Nanoparticles of Lovastatin: Design, Optimization and in vivo Evaluation.

INTRODUCTION: The aim of the study was to optimize the processing factors of precipitation-ultrasonication technique to prepare nano-sized particles of Lovastatin (LA) for enhancing its solubility, dissolution rate and in vivo bioavailability. METHODS: LA nanoparticles (LANs) were prepared using precipitation-ultrasonication technique under different processing factors. LANs were characterized in terms of particle size, zeta potential and in vitro release. Stability studies at 4°C, 25°C and 40°C were conducted for optimum formulation. In addition, the in vivo bioavailability of the optimum formula was studied in comparison to a marketed product in white master rats. RESULTS: The optimized LAN formula (LAN15) had particle size (190±15), polydispersity index (0.626±0.11) and a zeta potential (-25±1.9 mV). The dissolution study of the nanosuspensions showed significant enhancement compared with pure drug. After 50 min, only 20.12±1.85% of LA was dissolved while 99.1±1.09% of LA was released from LAN15. Stability studies verified that nanosuspensions at 4°C and 25°C showed higher stability with no particle growth compared to the samples studied at 40°C. In vivo studies conducted in rats verified that there was 1.45-fold enhancement of Cmax of LAN15 as compared to marketed tablets. CONCLUSION: Nanoparticle prepared by ultrasonication-assisted precipitation method is a promising formula for enhancing the solubility and hence the bioavailability of Lovastatin.

Method development for quantitative determination of seven statins including four active metabolites by means of high-resolution tandem mass spectrometry applicable for adherence testing and therapeutic drug monitoring.

Background Statins are used to treat and prevent cardiovascular diseases (CVDs) by reducing the total serum cholesterol concentration. Unfortunately, dose-related side effects and sub-optimal response, attributed to non-adherence amongst others, were described. Therefore, a fast and sensitive liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) method for adherence testing and therapeutic drug monitoring of all currently marketed statins and their active metabolites in human blood plasma should be developed, validated and tested for applicability. Methods Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, as well as ortho- and para-hydroxy-atorvastatin, lovastatin hydroxy acid and simvastatin hydroxy acid were included and several internal standards (IS) tested. Validation was performed according to the guideline of the European Medicines Agency including selectivity, carry-over, accuracy, precision, matrix effects, dilution integrity and analyte stability. Finally, applicability was tested using 14 patient samples submitted for regular toxicological analysis. Results Due to an analytical interference of atorvastatin-d5, diazepam-d5 and pentobarbital-d5 were chosen as IS for positive and negative ionization mode, respectively. All statins and metabolites fulfilled the validation acceptance criteria except for fluvastatin, which could not be quantified reliably and reproducibly, most probably due to instability. Analyses of human plasma samples revealed concentrations of statins and metabolites below the reference plasma concentrations in the case of eight patients. However, nothing was known concerning patients' adherence and time between intake and sampling. Conclusions An LC-HRMS/MS method for identification and quantification of atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and four active metabolites was successfully developed and applicability demonstrated.

Synergistic effect of Soluplus and hyaluronic acid on the supersaturation maintenance of lovastatin: The facilitated in vitro-in vivo performance and improved physical stability.

The objective of present study was to explore whether polysaccharide could be employed as potential crystal growth inhibitor and provides synergistic effect on the supersaturation maintaining of lovastatin (LOV) in combination of nucleation inhibitor. Soluplus (SOL) and hyaluronic acid (HA) were selected as the most effective nucleation and crystal growth inhibitor respectively. The interaction between SOL and HA was elucidated via characterizing the particle size, zeta potential, surface hydrophobicity, solvent relaxation time (T2) and FT-IR. The supersaturated drug solution was spray dried into amorphous solid dispersion, then, the in vitro release, moisture uptake and physical stability were investigated. The synergistic effect between SOL and HA was dependent on drug concentration, drug/carrier and SOL/HA weight ratio, which facilitated both in vitro and in vivo performance. It was disclosed that HA could insert into SOL structure providing both electrostatic and steric stabilization. In conclusion, the combination of nucleation and crystal growth inhibitors is a promising approach for supersaturated drug delivery system.

Analysis of a Skeletal Muscle Injury and Drug Interactions in Lovastatin- and Fenofibrate-Coadministered Dogs.

Because dogs are widely used in drug development as nonrodent experimental animals, using a dog model for drug-induced adverse reactions is considered to be relevant for an evaluation and investigation of a mechanism and a biomarker of clinical drug-induced adverse reactions. Skeletal muscle injury occurs by various drugs, including statins and fibrates, during drug development. However, there is almost no report of a dog model for drug-induced skeletal muscle injury. In the present study, we induced skeletal muscle injury in dogs by oral coadministration of lovastatin (LV) and fenofibrate (FF) for 4 weeks. Increases in plasma levels of creatine phosphokinase, myoglobin, miR-1, and miR-133a and degeneration/necrosis of myofibers in skeletal muscles but not in the heart were observed in LV- and FF-coadministered dogs. Plasma levels of lovastatin lactone and lovastatin acid were higher in LV- and FF-coadministered dogs than LV-administered dogs. Taken together, FF coadministration is considered to affect LV metabolism and result in skeletal muscle injury.

Effect of polymorphisms in CYP3A4, PPARA, NR1I2, NFKB1, ABCG2 and SLCO1B1 on the pharmacokinetics of lovastatin in healthy Chinese volunteers.

AIM: This study examined whether gene polymorphisms (CYP3A4, ABCG2, SLCO1B1, NR1I2, PPARA and NFKB1) influenced the pharmacokinetics of lovastatin in Chinese healthy subjects. PATIENTS & METHOD: Plasma concentrations of lovastatin and lovastatin acid were quantified using LC/MS/MS. RESULTS: PPARA c.208+3819 G allele carriers had approximately twofold higher AUC0-∞ and Cmax of lovastatin than wild-type (PPARA c.208+3819 AA) subjects. After adjustment for the PPARA variants, subjects with the SLCO1B1 521TT genotype had approximately 50% lower AUC0-∞ of lovastatin acid than those with 521TC/CC genotypes, while the AUC0-∞ of lovastatin lactone in NFKB1-94 DD wild-type carriers was twofold higher than in mutant homozygotes carriers. CONCLUSION: Gene polymorphisms of PPARA, SLCO1B1 and NFKB1 affected the pharmacokinetics of lovastatin.

Simultaneous determination of lovastatin and its metabolite lovastatin acid in rat plasma using UPLC-MS/MS with positive/negative ion-switching electrospray ionization: Application to a pharmacokinetic study of lovastatin nanosuspension.

Lovastatin (LOV) is an antihyperlipidemic agent which exhibits low bioavailability due to its poor solubility. Therefore, a nanosuspension (NS) was developed as an efficient strategy to improve its oral bioavailability. To evaluate the pharmacokinetics of LOV-NS, a novel, sensitive, and rapid UPLC-MS/MS method was developed and validated for the simultaneous determination of LOV and its metabolite lovastatin acid (LOVA) in rat plasma. Simvastatin (IS) was chosen as the internal standard, and a liquid-liquid extraction method was used to isolate LOV and LOVA from biological matrices. The analytes were analyzed on an Acquity UPLC BEH C18 column, and a gradient program was applied at a flow rate of 0.2mL/min. Then, a tandem quadrupole mass spectrometer coupled with a positive/negative ion-switching electrospray ionization interface was employed to detect the analytes. Quantitation of the analytes was performed in the multiple reaction monitoring mode to monitor the transitions of m/z 427.1→325.0 for LOV and m/z 441.1→325.0 for IS in the positive ion mode and m/z 421.0→101.0 for LOVA in the negative ion mode, respectively. The method was validated over the concentration range 0.25-500ng/mL (r(2)≥0.99) for both LOV and LOVA. The intra-day and inter-day precision (RSD%) of LOV and LOVA were less than 12.87% and the accuracy (RE%) was less than 5.22%. The average extraction recoveries were 90.1% and 91.9% for LOV and LOVA, and the matrix effects were found to be between 85% and 115%. The stability study showed that both analytes were stable during the experiment. Finally, this method has been successfully applied to a pharmacokinetic study in rats following a single oral dose of 10mg/kg LOV-NS.

Development of novel mesoporous nanomatrix-supported lipid bilayers for oral sustained delivery of the water-insoluble drug, lovastatin.

The purpose of this study was to investigate the effect of a core/shell structured nanocomposite, mesoporous nanomatrix-supported lipid bilayer (MN-SLB), as an oral drug nanocarrier, on the dissolution behavior and in vivo absorption of a water-insoluble drug, lovastatin (LOV). The formulation strategy was based on the use of drug-loaded mesoporous silica as the core for the fusion of liposomes. Field emission scanning electron microscopy (FESEM), cryogenic transmission electron microscopy (Cryo-TEM) and nitrogen adsorption were used to systematically characterize the drug carrier and drug-loaded MN-SLB formulation, confirming the successful inclusion of LOV into the nano-pores of MN-SLB. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) confirmed that the incorporated drug in the carrier was in an amorphous state. An in vitro dissolution study showed that LOV-loaded MN-SLB exhibited a sustained drug release behavior. Compared with the LOV-loaded mesoporous silica particles, LOV-loaded MN-SLB markedly suppressed the burst release. Furthermore, the pharmacokinetics and relative bioavailability of the LOV-loaded MN-SLB formulation was studied in beagle dogs after oral administration and using a commercially available immediate release formulation (Sandoz Lovastatin®) as a reference. It was found that the relative bioavailability of LOV and LOV ß-hydroxy acid (LOVA) for the LOV-loaded MN-SLB formulation was 207.2% and 192.1%, respectively. In addition, MN-SLB exhibited negligible toxicity against Caco-2 and HT-29 cells in cytotoxicity assays. The results of this study indicate that the MN-SLB nanocomposite is a promising candidate as a novel oral drug delivery nanovehicle for controlling the dissolution rate and improving the oral absorption of water-insoluble drugs.

Rod shaped nanocrystals exhibit superior in vitro dissolution and in vivo bioavailability over spherical like nanocrystals: a case study of lovastatin.

The objective of this study was to compare the in vitro and in vivo performance of rod shaped and spherical like nanocrystals for oral administration. Lovastatin (LOV) was chosen as the model drug and LOV rod shaped nanocrystals (LOV-RNs) and spherical like nanocrystals (LOV-SNs) were prepared by sonoprecipitation and bead milling, respectively. The dry powders obtained following freeze-drying were characterized by hydrodynamic diameter, polydispersity index, zeta potential, transmission electron microscope, scanning electron microscope, atomic force microscope, differential scanning calorimetry, Fourier transform infrared spectroscopy, and in vitro dissolution test. The pharmacokinetic study was performed in beagle dogs. The results obtained showed that LOV-RNs and LOV-SNs had similar hydrodynamic diameters (500.6±21.0 nm versus 503.2±20.4 nm), and the same crystalline state. The dissolution test showed that LOV-RNs had a higher dissolution rate than LOV-SNs. The AUC(0-24h) values of LOV-RNs and LOV-SNs were higher than Junning® for both LOV (p<0.05 for LOV-RNs, and p>0.05 for LOV-SNs) and lovastatin acid (p>0.05). More importantly, the oral bioavailability of LOV-RNs was higher than LOV-SNs (p>0.05). The findings of this study show that the crystal shape has a significant effect on oral bioavailability.

Liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of simvastatin, lovastatin, atorvastatin, and their major metabolites in human plasma.

Millions of individuals are treated with a variety of statins that are metabolized to a variety of active metabolites. A single assay capable of simultaneously quantifying commonly used statins and their major metabolites has not been previously reported. Herein we describe the development and validation of a novel and robust liquid chromatography-tandem mass spectrometry assay for simultaneously quantifying simvastatin, lovastatin, atorvastatin, and their metabolites, simvastatin acid, lovastatin acid, para-hydroxy atorvastatin, and ortho-hydroxy atorvastatin in human plasma. Plasma samples were processed with a simple protein precipitation technique using acetonitrile, followed by chromatographic separation using an Agilent Zorbax Extend C18 column. A 12.0min linear gradient elution was used at a flow rate of 400µL/min with a mobile phase of water and methanol, both modified with 2mM ammonium formate and 0.2% formic acid. The analytes and internal standard, hesperetin, were detected using the selected reaction monitoring mode on a TSQ Quantum Discovery mass spectrometer with positive electrospray ionization. The assay exhibited a linear range of 1-1000nM for simvastatin acid and lovastatin acid, and a linear range of 0.1-100nM for the other analytes in human plasma. The accuracy and the within- and between-day precisions of the assay were within acceptable ranges, and the method was successfully utilized to quantify the statins and their metabolites in human plasma samples collected from an ongoing pharmacokinetic study.

Impact of CYP2D6 polymorphisms on the pharmacokinetics of lovastatin in Chinese subjects.

PURPOSE: Although CYP3A4/5 enzymes play the predominant role in the metabolism of simvastatin and lovastatin, polymorphisms in CYP2D6 were reported to be associated with the cholesterol-lowering effect and/or tolerability of simvastatin. This study was performed to examine whether common CYP2D6 polymorphisms affect the pharmacokinetics of lovastatin, which is taken as the inactive prodrug lovastatin lactone and converted to active lovastatin acid. METHODS: A single-dose pharmacokinetic study was performed with lovastatin in 23 Chinese healthy male subjects. Plasma concentrations of lovastatin lactone and acid were determined by an LC-MS-MS method in samples collected over 24 h after single oral doses of 40-mg lovastatin. RESULTS: Compared with the CYP2D6 wt/wt group, the area under the plasma concentration-time curve (AUC(0-∞)) values for lovastatin lactone increased (P < 0.01) by average ratios (95% CI) of 1.57 (1.01-2.45), 2.11 (1.36-3.29), 2.52 (1.47-4.32), and 5.84 (3.16-10.78) in the wt/*10, *10/*10, *10/*5, and *5/*5 groups, and the values of lovastatin lactone plasma clearance (CL/F) were reduced on average (95% CI) by 40.4% (10.2-60.5%), 53.1% (29.3-68.9%), 63.8% (40.2-78.1%) and 84.2% (72.1-91.1%) in these genotype groups respectively. The pharmacokinetics of lovastatin acid did not differ among the genotype groups. CONCLUSION: This study demonstrates that CYP2D6 polymorphisms appeared to influence the disposition of lovastatin lactone in these subjects.

Simultaneous determination of simvastatin, lovastatin and niacin in human plasma by LC-MS/MS and its application to a human pharmacokinetic study.

A simple, sensitive and specific LC-MS/MS method for simultaneous determination of simvastatin (SV), lovastatin (LV) and niacin (NIA) in human plasma was developed and validated on API-4000 in positive ion mode. Nevirapine was used as internal standard (IS). The assay procedure involved a simple one-step liquid-liquid extraction of SV, LV, NIA and the IS from plasma into ethyl acetate. Separation of SV, LV, NIA and the IS was achieved on an Alltima C18 column with a mobile phase consisting of 5 mm ammonium acetate (pH 4.5) and acetonitrile (20:80, v/v) pumped at a flow rate of 1 mL/min. Nominal retention times obtained for SV, LV, NIA and IS were 2.12, 1.67, 0.50 and 0.65 min, respectively. The lower limits of quantification (LLOQ) for SV, LV and NIA were 0.10, 0.10 and 25.2 ng/mL, respectively. The response function was established for the range of concentrations 0.10-101 ng/mL for SV and LV, and 25.2-5020 ng/mL for NIA, with a coefficient of correlation of >0.99 for all the compounds. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. The proposed method was found to be applicable to clinical studies.

Development of biodegradable porous starch foam for improving oral delivery of poorly water soluble drugs.

A biodegradable porous starch foam (BPSF) was developed for the first time as a carrier in order to improve the dissolution and enhance the oral bioavailability of lovastatin - defined as a model poorly water soluble BCS type II drug. In this paper, BPSF was prepared by the solvent exchange method and characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis in order to perform the morphological and structural characterization of BPSF. Lovastatin was loaded by immersion/solvent evaporation into the BPSF which provided a stable hydrophilic matrix with a nano-porous structure. The solid state properties of the loaded BPSF samples were characterized by SEM, Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). In vitro and in vivo drug release studies showed that when BPSF was used as a carrier it allowed immediate release of lovastatin and enhanced the dissolution rate in comparison with crystalline lovastatin and commercial capsules. These results provide important information about the mechanism of drug adsorption and release from BPSF as a carrier. Accordingly, BPSF has a promising future as a device for the oral delivery of poorly water soluble drugs.

Novel extended-release formulation of lovastatin by one-step melt granulation: in vitro and in vivo evaluation.

The objective of this study was to apply a one-step melt granulation method to develop an extended-release formulation of lovastatin (LOV-ER). We prepared a formulation using PEG 6000 as binder agent in a laboratory scale high-shear mixer. In vitro dissolution studies showed that the release of the drug from the new formulation followed a zero-order kinetic with no differences in the release profile with either the pH media or the agitation rate. The pharmacokinetic of lovastatin and its metabolite lovastatin acid was evaluated after the administration of the new formulation to Beagle dogs in fasted conditions and after a high-fat meal, and compared to the marketed formulation Altoprev®. After the administration of LOV-ER, extended plasma profiles of lovastatin and its active metabolite were achieved in both fasted conditions and after the high-fat meal. Plasma levels of lovastatin and lovastatin acid were always higher when the LOV-ER formulation was administered with the high-fat meal. A high variability in plasma levels and pharmacokinetic parameters was obtained, being this variability higher when the formulation was administered under fasting conditions. Our results suggest that there is an increase in lovastatin bioavailability when the formulation is administered after the high-fat meal. When we compare LOV-ER and Altoprev®, both administered after the high-fat meal, we found significant differences (p<0.05) in C(max) of lovastatin and in AUC(0-∞) and MRT of lovastatin acid. No differences were detected between both formulations in fasting conditions. In this regard, the high-fat meal seems to increase the absorption extent of lovastatin from LOV-ER formulation and to delay the absorption rate of the drug from Altoprev®. In conclusion, we developed a lovastatin formulation that provided extended plasma levels that confirm that one-step melt granulation in high-shear mixer could be an easy and cost-effective technique for extended-release formulation development.

A simple and sensitive HPLC-UV method for quantitation of lovastatin in human plasma: application to a bioequivalence study.

An available, simple, sensitive, and rapid method has been developed for determination of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, lovastatin in human plasma. The analytical procedure involves a one-step liquid-liquid extraction method using atorvastatin as internal standard. Chromatographic separation was carried out on a reversed phase C(18) column using a mixture of 0.05 M phosphate buffer (pH 7) and acetonitrile (44.5 : 55.5, v/v) as mobile phase with UV detection set at 238 nm. The total run time of analysis was 6 min with the retention time of lovastatin being 4.3 min. A complete set of analytical method validation tests were carried out on the method. Accordingly, the method was linear in the wide range of 1-100 ng/ml. The limit of detection (LOD) and limit of quantification (LOQ) for lovastatin were 0.5 and 1 ng/ml, respectively. The method was shown to be precise with average within-run and between-run variations of 10.45+/-6.88 and 8.68+/-5.13%, respectively. The average within-run and between-run accuracy of the method throughout its linear range was 113.33+/-3.98 and 105.72+/-5.07%, respectively. The mean relative recovery of lovastatin from human plasma by the developed method was 88.61+/-7.00%. The applicability of the method in real pharmacokinetic situations was evaluated successfully during a bioequivalence study in 14 fasting healthy male volunteers.

[Determination of lovastatin and its active metabolites in human plasma with high performance liquid chromatography-tandem mass spectrometry].

OBJECTIVE: To develop a sensitive LC-MS/MS method for analyzing lovastatin and its active metabolites lovastatin acid in human plasma. METHODS: Lovastatin and lovastatin acid were extracted from plasma by ethyl ether -dichloromethane (V/V, 1:1), with simvastatin serving as an internal standard. The analytes went through the column of Phenomenex Gemini C18 (50 x 3 mm, 3 microm) with mobile phase acetonitrile-water (85:15), and was analyzed by API3000 after protonated with ESI mode. The ion pairs being detected were 427.4-->325.4, 445.4-->343.4 and 436.4-->325.4, respectively. RESULTS: The established method was able to determine lovastatin in human plasma over the range of 0.03125-64 microg/L, with recovery rates ranging from 96% to 102%. The intra and inter day variances were below 9.3%. CONCLUSION: The LC-MS/MS method for analyzing lovastatin is validated and is suitable for clinical pharmacokinetic studies.

Pharmacokinetics and bioequivalence study of two tablet formulations of lovastatin in healthy volunteers.

Lovastatin is a lipid-lowering agent indicated for primary hypercholesterolemia. This study has assessed single-dosing pharmacokinetics of lovastatin and of its main metabolite, lovastatin beta-hydroxyacid, and has compared the pharmacokinetics of two formulations of lovastatin, a test lovastatin generic (LVSG), and a reference (mevinacor 40 MSD) preparation. The pharmacokinetics and bioequivalence of the two formulations of lovastatin were evaluated by a two-way cross-over randomized double blinded study, in 36 healthy volunteers after a single oral dose of 2 x 40 mg per subject. On plasma samples, collected at given intervals of time (0-24h), lovastatin and its main active metabolite were assayed by high pressure liquid chromatography with positive turbo ion spray ionization tandem mass spectrometry detection. The pharmacokinetic parameters, area under the curve total (AUC(t)) and to infinity (AUC(inf)), peak plasma concentration (C(max)), time to attain peak (t(max)), and elimination half-life (t(1/2)) were determined and analyzed statistically. Only minor differences in the pharmacokinetics of lovastatin and lovastatin hydroxyacid between LVSG and mevinacor were found. Analysis of variance (ANOVA) did not show any significant difference between the two formulations, and 90% confidence intervals fell within the acceptable range for bioequivalence. The tolerability profile was good and comparable for the two formulations of lovastatin. Our study, which was performed with the largest number of subjects compared with those published in literature, indicates the bioequivalence of LVSG and mevinacor tablets. The high inter-subject variability of parameters investigated indicate the need of appropriate sample size in pharmacokinetics studies with lovastatin.

Determination of lovastatin in human plasma by ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry and its application in a pharmacokinetic study.

A selective, rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the quantitative determination of lovastatin in human plasma and its application in a pharmacokinetic study. With mycophenolate mofetil as internal standard, sample pretreatment involved a one-step extraction with tert-butyl methyl ether of 0.2 ml plasma. The analysis was carried out on an ACQUITY UPLCTM BEH C18 column (50 mm x 2.1 mm, i.d., 1.7 microm) with flow rate of 0.35 ml/min. The mobile phase was 20% water and 80% acetonitrile (v/v). The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI). Linear calibration curves were obtained in the concentration range of 0.08-24.50 ng/ml, with a lower limit of quantification of 0.08 ng/ml. The intra- and inter-day precision (RSD) values were below 15% and accuracy (RE) was -7.6 to 9.3% at all QC levels. The method was applicable to clinical pharmacokinetic study of lovastatin in healthy volunteers following oral administration.

Determination of lovastatin in human plasma by ultra-performance liquid chromatography/electrospray ionization tandem mass spectrometry.

A fast and sensitive ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of lovastatin in human plasma. With simvastatin as internal standard, sample pretreatment involved one-step extraction with n-hexane-methylene dichloride-isopropanol (20:10:1, v/v/v) of 0.5 mL plasma. Chromatographic separation was carried out on an Acquity UPLC BEH C(18) column with mobile phase consisting of acetonitrile-water (containing 5 mmol/L ammonium acetate; 85:15, v/v) at a flow-rate of 0.35 mL/min. The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) via electrospray ionization source with positive mode. The analysis time was shorter than 1.7 min per sample. The standard curve was linear (r2>or=0.99) over the concentration range 0.025-50.0 ng/mL with a lower limit of quantification of 0.025 ng/mL. The intra- and inter-day precision values were below 11% and the accuracy (relative error) was within 6.0% at three quality control levels. This is the first method of MS with MRM coupled to UPLC for the determination of lovastatin, which showed great advantages of high sensitivity, selectivity and high sample throughput. It was fully validated and successfully applied to the pharmacokinetic study of lovastatin tablets in healthy Chinese male volunteers after oral administration.

P-glycoprotein has differential effects on the disposition of statin acid and lactone forms in mdr1a/b knockout and wild-type mice.

In the present study we examined the disposition of atorvastatin, lovastatin, and simvastatin in acid and lactone forms and pravastatin in acid form in multidrug-resistant gene (mdr1a/b) knockout (KO), and wild-type (WT) mice. Each statin was administered s.c. to mdr1a/b KO and WT mice at 3.0 mg/kg (n > or = 3 mice/time point). Blood, brain, and liver samples were harvested at 0, 0.5, 1.5, and 3 h postdose. Plasma and tissue concentrations of the acid and lactone (only the acid form was determined for pravastatin) were determined using a liquid chromatography-mass spectrometry method. Both lactone and acid were observed in plasma when lactones were administered, but only acids were detected when the acid forms were administered. The plasma and liver concentrations of acid or lactone were similar between the KO and WT mice. Two- to 23-fold higher concentrations were observed in liver than in plasma, suggesting potential uptake transporters involved. A significantly higher (p < 0.05) brain penetration in the KO compared with the WT mice was observed for lovastatin acid (but the brain/plasma ratio was low for both KO and WT mice) and lactone and simvastatin lactone but not for atorvastatin or pravastatin. The present results suggest that mouse P-glycoprotein does not affect the lactone-acid interconversion or liver-plasma distribution. Furthermore, P-glycoprotein plays a limited role in restricting the brain penetration of the acid forms of atorvastatin, pravastatin, simvastatin, lovastatin, and atorvastatin lactone but may limit the brain availability of the lactone forms of simvastatin and lovastatin.

The comparative bioavailability of an extended-release niacin and lovastatin fixed dose combination tablet versus extended-release niacin tablet, lovastatin tablet and a combination of extended-release niacin tablet and lovastatin tablet.

Lovastatin and extended-release (ER) niacin in a fixed dose combination (Advicor) is approved for the treatment of dyslipidemia. Since both drugs are extensively metabolized, this study investigated the bioavailability and pharmacokinetics of their co-administration following single-dose administration. In a 4-way crossover study 40 subjects received: two 1000/20 Advicor tablets (ADV), two 1000 mg niacin ER tablets (NSP), two 20mg lovastatin tablets (Mevacor; MEV), and two niacin ER 1000 mg tablets with two lovastatin 20mg tablets (NSP+MEV). Plasma was assayed for niacin, nicotinuric acid (NUA), lovastatin, lovastatin acid and HMGCoA reductase inhibition. Urine was assayed for niacin and its metabolites, NUA, N-methylnicotinamide and N-methyl-2pyridone-5-carboxamide. Least square mean ratios and 90% confidence intervals for C(max) and AUC((0-t)) were determined for NSP+MEV versus MEV or NSP, ADV versus MEV or NSP, and ADV versus NSP+MEV. Co-administration of niacin and lovastatin did not significantly influence C(max) and AUC((0-t)) of lovastatin, niacin, NUA and total urinary recovery of niacin and metabolites. A 22 to 25% decrease in lovastatin acid C(max) was observed while lovastatin acid AUC((0-t)) was not affected. The HMGCoA reductase inhibition C(max) and AUC((0-t)) were not affected indicating that the difference in lovastatin acid C(max) was not clinically relevant.