Guideline on bioanalytical method validation (2011) European Medical Agency. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf. Accessed 09 March 2014
- Guidance for Industry: Bioanalytical Method Validation (2001) US Food and Drug Administration. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm368107.pdf. Accessed 09 March 2014
- Haiyan Y, Feng W, Jiying T, Wenxing P, Huande L (2008) Determination of lovastatin in human plasma by ultra-performance liquid chromatography–electrospray ionization tandem mass spectrometry and its application in a pharmacokinetic study. J Pharm Biomed Anal 46:808–813View ArticleGoogle Scholar
- Hsu I, Spinler SA, Johnson NE (1995) Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmacother 29:743–759Google Scholar
- Islam UK, Tayyaba K, Muhammad A, Shaazad S (2010) Development and validation of liquid chromatographic method for the simultaneous estimation of ezetimibe and lovastatin in human plasma. J Chil Chem Soc 55:461–464View ArticleGoogle Scholar
- Jacobsen W, Gabriele K, Katrin H, Laviero M, Michael D, Ingelore H, Benet LZ, Sewing KF, Christians U (1998) Comparison of cytochrome p-450 dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-coa reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Dispos 27:173–179Google Scholar
- Kearney AS, Crawford LF, Surendra CM, Galen WR (1993) The interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxy acid forms of the HMG-CoA reductase inhibitor, CI-981. Pharm Res 10:1461–1465View ArticleGoogle Scholar
- Lily YY, Patricia SF, Malcolm JM (2000) Determination of lovastatin in human plasma using reverse phase high performance liquid chromatography with UV detection. Ther Drug Monit 22:737–741View ArticleGoogle Scholar
- Lin F, Dai Z, Hou S, Wan Y (2004) Pharmacokinetic study on lovastatin sustained-release tablet and sustained-release capsule in begal dogs. J Huazhong Univ Sci Technolog 24:116–119View ArticleGoogle Scholar
- Lin L, Jin S, Yaxin S, Zhonggui H (2008) LC–ESI–MS determination of lovastatin in human plasma. Chromatographia 67:621–625View ArticleGoogle Scholar
- Morris MJ, Gilbert JD, Hsieh JY, Matuszewski BK, Ramjit HG, Bayne WF (1993) Determination of the HMG-CoA reductase inhibitors simvastatin, lovastatin, and pravastatin in plasma by gas chromatography/chemical ionization mass spectrometry. Biol Mass Spectrom 22:1–8View ArticleGoogle Scholar
- Mullangi R, Pasha MK, Jafar SB, Syed M, Shashikumar D, Srinivas NR (2006) Analysis of five HMG-CoA reductase inhibitors-atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin: pharmacological, pharmacokinetic and analytical overview and development of a new method for use in pharmaceutical formulations analysis and in vitro metabolism studies. Biomed Chromatogr 20:282–293View ArticleGoogle Scholar
- Nageswararao P, Ramesh M, Jaswanth KI, Indira KN, Seshagirirao JVLN (2012) Simultaneous determination of simvastatin, lovastatin and niacin in human plasma by LC-MS/MS and its application to a human pharmacokinetic study. Biomed Chromatogr 26:476–484View ArticleGoogle Scholar
- O’Connor P, Feely J, Shepherd J (1990) Lipid lowering drugs. Br Med J 300:667–672View ArticleGoogle Scholar
- Prescribing Information (2012) Mevacor (lovastatin Tablets). MERCK & CO., INC., USA Whitehouse Station (NJ)
- Ramakrishna N, Koteshwara M, Vishwottam K (2007) Chromatography-mass spectrometry methods for the quantitation of statins in biological samples. J Pharm Biomed Anal 44:379–387View ArticleGoogle Scholar
- Strode JT, Taylor LT, Howard AL, Ip D (1999) Feasibility of lovastatin analysis by packed column supercritical fluid chromatography with ultraviolet detection. J Pharm Biomed Anal 20:137–143View ArticleGoogle Scholar
- Viswanathan CT, Bansal S, Booth B (2007) Workshop/conference report-quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. AAPS J 9:E30–E42View ArticleGoogle Scholar
- Won CM (1994) Epimerization and hydrolysis of dalvastatin, a new hydroxymethylglutaryl coenzyme (HMG-CoA) reductase inhibitor. Pharm Res 11:165–170View ArticleGoogle Scholar
- Wu Y, Jamie Z, Jack H, Walter AK, Amelia PL, Lin CC (1997) Microsample determination of lovastatin and its hydroxy acid metabolite in mouse and rat plasma by liquid chromatography/ionspray tandem mass spectrometry. J Mass Spectrom 32:379–387View ArticleGoogle Scholar
- Xiao H, Shen H, Chen JF, Xaio D (2006) Determination of lovastatin level in human plasma and lovastatin capsules bioavailability in healthy volunteers using HPLC-MS. J Chin Pharm Sci 15:233–237Google Scholar
- Xiu SM, Chris DM (2003) Determination of cholesterol-lowering statin drugs in aqueous samples using liquid chromatography–electrospray ionization tandem mass spectrometry. J Chromatogr A 998:133–141View ArticleGoogle Scholar
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