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Contemporary treatment of vitiligo remains a great challenge to practitioners. The vast majority of currently conducted clinical trials of modern therapeutic methods are focused on systemic medications, while there is only a very limited number of reports on new topical treatment in vitiligo. With their pleiotropic activities statins turned out to be efficient in the treatment of various autoimmune/autoinflammatory disorders. The randomized, double-blind placebo-controlled study of topical administration of the active forms of simvastatin and atorvastatin has been designed to evaluate their efficacy in patients with vitiligo. The study was registered in clinicaltrials.gov (registration number NCT03247400, date of registration: 11th August 2017). A total of 24 patients with the active form of non-segmental vitiligo were enrolled in the study. The change of absolute area of skin lesions, body surface area and vitiligo area scoring index were evaluated throughout the 12 week application of ointments containing simvastatin and atorvastatin. Measurements were performed with planimetry and processed using digital software. Use of active forms of simvastatin and atorvastatin did not result in a significant repigmentation of the skin lesions throughout the study period. Within the limbs treated with topical simvastatin, inhibition of disease progression was significantly more frequent than in the case of placebo (p = 0.004), while the difference was not statistically significant for atorvastatin (p = 0.082). Further studies of topical simvastatin in vitiligo patients should be considered., (© 2024. The Author(s).)

Statins are effective drugs in reducing cardiovascular morbidity and mortality by inhibiting cholesterol synthesis. These effects are primarily beneficial for the patient's vascular system. A significant number of statin users suffer from muscle complaints probably due to mitochondrial dysfunction, a mechanism that has recently been elucidated. This has raised our interest in exploring the effects of statins on cardiac muscle cells in an era where the elderly and patients with poorer functioning hearts and less metabolic spare capacity start dominating our patient population. Here, we investigated the effects of statins on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-derived CMs). hiPSC-derived CMs were exposed to simvastatin, atorvastatin, rosuvastatin, and cerivastatin at increasing concentrations. Metabolic assays and fluorescent microscopy were employed to evaluate cellular viability, metabolic capacity, respiration, intracellular acidity, and mitochondrial membrane potential and morphology. Over a concentration range of 0.3-100 µM, simvastatin lactone and atorvastatin acid showed a significant reduction in cellular viability by 42-64%. Simvastatin lactone was the most potent inhibitor of basal and maximal respiration by 56% and 73%, respectively, whereas simvastatin acid and cerivastatin acid only reduced maximal respiration by 50% and 42%, respectively. Simvastatin acid and lactone and atorvastatin acid significantly decreased mitochondrial membrane potential by 20%, 6% and 3%, respectively. The more hydrophilic atorvastatin acid did not seem to affect cardiomyocyte metabolism. This calls for further research on the translatability to the clinical setting, in which a more conscientious approach to statin prescribing might be considered, especially regarding the current shift in population toward older patients with poor cardiac function., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

A highly sensitive LC-MS/MS method for simultaneous detection of both simvastatin (SV) and simvastatin acid (SVA) in beagle plasma was developed and successfully applied to an absolute bioavailability study. Lovastatin (LV) was used as internal standard (IS). The analysis was performed using electrospray ionization and selective reaction monitoring in positive mode at m/z 441.0 → 325.0 for SV, 459.0 → 343.0 for SVA and 427.0 → 325.0 for the IS, respectively. The assay procedure involved a simple liquid-liquid extraction of SV, SVA and LV from beagle plasma into methyl tert-butyl ether. Separation of SV, SVA and the IS was achieved on a Shim-pack VP-ODS column (150 × 2.0 mm, 5 μm) with a binary gradient solvent system of 0.1% formic acid in water and methanol (15:85, v/v) as the mobile phase. The method was validated over the range of 0.25-500 ng/ml for SV (r 2  ≥ 0.9923) and 0.24-481.23 ng/ml for SVA (r 2  ≥ 0.9987). The results of method validation for accuracy, precision, extraction recovery, matrix effect and stability were within the acceptance criteria. The values of absolute bioavailability of SV and SVA in beagles were 2.97 and 25.40%, respectively. It is the first study developed for the measurement of absolute bioavailability of SV and SVA acid in beagles., (© 2021 John Wiley & Sons, Ltd.)

Simvastatin is known as a pro-drug, which could be hydrolyzed by esterases to its active form, simvastatin acid. Although pharmacokinetics of simvastatin and simvastatin acid have been widely studied, hydrolysis of simvastatin to simvastatin acid during blood sampling and plasma preparation has been overlooked in the previous studies, leading to underestimation of simvastatin concentration and overestimation of simvastatin acid concentration in plasma. Since both efficacy and adverse drug reaction of simvastatin are highly dependent on simvastatin and simvastatin acid concentrations in vivo, accurate assessment of the two compounds are critical in their pharmacokinetic and pharmacodynamic studies. The current study was proposed aiming to investigate the esterase mediated hydrolysis of simvastatin in human and rat blood and its impact on the pharmacokinetic study of simvastatin and simvastatin acid. Using various esterase inhibitors including potassium florid (KF), bis(4-nitrophenyl) phosphate (BNPP), and ethylenediaminetetraacetic acid (EDTA), carboxylesterase was found to be the major esterase that hydrolyzed simvastatin in rat blood, while carboxylesterase and paraoxonase were the major esterases mediating the hydrolysis of simvastatin in human blood. Further studies using human recombinant enzymes identified simvastatin as substrates of PON1, CES1b, PON3 and CES1c with Cl int of 8.75, 5.77, 3.93, and 2.45 μL/min/mg protein. Therefore, inhibition treatments with 20 mM BNPP and 50 mM KF/ 10 mM EDTA were developed to efficiently prevent the hydrolysis of simvastatin during blood sampling and plasma preparation in rat/human. The subsequent pharmacokinetics of orally administered simvastatin at 8.66 mg/kg in rats found that the C max and AUC 0- ∞ of simvastatin in absence of such esterase inhibitors in the blood sampling process were only 17.04 ± 6.60% and 15.30 ± 6.76% of those in presence of the inhibitors, whereas the C max and AUC 0- ∞ of simvastatin acid were 1.60 ± 0.30 and 1.80 ± 0.22 times of that obtained in presence of the inhibitors. Nevertheless, T 1/2 of simvastatin and simvastatin acid remained the same regardless of the blood sampling method. Our current study for the first time demonstrated the importance for assessment of simvastatin stability during the blood sampling and plasma preparation process, which may be applicable to therapeutic drug monitoring of not only simvastatin but also other pro-drugs/compounds sharing similar metabolic properties., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Statins, HMG-CoA reductase inhibitors, are considered the first line treatment of hyperlipidemia to reduce the risk of atherosclerotic cardiovascular diseases. The prevalence of hyperlipidemia and the risk of atherosclerotic cardiovascular diseases are higher in obese patients. Published methods for the quantification of statins and their active metabolites did not test for matrix effect of or validate the method in hyperlipidemic plasma. A sensitive, specific, accurate, and reliable LC-MS/MS method for the simultaneous quantification of simvastatin (SMV), active metabolite of simvastatin acid (SMV-A), atorvastatin (ATV), active metabolites of 2-hydroxy atorvastatin (2-OH-ATV), 4-hydroxy atorvastatin (4-OH-ATV), and rosuvastatin (RSV) was developed and validated in plasma with low (52-103 mg/dl, <300 mg/dl) and high (352-403 mg/dl, >300 mg/dl) levels of triglyceride. The column used in this method was ACQUITY UPLC BEH C18 column (2.1 × 100 mm I.D., 1.7 μm). A gradient elution of mobile phase A (10 mM ammonium formate and 0.04% formic acid in water) and mobile phase B (acetonitrile) was used with a flow rate of 0.4 ml/min and run time of 5 min. The transitions of m/z 436.3 → 285.2 for SMV, m/z 437.2 → 303.2 for SMV-A, m/z 559.2 → 440.3 for ATV, m/z 575.4 → 440.3 for 2-OH-ATV and 4-OH-ATV, m/z 482.3 → 258.1 for RSV, and m/z 412.3 → 224.2 for fluvastatin (internal standard, IS) were determined by Selected Reaction Monitoring (SRM) method to detect transitions ions in the positive ion mode. The assay has a linear range of 0.25 (LLOQ) -100 ng/ml for all six analytes. Accuracy (87-114%), precision (3-13%), matrix effect (92-110%), and extraction recovery (88-100%) of the assay were within the 15% acceptable limit of FDA Guidelines in variations for plasma with both low and high triglyceride levels. The method was used successfully for the quantification of SMV, ATV, RSV, and their active metabolites in human plasma samples collected for an ongoing clinical pharmacokinetic and pharmacodynamic study on patients prior to and post gastric bypass surgery (GBS)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Vitiligo is a chronic skin disorder presenting with depigmentation, the pathogenesis of which is complex but the autoimmune theory is now preferred. Multiple immunologic processes, including stimulation of the T-helper (Th)1 response, formation of autoreactive melanocyte-specific CD8 + T lymphocytes, a decrease in the blood concentration of T regulatory (Treg) cells, and an increase in interleukin (IL)-17 and interferon (IFN) concentration, have been shown to contribute to vitiligo progression and maintenance. The aim of this study is to evaluate the influence of simvastatin and atorvastatin on vitiligous lesions in patients with nonsegmental vitiligo (NSV). According to available data, statins act through several immunological pathways, potentially reversing undesirable phenomena underlying autoimmune vitiligo pathogenesis., Methods/design: A study has been designed as a single-center, randomized, double-blind, placebo-controlled pilot study with the enrollment of at least 24 active NSV patients presenting with vitiligous lesions on both upper and lower limbs. The clinical effects of ointments containing 1% simvastatin-acid sodium salt or 1% atorvastatin calcium salt applied on a preselected limb will be assessed in comparison with vehicle ointment applied on the opposite limb. All study participants will undergo clinical evaluation using body surface area (BSA) and Vitiligo Area Scoring Index (VASI) scales at baseline and at weeks 4, 8, and 12 time points. A precise assessment of skin lesions will be performed using photographic documentation obtained during each study visit and processed with NIS-Elements software., Discussion: Currently available vitiligo topical therapeutic approaches including calcineurin inhibitors and corticosteroids remain poorly effective and are associated with either relatively high cost or potentially dangerous adverse effects. The clinical application of orally administrated statins, widely used as systemic cholesterol-lowering agents, in vitiligous patients has only been tested in two clinical trials; however, data on their potential usefulness is scarce. Moreover, due to a high risk of clinically significant toxicity, topical administration was recommended by researchers. This study is the first to evaluate safety and efficacy of the topical use of statins in patients presenting with NSV., Trial Registration: Clinicaltrials.gov, NCT03247400 . Registered on 05 August 2017.

Purpose: We evaluated potential drug-drug interactions between cilostazol and simvastatin, both CYP3A substrates, in healthy subjects., Methods: An open-label, two-period, fixed-sequence clinical study was conducted. Seventeen subjects were given a single oral dose of simvastatin 40 mg on day 1 and multiple oral doses of cilostazol 100 mg twice daily on days 2 to 5 followed by a single dose of cilostazol and simvastatin on day 6. Plasma concentrations of simvastatin and its active metabolite, simvastatin acid, were measured using liquid chromatography-tandem mass spectrometry for pharmacokinetic assessment. Moreover, serum lipid profiles under fasting conditions were determined., Results: The geometric mean ratios of the area under the plasma concentration-time curve from time zero to time infinity of simvastatin combined with cilostazol to that of simvastatin alone were 1.64 (90% CI, 1.38-1.95) for simvastatin and 1.31 (1.04-1.66) for simvastatin acid. In addition, coadministration with cilostazol significantly increased the maximum concentration of simvastatin and simvastatin acid, up to 1.8-fold and 1.6-fold, respectively. However, the effects of a single dose of simvastatin on serum lipid profiles were not affected notably when simvastatin was coadministered with cilostazol., Conclusions: Multiple doses of cilostazol increased the systemic exposure of simvastatin and simvastatin acid following a single dose of simvastatin.

A previous attempt to accurately quantify the increased simvastatin acid exposure due to drug-drug interaction (DDI) with coadministered telithromycin, using a mechanistic static model, substantially underpredicted the magnitude of the area under the plasma concentration-time curve ratio (AUCR) based on reversible inhibition of CYP3A4 and organic anion transporting polypeptide 1B1 (OATP1B1). To reconcile this disconnect between predicted and clinically observed AUCR, telithromycin was evaluated as a time-dependent inhibitor of CYP3A4 in vitro, as well as an inhibitor of OATP1B1. Telithromycin inhibited OATP1B1-mediated [ 3 H]-estradiol 17 β -d-glucuronide (0.02 µ M) transport with a mean IC 50 of 12.0 ± 1.45 µ M and was determined by IC 50 shift and kinetic analyses to be a competitive reversible inhibitor of CYP3A4-mediated midazolam1- hydroxylation with a mean absolute inhibition constant (K i ) value of 3.65 ± 0.531 µ M. The 2.83-fold shift in IC 50 (10.4-3.68 µ M) after a 30-minute metabolic preincubation confirmed telithromycin as a time-dependent inhibitor of CYP3A4; the mean inhibitor concentration that causes half-maximal inactivation of enzyme (K I ) and maximal rate of inactivation of enzyme (k inact ) values determined for inactivation were 1.05 ± 0.226 µ M and 0.02772 ± 0.00272 min -1 , respectively. After the integration of an enzyme time-dependent inhibition component into the previous mechanistic static model using the in vitro inhibitory kinetic parameters determined above, the newly predicted simvastatin acid AUCR (10.8 or 5.4) resulting from perturbation of its critical disposition pathways matched the clinically observed AUCR (10.8 or 4.3) after coadministration, or staggered administration, with telithromycin, respectively. These results indicate the time-dependent inhibition of CYP3A4 by telithromycin as the primary driver underlying its clinical DDI with simvastatin acid., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: Simvastatin (SIM), a HMG-CoA reductase inhibitor widely prescribed for hypercholesterolemia, has been reported to ameliorate inflammation and promote osteogenesis. Its clinical applications on these potential secondary indications, however, have been hampered by its lack of osteotropicity and poor water solubility. To address this challenge, we propose to design and evaluate the therapeutic efficacy of a novel simvastatin prodrug with better water solubility and bone affinity., Method: The prodrug (SIM-PPi) was synthesized by directly conjugating a SIM trimer to a pyrophosphate (PPi). It was characterized and evaluated in vitro for its water solubility, osteotropicity, toxicity, anti-inflammatory and osteoinductive properties. It was then tested for anti-inflammatory and osteoinductive properties in vivo by three weekly injections into gingiva of a ligature-induced experimental periodontitis rat model., Results: In vitro studies showed that SIM-PPi has greatly improved water-solubility of SIM and shows strong binding to hydroxyapatite (HA). In macrophage culture, SIM-PPi inhibited LPS-induced pro-inflammatory cytokines (IL-1β, IL-6). In osteoblast culture, it was found to significantly increase alkaline phosphatase (ALP) activity with accelerated mineral deposition, confirming the osteogenic potential of SIM-PPi. When tested in vivo on an experimental periodontal bone-loss model, SIM-PPi exhibited a superior prophylactic effect compared to dose equivalent SIM in reducing inflammatory cells and in preserving alveolar bone structure, as shown in the histological and micro-CT data., Conclusion: SIM-PPi may have the potential to be further developed for better clinical management of bone loss associated with periodontitis.

Hybrid nanocapsules constituted of phospholipids and polysaccharides have been proposed as colloidal systems for the delivery of drugs via non-parenteral administration routes, due their capacity of high drug loading, controlled drug release and targeted delivery to the specific organ. Moreover, nanoparticles systems offer the possibility of co-encapsulation of drugs in the same drug delivery system and, consequently, the simultaneous administration of compounds. Characterization of nanoparticles properties, specifically involves quantification of the active pharmaceutical ingredients and is pivotal in the development of innovative nanomedicines. Therefore, this study has proposed and validated a new RP-HPLC-UV method for the simultaneous determination of simvastatin and coenzyme Q10 in hybrid nanoparticles systems. A reversed phase (RP) C8 column and a gradient elution of water: methanol at flow rate of 1.5 ml/min was used. Simvastatin (SVT), simvastatin hydroxyacid isoform (SVA) and coenzyme Q10 were identified by dual wavelength-UV detection at 238 nm (statins) and 275 nm, respectively. The proposed method was selective and linear in the range of 0.5-25 μg/ml (r 2  > 0.999), precise, with values of relative standard deviation (RSD) lower than 2%, robust and accurate (recovery values of 100 ± 5%), satisfying FDA guidelines. Furthermore, low detection (LOD <0.2 μg/ml) and quantification limits (LOQ <0.4 μg/ml) were suitable for the application of the method for the in vitro study of release kinetics of simvastatin and coenzyme Q10 co-encapsulated in lecithin/chitosan nanoparticles. The proposed method represents, to our knowledge, the only method for the simultaneous quantification of simvastatin, coenzyme Q10 and of the hydrolysed hydroxyacid isoform of the statin in nanoparticles., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cardiovascular disease (CVD) is the most common cause of death in patients with non-alcoholic fatty liver disease (NAFLD). New therapeutic strategies which have the potential for slowing down the evolution of NAFLD and reducing CVD-related mortality are urgently needed. Statins are well recognized in the treatment of dyslipidemia, but their use in the treatment of NAFLD is limited due to the safety concerns. Ilexgenin A (IA) is one of the main bioactive compounds in 'Shan-lv-cha', an herbal tea commonly used in China. In the present study, we investigated the possible synergistic therapeutic effects of IA and simvastatin (SV) on NAFLD. IA or SV showed beneficial effects on the rats with NAFLD by lowering the liver weight, liver index and plasma levels of alanine aminotransferase and aspartate aminotransferase, regulating abnormal metabolism of lipids and ameliorating steatosis in liver. IA significantly enhanced the hypolipidemic and anti-inflammation effects of SV. Furthermore, a sensitive, accurate, convenient and reproducible LC-MS method was developed to investigate the effects of IA on the pharmacokinetics of SV. No significant changes were observed in pharmacokinetic parameters of SV and simvastatin hydroxy acid in the IA plus SV co-treated group in comparison with those in the group treated with SV alone. The mRNA levels and activity of CYP3A1 were not altered by IA. In conclusion, the results obtained from the present study should be helpful for further clinical application of SV and IA alone or in combination., (Copyright © 2018 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

This study investigated the impact of allelic variation in SLCO1B1, a gene encoding for the liver-specific solute carrier organic anion transporter family member 1B1 protein (SLCO1B1), on simvastatin and simvastatin acid (SVA) systemic exposure in children and adolescents. Participants (8-20 years old) with at least 1 variant SLCO1B1 c.521T>C allele (521TC, n = 15; 521CC, n = 2) and 2 wild-type alleles (521TT, n = 15) completed a single oral dose pharmacokinetic study. At equivalent doses, SVA exposure was 6.3- and 2.5-fold greater in 521CC and TC genotypes relative to 521TT (C max , 2.1 ± 0.2 vs 1.0 ± 0.5 vs 0.4 ± 0.3 ng/mL; P < .0001; and AUC, 12.1 ± 0.3 vs 4.5 ± 2.5 vs 1.9 ± 1.8 ng·h/mL; P < .0001). The impact of the SLCO1B1 c.521 genotype was more pronounced in children, although considerable interindividual variability in SVA exposure was observed within genotype groups. In addition, SVA systemic exposure was negligible in 25% of pediatric participants. Further investigation of the ontogeny and genetic variation of SVA formation and SLCO1B1-mediated hepatic uptake is necessary to better understand the variability in SVA exposure in children and its clinical consequences., (© 2018, The American College of Clinical Pharmacology.)

With financial considerations impeding research and development of new antibiotics, drug repurposing (finding new indications for old drugs) emerges as a feasible alternative. Statins are extensively prescribed around the world to lower cholesterol, but they also possess inherent antimicrobial properties. This study identifies statins with the greatest potential to be repurposed as topical antibiotics and postulates a mechanism of action for statins' antibacterial activity. Using broth microdilution, the direct antibacterial effects of all seven parent statins currently registered for human use and three selected statin metabolites were tested against bacterial skin pathogens Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Serratia marcescens. Simvastatin and pitavastatin lactone exerted the greatest antibacterial effects (minimum inhibitory concentrations of 64 and 128 μg/mL, respectively) against S. aureus. None of the statins tested were effective against E. coli, P. aeruginosa, or S. marcescens, but simvastatin hydroxy acid acid might be active against S. aureus, E. coli, and S. marcescens at drug concentrations > 256 μg/mL. It was found that S. aureus may exhibit a paradoxical growth effect when exposed to simvastatin; thus, treatment failure at high drug concentrations is theoretically probable. Through structure-activity relationship analysis, we postulate that statins' antibacterial action may involve disrupting the teichoic acid structures or decreasing the number of alanine residues present on Gram-positive bacterial cell surfaces, which could reduce biofilm formation, diminish bacterial adhesion to environmental surfaces, or impede S. aureus cell division.

The natural alkaloid berberine has been ascribed numerous health benefits including lipid and cholesterol reduction and improved insulin sensitivity in diabetics. However, oral (PO) administration of berberine is hindered by poor bioavailability and increasing dose often elicits gastro-intestinal side effects. To overcome the caveats associated with oral berberine, we developed transdermal (TD) formulations of berberine (BBR) and the berberine precursor dihydroberberine (DHB). These formulations were compared to oral BBR using pharmacokinetics, metabolism, and general safety studies in vivo. To complete this work, a sensitive quantitative LC-MS/MS method was developed and validated according the FDA guidelines for bioanalytical methods to simultaneously measure berberine, simvastatin, and simvastatin hydroxy acid with relative quantification used for the berberine metabolite demethylene berberine glucuronide (DBG). Acute pharmacokinetics in Sprague-Dawley rats demonstrated a statistically relevant ranking for berberine bioavailability based upon AUC0-8 as DHB TD > BBR TD >> BBR PO with similar ranking for the metabolite DBG, indicating that transdermal administration achieves BBR levels well above oral administration. Similarly, chronic administration (14 days) resulted in significantly higher levels of circulating BBR and DBG in DHB TD treated animals. Chronically treated rats were given a single dose of simvastatin with no observed change in the drugs bioavailability compared with control, suggesting the increased presence of BBR had no effect on simvastatin metabolism. This observation was further supported by consistent CYP3A4 expression across all treatment groups. Moreover, no changes in kidney and liver biomarkers, including alanine aminotransferase and alkaline phosphatase, were observed between treatment formats, and confirming previous reports that BBR has no effect on HMG-CoA expression. This study supports the safe use of transdermal compositions that improve on the poor bioavailability of oral berberine and have the potential to be more efficacious in the treatment of dyslipidemia or hypercholesterolemia.

Background and Purpose: Statins are amongst the most widely prescribed drugs for those at risk of cardiovascular disease, lowering cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase. Although effective at preventing cardiovascular disease, statin use is associated with muscle weakness, myopathies and, occasionally, fatal rhabdomyolysis. As simvastatin, a commonly prescribed statin, promotes Ca 2+ release from sarcoplasmic reticulum (SR) vesicles, we investigated if simvastatin directly activates skeletal (RyR1) and cardiac (RyR2) ryanodine receptors., Experimental Approach: RyR1 and RyR2 single-channel behaviour was investigated after incorporation of sheep cardiac or mouse skeletal SR into planar phospholipid bilayers under voltage-clamp conditions. LC-MS was used to monitor the kinetics of interconversion of simvastatin between hydroxy-acid and lactone forms during these experiments. Cardiac and skeletal myocytes were permeabilised to examine simvastatin modulation of SR Ca 2+ release., Key Results: Hydroxy acid simvastatin (active at HMG-CoA reductase) significantly and reversibly increased RyR1 open probability (Po) and shifted the distribution of Ca 2+ spark frequency towards higher values in skeletal fibres. In contrast, simvastatin reduced RyR2 Po and shifted the distribution of spark frequency towards lower values in ventricular cardiomyocytes. The lactone pro-drug form of simvastatin (inactive at HMG-CoA reductase) also activated RyR1, suggesting that the HMG-CoA inhibitor pharmacophore was not responsible for RyR1 activation., Conclusion and Implications: Simvastatin interacts with RyR1 to increase SR Ca 2+ release and thus may contribute to its reported adverse effects on skeletal muscle. The ability of low concentrations of simvastatin to reduce RyR2 Po may also protect against Ca 2+ -dependent arrhythmias and sudden cardiac death., (© 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

In the present work, we propose silk fibroin/alginate (SF/Alg) beads embedding simvastatin-loaded biodegradable microparticles as a versatile platform capable of tuning SVA release and in so doing osteogenic effects. In a first part of the study, microparticles of poly(lactic-co-glycolic) acid incorporating simvastatin either as lactone (SVL) or as hydroxyacid form (SVA) were prepared by spray-drying. While SVA-loaded microparticles released the drug in three days, long-term release of SVA could be obtained from SVL-loaded microparticles. In this latter case, SVL was promptly transformed to the osteogenic active SVA during release. When tested on mesenchymal stem cells, a time- and dose-dependent effect of SVL-loaded microparticles on cell proliferation and alkaline phosphatase (ALP) activity was found. Thereafter, SVL-loaded microparticles were embedded in SF/Alg beads to limit the initial simvastatin burst and to achieve easier implantation as well. Microparticle-embedded beads showed no cytotoxicity while ALP activity increased. If correctly exploited, the developed system may be suitable as osteogenic polymer scaffolds releasing correct amount of the drug locally for long time-frames., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Elevated interleukin (IL)-6 occurs in patients with active rheumatoid arthritis (RA), which has been shown to lead to a decrease in cytochrome P450 (CYP) enzyme activity and alterations in drug concentrations metabolized by CYP. IL-6 signaling blockade by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. This study evaluated the pharmacokinetic profile of simvastatin (a CYP3A4 substrate) before and 1 week after a single dose of sarilumab (a human monoclonal antibody [mAb] blocking the IL-6Rα) in patients with RA, to assess potential interaction., Methods: Nineteen patients with active RA received oral simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg. The pharmacokinetic parameters of simvastatin and its primary metabolite, β-hydroxy-simvastatin acid, were calculated using noncompartmental analysis., Results: Compared with simvastatin alone, single-dose simvastatin administration 7 days after single-dose sarilumab administration in patients with RA resulted in reduced simvastatin and β-hydroxy-simvastatin acid exposure in plasma. Mean effect ratios (90 % confidence interval) for simvastatin peak plasma concentration (C max ) and area under the concentration-time curve extrapolated to infinity (AUC ∞ ) were 54.1 % (42.2-69.4 %) and 54.7 % (47.2-63.3 %), respectively. No changes occurred in time to C max or half-life for either simvastatin or β-hydroxy-simvastatin acid after sarilumab administration., Conclusions: Sarilumab treatment resulted in a reduction in exposure of simvastatin, consistent with reversal of IL-6-mediated CYP3A4 suppression in patients with active RA, as was reported for tocilizumab with simvastatin and for sirukumab with midazolam., Clinical Trial Registration Number: NCT02017639.

1. This study aimed to investigate the potential impact of epigallocatechin-3-gallate (EGCG) on the pharmacokinetic behaviors of simvastatin and its metabolite simvastatin acid and explored the possible role of metabolizing enzymes and transporters of this food-drug interaction. 2. Female SD rats were intravenously administered with EGCG (5 mg/kg), ketoconazole (10 mg/kg) and rifampin (10 mg/kg), followed by intravenous administration of 2 mg/kg simvastatin. In vitro, the effects of EGCG on Cytochrome P450 enzymes (CYP450) and organic anion transporting polypeptides (OATPs) were studied using human hepatic microsomes and human embryonic kidney 293 (HEK293) cells overexpressing OATP1B1 or OATP1B3. The results showed that areas under concentration-time (AUC) curves of simvastatin and simvastatin acid increased by 2.21- and 1.4-fold while the clearance was reduced by 2.29- and 1.4-fold, respectively, when co-administered with EGCG. In vitro experiments suggested the inhibitory effect of EGCG on CYP enzymes (IC 50 : 18.37 ± 1.36 μM, 26.08 ± 1.51 μM for simvastatin and simvastatin acid, respectively). Simvastatin transport by OATP1B1 and OATP1B3 was also inhibited by EGCG (IC 50 : 8.68 ± 1.27 μM and 22.67 ± 1.42 μM, respectively). 3. The presently reported novel food-drug interaction between EGCG and simvastatin involves the inhibition of not only CYP450 enzymes but also OATPs by EGCG.

Despite recent advances in modern medicine, castration-resistant prostate cancer remains an incurable disease. Subpopulations of prostate cancer cells develop castration-resistance by obtaining the complete steroidogenic ability to synthesize androgens from cholesterol. Statin derivatives, such as simvastatin, inhibit cholesterol biosynthesis and may reduce prostate cancer incidence as well as progression to advanced, metastatic phenotype. In this study, we demonstrate novel simvastatin-related molecules SVA, AM1, and AM2 suppress the tumorigenicity of prostate cancer cell lines including androgen receptor-positive LNCaP C-81 and VCaP as well as androgen receptor-negative PC-3 and DU145. This is achieved through inhibition of cell proliferation, colony formation, and migration as well as induction of S-phase cell-cycle arrest and apoptosis. While the compounds effectively block androgen receptor signaling, their mechanism of inhibition also includes suppression of the AKT pathway, in part, through disruption of the plasma membrane. SVA also possess an added effect on cell growth inhibition when combined with docetaxel. In summary, of the compounds studied, SVA is the most potent inhibitor of prostate cancer cell tumorigenicity, demonstrating its potential as a promising therapeutic agent for castration-resistant prostate cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of simvastatin (SV) and simvastatin acid (SVA) in human plasma. To improve assay sensitivity and achieve simultaneous analysis, SVA monitored in (-)ESI (electrospray ionization) mode within the first 4.5 min and SV thereafter in (+)ESI mode. The separation of all compounds was achieved in about 6.2 min using a C18 reverse-phase fused-core(®) column (Ascentis(®) Express C18) and a mobile phase, which was composed of 2.00 ± 0.05 mM ammonium acetate buffer titrated to pH 3.8 with glacial acetic acid-acetonitrile (25:75, v/v), in isocratic mode at a flow rate of 0.500 mL/min. Additionally, a solid-phase extraction step was performed to reduce any ion-suppression and/or enhancement effects. The developed method was linear in the concentration range of 0.100-74.626 ng/mL for SV, and 0.100-48.971 ng/mL for SVA, with correlation coefficient greater than 0.99 for both analytes. The method has shown tremendous reproducibility, with intra- and inter-day precision <7.6%, and intra- and interday accuracy within ±10.9% of nominal values, for the both analytes. The method was successfully applied to characterize the pharmacokinetic profiles of SV and SVA following an oral administration of 40 mg SV tablet to healthy human volunteers., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Disturbances in acid-base balance, such as acidosis and alkalosis, have potential to alter the pharmacologic and toxicologic outcomes of statin therapy. Statins are commonly prescribed for elderly patients who have multiple comorbidities such as diabetes mellitus, cardiovascular, and renal diseases. These patients are at risk of developing acid-base imbalance. In the present study, the effect of disturbances in acid-base balance on the interconversion of simvastatin and pravastatin between lactone and hydroxy acid forms have been investigated in physiological buffers, human plasma, and cell culture medium over pH ranging from 6.8-7.8. The effects of such interconversion on cellular uptake and myotoxicity of statins were assessed in vitro using C2C12 skeletal muscle cells under conditions relevant to acidosis, alkalosis, and physiological pH. Results indicate that the conversion of the lactone forms of simvastatin and pravastatin to the corresponding hydroxy acid is strongly pH dependent. At physiological and alkaline pH, substantial proportions of simvastatin lactone (SVL; ∼87% and 99%, respectively) and pravastatin lactone (PVL; ∼98% and 99%, respectively) were converted to the active hydroxy acid forms after 24 hours of incubation at 37°C. At acidic pH, conversion occurs to a lower extent, resulting in greater proportion of statin remaining in the more lipophilic lactone form. However, pH alteration did not influence the conversion of the hydroxy acid forms of simvastatin and pravastatin to the corresponding lactones. Furthermore, acidosis has been shown to hinder the metabolism of the lactone form of statins by inhibiting hepatic microsomal enzyme activities. Lipophilic SVL was found to be more cytotoxic to undifferentiated and differentiated skeletal muscle cells compared with more hydrophilic simvastatin hydroxy acid, PVL, and pravastatin hydroxy acid. Enhanced cytotoxicity of statins was observed under acidic conditions and is attributed to increased cellular uptake of the more lipophilic lactone or unionized hydroxy acid form. Consequently, our results suggest that comorbidities associated with acid-base imbalance can play a substantial role in the development and potentiation of statin-induced myotoxicity., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

What Is Known and Objective: Sacubitril/valsartan (LCZ696) has been recently approved for the treatment of heart failure (HF) patients with reduced ejection fraction. Several HF patients receive statins as co-medication., Methods: Because clearance of statins is meditated via OATP1B1/1B3, the inhibition potential of these transporters by LCZ696 analytes was evaluated in vitro. Furthermore, an open-label, fixed-sequence clinical study was conducted to determine the effect of LCZ696 on the exposure of simvastatin and its active metabolite simvastatin acid. In this clinical study, 26 healthy subjects received simvastatin 40 mg alone or in combination with LCZ696 or after 1 or 2 h of LCZ696 dosing., Results and Discussion: Although no significant inhibition by LBQ657 (an active metabolite of sacubitril) and valsartan was observed, sacubitril inhibited OATP1B1 and OATP1B3 in vitro, with IC50 of 1·91 and 3·81 μm, respectively. Upon co-administration of simvastatin with LCZ696, the Cmax of simvastatin and simvastatin acid decreased by 7% and 13%, respectively. When administered 1 h after LCZ696 dosing, the corresponding Cmax of simvastatin and simvastatin acid decreased by 16% and 4%, respectively. When administered 2 h after LCZ696 dosing, the Cmax of simvastatin decreased by 33% and that of simvastatin acid increased by 16%. However, no notable changes were observed in the AUCs of simvastatin or simvastatin acid upon co-administration or time-separated administration with LCZ696. No notable impact of simvastatin co-administration was observed on the pharmacokinetics of LCZ696 analytes. LCZ696 and simvastatin were generally well tolerated when administered alone or in combination., What Is New and Conclusions: Overall, the results of this study suggest that although sacubitril inhibited OATP1B1 and OATP1B3 in vitro, it does not translate into any clinically relevant in vivo effect., (© 2016 John Wiley & Sons Ltd.)

A simple, selective, sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS-MS) method has been developed and validated for the simultaneous quantification of simvastatin (SS), simvastatin acid (SSA, active metabolite of SS) and ezetimibe (EZM) in K2 EDTA containing human plasma, using simvastatin D6, simvastatin acid D3 and ezetimibe D4 as internal standards (ISTDs), respectively. A volume of plasma sample of only 400 µL was processed by the solid phase extraction technique; then 20 µL of processed sample was run on a Phenomenex, Kinetix XB C18, 150 × 4.6 mm, 5 µm column using an isocratic mobile phase consisting of 10 mM ammonium formate buffer (pH 4.0 ± 0.3): acetonitrile (27 : 73, v/v) with a run time of 6.3 min. The precursor and product ions of SSA, EZM and their ISTDs were monitored on a triple quadrupole instrument operated in the negative ionization mode, and SS was monitored in the positive mode. The method was validated over a concentration range of 0.2-80 ng/mL for SS, 0.1-60 ng/mL for SSA and 0.05-15 ng/mL for EZM. The method has been successfully applied in clinical pharmacokinetic study in the Indian population. The Cmax, AUC0-inf and Tmax values obtained in our study were 10.61 ± 5.287, 77.58 ± 29.367 and 1.62 ± 0.436 for EZM; 69.74 ± 45.274, 190.71 ± 107.271 and 1.74 ± 0.480 for SS; and 25.36 ± 23.576, 139.24 ± 131.653 and 3.95 ± 0.671 for SSA, respectively., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were potent hits against a mouse ependymoma cell line, but their effectiveness against central nervous system tumors will depend on their ability to cross the blood-brain barrier and attain a sufficient exposure at the tumor. Among 3-hydroxy-3-methylglutaryl coenzyme A inhibitors that had activity in vitro, we prioritized simvastatin (SV) as the lead compound for preclinical pharmacokinetic studies based on its potential for central nervous system penetration as determined from in silico models. Furthermore, we performed systemic plasma disposition and cerebral microdialysis studies of SV (100 mg/kg, p.o.) in a murine model of ependymoma to characterize plasma and tumor extracellular fluid (tECF) pharmacokinetic properties. The murine dosage of SV (100 mg/kg, p.o.) was equivalent to the maximum tolerated dose in patients (7.5 mg/kg, p.o.) based on equivalent plasma exposure of simvastatin acid (SVA) between the two species. SV is rapidly metabolized in murine plasma with 15 times lower exposure compared with human plasma. SVA exposure in tECF was <33.8 ± 11.9 µg/l per hour, whereas the tumor to plasma partition coefficient of SVA was <0.084 ± 0.008. Compared with in vitro washout IC50 values, we did not achieve sufficient exposure of SVA in tECF to suggest tumor growth inhibition; therefore, SV was not carried forward in subsequent preclinical efficacy studies., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Finding pleiomorphic targets for drugs allows new indications or warnings for treatment to be identified. As test of concept, we applied a new chemical genomics approach to uncover additional targets for the widely prescribed lipid-lowering pro-drug simvastatin. We used mRNA extracted from internal mammary artery from patients undergoing coronary artery surgery to prepare a viral cardiovascular protein library, using T7 bacteriophage. We then studied interactions of clones of the bacteriophage, each expressing a different cardiovascular polypeptide, with surface-bound simvastatin in 96-well plates. To maximise likelihood of identifying meaningful interactions between simvastatin and vascular peptides, we used a validated photo-immobilisation method to apply a series of different chemical linkers to bind simvastatin so as to present multiple orientations of its constituent components to potential targets. Three rounds of biopanning identified consistent interaction with the clone expressing part of the gene GJC3, which maps to Homo sapiens chromosome 7, and codes for gap junction gamma-3 protein, also known as connexin 30.2/31.3 (mouse connexin Cx29). Further analysis indicated the binding site to be for the N-terminal domain putatively 'regulating' connexin hemichannel and gap junction pores. Using immunohistochemistry we found connexin 30.2/31.3 to be present in samples of artery similar to those used to prepare the bacteriophage library. Surface plasmon resonance revealed that a 25 amino acid synthetic peptide representing the discovered N-terminus did not interact with simvastatin lactone, but did bind to the hydrolysed HMG CoA inhibitor, simvastatin acid. This interaction was also seen for fluvastatin. The gap junction blockers carbenoxolone and flufenamic acid also interacted with the same peptide providing insight into potential site of binding. These findings raise key questions about the functional significance of GJC3 transcripts in the vasculature and other tissues, and this connexin's role in therapeutic and adverse effects of statins in a range of disease states.

Objective: The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men., Methods: Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype., Results: CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio., Conclusion: The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.

A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method was developed and validated for simultaneous quantification of simvastatin (SV), its metabolite simvastatin hydroxy acid (SVA) and berberine (BBR) in rat plasma. Separation was performed on Poroshell 120 EC-C18 column (4.6×50mm, 2.7μm) using gradient elution by mobile phase containing acetonitrile and 10mM ammonium acetate (pH 4.5). Polarity switch (positive-negative-positive ionization mode) was performed in a total run time of 4.0min. The lower limits of quantification (LLOQ) for SV, SVA and BBR were 0.10, 0.20 and 0.10ng/mL, respectively. The response function was established for concentration range of 0.10-100ng/mL for SV and BBR and 0.20-3000ng/mL for SVA, with a coefficient of correlation of >0.99 for all the compounds. The proposed method was applied to the drug-drug pharmacokinetic interaction study of SV combined with BBR after oral administration in rats., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism [the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)*22 and the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5)*3] and transport [the gene encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) T521C] with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and the concentrations were quantified by high performance liquid chromatography-tandem mass spectrometry in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/d SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared with CYP3A4*1/*1 participants (P = 0.006). SLCO1B1 521T/C and 521C/C participants had 71% (P < 0.001) and 248% (P < 0.001) higher 12-hour plasma SVA compared with SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (≈1), and high (>1) SVA/SV ratio groups (P = 0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased 12-hour plasma SV and SVA concentrations, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles.

Purpose: To develop a population physiologically-based pharmacokinetic (PBPK) model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that allows extrapolation and prediction of their concentration profiles in liver (efficacy) and muscle (toxicity)., Methods: SV/SVA plasma concentrations (34 healthy volunteers) were simultaneously analysed with NONMEM 7.2. The implemented mechanistic model has a complex compartmental structure allowing inter-conversion between SV and SVA in different tissues. Prior information for model parameters was extracted from different sources to construct appropriate prior distributions that support parameter estimation. The model was employed to provide predictions regarding the effects of a range of clinically important conditions on the SV and SVA disposition., Results: The developed model offered a very good description of the available plasma SV/SVA data. It was also able to describe previously observed effects of an OATP1B1 polymorphism (c.521 T > C) and a range of drug-drug interactions (CYP inhibition) on SV/SVA plasma concentrations. The predicted SV/SVA liver and muscle tissue concentrations were in agreement with the clinically observed efficacy and toxicity outcomes of the investigated conditions., Conclusions: A mechanistically sound SV/SVA population model with clinical applications (e.g., assessment of drug-drug interaction and myopathy risk) was developed, illustrating the advantages of an integrated population PBPK approach.

Objectives: This study focuses on the development of a dry powder inhaler (DPI) formulation of simvastatin (SV), and the effects of SV on the respiratory epithelium., Methods: Micronised SV samples were prepared by dry jet-milling. The long-term chemical stability and physicochemical properties of the formulations were characterised in terms of particles size, morphology, thermal and moisture responses. Furthermore, in vitro aerosol depositions were performed. The formulation was evaluated for cell viability and its effect on cilia beat activity, using ciliated nasal epithelial cells in vitro. The formulation transport across an established air interface Calu-3 bronchial epithelial cells and its ability to reduce mucus secretion was also investigated., Results: The particle size of the SV formulation and its aerosol performance were appropriate for inhalation therapy. Moreover, the formulation was found to be non-toxic to pulmonary epithelia cells and cilia beat activity up to a concentration of 10(-6) M. Transport studies revealed that SV has the ability to penetrate into airway epithelial cells and is converted into its active SV hydroxy acid metabolite. Single dose of SV DPI also decreased mucus production after 4 days of dosing., Conclusion: This therapy could potentially be used for the local treatment of diseases like chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis given its anti-inflammatory effects and ability to reduce mucus production.

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins., Methods: Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed., Results: Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51-130 %) and 55 % (26-91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25-88 %) and 69 % (37-108 %) higher for atorvastatin, 23 % (0-52 %) and 12 % (-0.9-39 %) higher for simvastatin and 28 % (5-56 %) and 34 % (10-64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively., Conclusion: Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

The 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors known as "statins" are widely prescribed for the management of dyslipidemia. In spite of their muscle toxicity, use of statins has alarmingly increased worldwide. A recent report suggests that vitamin D (VD) levels are closely associated with lipid lowering activity and muscular toxicity of statins. However, data are limited and inconclusive. The present study was undertaken to investigate the effect of VD supplementation on the bioavailability and lipid lowering effect of simvastatin (ST). Adult Sprague-Dawley male rats (250 ± 10 g) were divided into four groups including control, ST (100 mg/kg/day), VD (100 μg/kg/day) and ST + VD group, respectively. After the dosing period of 8 days the animals were sacrificed and the blood was collected for the analysis of ST, its active metabolite simvastatin acid (STA), total cholesterol, triglyceride and liver enzymes including aspartate transaminase and alanine transaminase. The result of this study showed a significant decrease in the level of cholesterol and triglyceride in ST alone treated group, whereas VD alone failed to alter the blood lipid levels. Concomitant treatment with VD produced significant decrease in the bioavailability of ST and STA. However, there was no significant difference in the level of cholesterol in ST alone and in ST + VD treated group. Our results on the liver enzyme suggest that ST alone or in combination with VD does not produce any hepatotoxicity. Further studies using VD along with various statins for a longer duration are suggested.

1. Concomitant traditional Chinese medicines (TCMs) could be the reason for relative poor efficacy of statins in dyslipidemia patients in China. 2. An open-label, randomized, 5-period crossover study in healthy Chinese was designed to evaluate the pharmacokinetic interaction and tolerability of multiple doses of certain TCMs on a single dose of simvastatin. In each period, subjects received one of five treatments. In Treatment A, subjects received a single dose of 20 mg simvastatin. In Treatment B, C, D or E, subjects received Tong Xin Luo, Nao Xin Tong, Guan Mai Ning or Yin Xing Ye for 7 days and a single dose of 20 mg simvastatin on Day 7. The washout period was 7 days. 3. The 97.5% confidence interval of the AUC0-48 h geometric mean ratio of simvastatin acid and simvastatin for simvastatin given after multiple oral doses of one of the TCMs versus simvastatin given alone were fully contained within the prespecified bounds of (0.50, 2.00). 4. Exposures to simvastatin acid and simvastatin following a single dose of simvastatin alone were similar to those following coadministration of a single dose of simvastatin with multiple doses of each of the TCM preparations tested. Simvastatin and these TCMs were well tolerated.

Purpose: Setipiprant, a selective oral CRTH2 antagonist, has been investigated for the treatment of allergic rhinitis and asthma. In vitro data showed that setipiprant has a weak induction potential on CYP3A4. An interaction at the hepatic level between setipiprant and CYP3A4 substrates was not expected even at the dosing regimen of 1,000 mg setipiprant b.i.d. due to the high plasma protein binding. However, at this dosing regimen, interactions at the gut level could not be excluded., Methods: In this single-center, open-label study, 40 mg of simvastatin was administered orally on Day 1, and then concomitantly with setipiprant on Day 10 following 9 days of setipiprant 1,000 mg b.i.d. to 22 healthy male subjects., Results: In the presence of setipiprant, the simvastatin concentration-time profile was similar to that of simvastatin alone. The concentrations of simvastatin were, however, slightly lower, resulting in a 9 % decrease in C max (geometric mean ratio (GMR) 0.91, 90 % confidence interval (CI) (0.73, 1.13)) and in a 16 % lower AUC0-∞ (GMR 0.84, 90 % CI (0.72, 0.99)). Exposure to simvastatin acid was similar when comparing simvastatin with or without setipiprant. The GMR and 90 % CI for AUC0-∞ were within the 0.8 to 1.25 limits, whereas those for C max were outside (GMR 2.73, 90 % CI (2.11, 3.53)). Moreover, the median t max of simvastatin acid occurred earlier (1.8 h) when combined compared to 3.0 h when administered alone., Conclusions: As setipiprant has little impact on simvastatin pharmacokinetics, it does not modulate CYP3A4 in a clinically relevant manner.

Objective: This study was undertaken to investigate potential drugdrug interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and simvastatin., Materials and Methods: In this open-label, randomized crossover trial, healthy volunteers (median (range) age 36.5 (20 - 50) years) received 3 single-dose treatments: 25 mg empagliflozin (n = 18), 40 mg simvastatin (n = 17), and 25 mg empagliflozin with 40 mg simvastatin (n = 18)., Results: Based on standard criteria, simvastatin had no effect on empagliflozin area under the plasma concentration-time curve (AUC(0-∞), adjusted geometric mean ratio (GMR): 102.05; 90% CI: 98.90 - 105.29) or maximum plasma concentration (C(max), GMR: 109.49; 90% CI: 96.91 - 123.69). There were only minor deviations in simvastatin AUC(0-∞) (GMR: 101.26; 90% CI: 80.06 - 128.07) and C(max) (GMR: 97.18; 90% CI: 76.30 - 123.77) when co-administered with empagliflozin. Empagliflozin had no effect on AUC(0-∞) (GMR: 104.87; 90% CI: 90.09 - 122.07) or C(max) (GMR: 97.27; 90% CI: 84.90 - 111.44) of simvastatin acid, the active metabolite of simvastatin. Adverse events (AEs) were reported for 6 subjects on empagliflozin, 4 on simvastatin, and 5 on co-administered treatment. No serious AEs or investigator-defined drug-related AEs were reported., Conclusion: No relevant drug-drug interaction was observed, and pharmacokinetic results suggest that no dose adjustments for either drug are necessary when empagliflozin and simvastatin are co-administered. Empagliflozin was well tolerated when administered alone or in combination with simvastatin.

For the first time, structural information regarding the role of simvastatin in bone anabolism is described, and a bone-specific statin is introduced. Polyaspartate-conjugated simvastatin was synthesized by solid-phase synthesis with the assistance of microwave irradiation. It displays significant bone targeting and bone formation with less toxicity than simvastatin.

Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes., Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR., Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp., Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.

The aim of this work was to develop a joint population pharmacokinetic model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that incorporates the effects of multiple genetic polymorphisms and clinical/demographic characteristics. SV/SVA plasma concentrations, demographic/clinical data, and genotypes for 18 genetic variants were collected from 74 individuals (three clinical trials) and analyzed using a nonlinear mixed-effects modeling approach. The structural model that best described the data included a two- and a one-compartment disposition model for SV and SVA, respectively. Age, weight, Japanese ethnicity, and seven genetic polymorphisms-rs4149056 (SLCO1B1), rs776746 (CYP3A5), rs12422149 (SLCO2B1), rs2231142 (ABCG2), rs4148162 (ABCG2), rs4253728 (PPARA), and rs35599367 (CYP3A4)-were identified as significantly affecting model parameters. The developed model was used to assess combinations of these covariates, highlighting specific risk factors associated with altered SV/SVA pharmacokinetics, and consequently myopathy cases that cannot be solely attributed to the rs4149056 CC genotype.

Purpose: The pharmacokinetics of simvastatin is complex with multiple peaks in the absorption phase, which cannot be adequately described by a conventional first order absorption model. The biotransformation of simvastatin into simvastatin acid, an active metabolite, is reversible. This study evaluated the pharmacokinetics of simvastatin and simvastatin acid, focusing on the absorption kinetics., Methods: Data were collected from three bioequivalence studies, in which subjects were administered 60 mg simvastatin, and from one crossover study, in which subjects were administered two doses randomly selected from 10, 20, 30, 40 to 80 mg simvastatin with washout period. The pharmacokinetics of simvastatin was assessed in 133 healthy males. Plasma concentrations of simvastatin and simvastatin acid were measured in 2,182 and 2,130 samples, respectively, and the pharmacokinetic data were analyzed using NONMEM., Results: The time course of changes in the plasma simvastatin concentration was best described by a two-compartment linear model with three parallel absorption processes, each of which consisted of mixed zero-and first order absorption. Additions of inter-occasional variability to the absorption parameters significantly improved the model's fit. The disposition parameter estimates were significantly different when different absorption models were applied, indicating the importance of the appropriate absorption modeling. Pharmacokinetic modeling preferred the inter-conversion between simvastatin and simvastatin acid., Conclusion: A pharmacokinetic model describing the complex, multiple peak, absorption kinetics of simvastatin was formulated using three parallel, mixed zero and first-order absorptions. This type of absorption model may be applicable to other drugs that show irregular, multiple-peak concentrations during their absorption phase.

Objective: A fixed dose combination tablet of niacin extended release (ER)/simvastatin was recently developed in China. This study was designed to assess and compare the pharmacokinetics of niacin, simvastatin and their metabolites in healthy Chinese subjects after single and multiple doses administration., Methods: From day 1 to day 7, 12 Chinese subjects were given a tablet every day at approximately 10 p.m. Serial blood samples were collected. Niacin and nicotinuric acid (NUA) in plasma, niacin, NUA, N-methylnicotinamide (MNA) and N-methyl-2-pyridone-5-carboxamide (2PY) in urine, simvastatin and simvastatin acid in plasma were determined by LC/MS/MS methods. Pharmacokinetic parameters on days 1 and 7 were compared., Results: The main pharmacokinetic parameters for the single and multiple doses were as -follows: Niacin: Tmax were 3.8±1.5 h and 3.9±2.0 h; Cmax were 2 091±1 315 ng/ml and 2 323±1 542 ng/ml; AUC0-t were 4 123.88±3 138.48 ng ∙ h/ml and 4 385.98±3 127.05 ng ∙ h/ml. NUA: Tmax were 4.7±1.7 h and 3.8±1.5 h; Cmax were 1 057±549 ng/ml and 1 087±470 ng/ml; AUC0-t were 4 012.49±2 168.68 ng ∙ h/ml and 4 040.45±1 886.57 ng ∙ h/ml. Simvastatin: Tmax were 1.8±1.0 h and 2.5±2.5 h; Cmax were 3.15±1.67 ng/ml and 4.87±4.11 ng/ml; AUC0-t were 9.03±5.10 ng ∙ h/ml and 17.63±13.93 ng ∙ h/ml. Simvastatin acid: Tmax were 5.8±1.7 h and 6.5±1.4 h; Cmax were 4.22±2.10 ng/ml and 9.30±8.09 ng/ml; AUC0-t were 34.65±16.89 ng ∙ h/ml and 61.62±46.41 ng ∙ h/ml. Urine Recovery rate of total niacin: (40.55±7.38)% and (62.87±12.04)%., Conclusion: Compared with those after a single dose, pharmacokinetics of niacin and NUA was similar; total urine recovery of niacin was higher; exposure to simvastatin and simvastatin acid were higher following multiple doses., (© Georg Thieme Verlag KG Stuttgart · New York.)

Simvastatin (SIM)-induced myopathy is a dose-dependent adverse drug reaction (ADR) that has been reported to occur in 18.2% of patients receiving a 40- to 80-mg dose. The pharmacokinetics of SIM hydroxy acid (SIMA), the bioactive form of SIM, and the occurrence of SIM-induced myopathy are linked to the function of the organic anion transporting polypeptide (Oatp) hepatic uptake transporters. Genetic polymorphisms in SLCO1B1, the gene for human hepatic OATP1B1, cause decreased elimination of SIMA and increased risk of developing myopathy. Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease, and is known to alter drug transporter expression and drug disposition. The purpose of this study was to assess the metabolism and disposition of SIM in a diet-induced rodent model of NASH. Rats were fed a methionine- and choline-deficient diet for 8 weeks to induce NASH and SIM was administered intravenously. Diet-induced NASH caused increased plasma retention and decreased biliary excretion of SIMA due to decreased protein expression of multiple hepatic Oatps. SIM exhibited increased volume of distribution in NASH as evidenced by increased muscle, decreased plasma, and no change in biliary concentrations. Although Cyp3a and Cyp2c11 proteins were decreased in NASH, no alterations in SIM metabolism were observed. These data, in conjunction with our previous data showing that human NASH causes a coordinated downregulation of hepatic uptake transporters, suggest that NASH-mediated transporter regulation may play a role in altered SIMA disposition and the occurrence of myopathy.

Simvastatin attenuates airway inflammation and hyperreactivity, hallmarks of asthma, in allergen-challenged mice. As such, it is under consideration as a novel therapeutic, thus it is important to quantify the levels of simvastatin and its pharmacologically active and interconvertible metabolite, simvastatin hydroxy acid, that can be attained in the body. Methods exist to measure the concentrations of these compounds in biological media; however they do not maintain a physiological pH, and as a result do not accurately measure the ratio of these two compounds that exists in vivo. We developed a new method to measure simvastatin and simvastatin hydroxy acid more accurately in serum from mice by ultra high performance liquid chromatography-tandem mass spectrometry. We minimized the time that the compounds were in aqueous solution, and buffered samples to a physiological pH value of 7.4. Limits of quantification (LOQ) were 0.16 ng mL(-1) extract (1.3 ng mL(-1) serum) for simvastatin, and 8.3 ng mL(-1) extract (66 ng mL(-1) serum) for simvastatin hydroxy acid, respectively. No interconversion was observed, based on spike-and-recovery experiments of solutions containing both compounds. The method was applied using biological samples from mice challenged with house dust mite extract and simultaneously treated with subcutaneous simvastatin injection. Simvastatin hydroxy acid concentrations became significantly increased after a 2 week pre-treatment regime, whereas simvastatin concentrations were below the LOQ for all serum samples., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Gender differences in pharmacokinetics have been reported to have important clinical consequences; however, no information about differences in the pharmacokinetics of the cholesterol-lowering drug simvastatin lactone and its metabolite, simvastatin hydroxy acid, in males and females is available., Objective: The aim of this study was to investigate the effect of gender on the pharmacokinetics of simvastatin lactone and simvastatin hydroxy acid in healthy Han Chinese volunteers., Methods: 16 healthy volunteers (8 males and 8 females) were orally administered a single dose of 40 mg simvastatin lactone after an overnight fast. Plasma was then collected 24 hours after simvastatin lactone administration. Concentrations of simvastatin lactone and simvastatin hydroxy acid were measured by high performance liquid chromatography/mass spectrometry/mass spectrometry (HPLC/MS/MS)., Results: There were no significant associations between the pharmacokinetic parameters of simvastatin lactone and gender. For simvastatin hydroxy acid, peak plasma concentrations (Cmax) and dose-normalized by the subject weight Cmax (NCmax) were higher in females than in males. Furthermore, NCmax and dose-normalized by the subject weight AUC (NAUC0-24h, NAUC0-∞) ratios of simvastatin hydroxy acid to simvastatin lactone in females were higher than in males., Conclusion: This study indicates that gender affects the plasma concentrations of active simvastatin hydroxy acid, but has no significant effect on parent simvastatin lactone. Raised plasma concentrations of simvastatin hydroxy acid in females may enhance the risk of systemic adverse effects during simvastatin lactone treatment.

An automated model development was performed for simvastatin, co-administered with amlodipine concurrently or non-concurrently (i.e., 4 hours later) in 17 patients with coexisting hyperlipidemia and hypertension. The single objective hybrid genetic algorithm (SOHGA) was implemented in the NONMEM software by defining the search space for structural, statistical and covariate models. Candidate models obtained from the SOHGA runs were further assessed for biological plausibility and the precision of parameter estimates, followed by traditional backward elimination process for model refinement. The final population pharmacokinetic model shows that the elimination rate constant for simvastatin acid, the active form by hydrolysis of its lactone prodrug (i.e., simvastatin), is only 44% in the concurrent amlodipine administration group compared with the non-concurrent group. The application of SOHGA for automated model selection, combined with traditional model selection strategies, appears to save time for model development, which also can generate new hypotheses that are biologically more plausible., (© 2013, The American College of Clinical Pharmacology.)

Background: Verapamil is a calcium channel blocker commonly used in treatments of hypertension. Verapamil and its active metabolite, norverapamil, are known to be CYP3A4 inhibitors. Co-administration of verapamil with CYP3A4 substrates can alter the pharmacokinetics of the substrates. Simvastatin, a commonly used HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia is extensively metabolized by CYP3A4. Therefore, concomitant use of simvastatin and verapamil can increase simvastatin plasma concentration levels, resulting in a higher risk of rhabdomyolysis, a serious adverse drug reaction. Even though, pharmacokinetic data regarding the interaction between both drugs have been published, their use is limited to semiquantitative applications. Therefore, we aimed to develop a mathematical model describing drug-drug interaction between simvastatin and verapamil in humans., Methods: Eligible pharmacokinetic interaction study between simvastatin and verapamil in humans was selected from PubMed database. The concentration-time courses from this study were digitally extracted and used for model development., Results: The drug-drug interaction between simvastatin and verapamil was modeled simultaneously with a two compartment model for verapamil with its active metabolite, norverapamil and a one compartment model for simvastatin with its active form, simvastatin hydroxy acid. The effects of verapamil and norverapamil on pharmacokinetics of simvastatin and its active form, simvastatin hydroxy acid were described by Michaelis-Menten equation. Simulated simvastatin and simvastatin hydroxy acid concentrations obtained from the final model produced a good fit to the dataset from a literature. The final model adequately describes pharmacokinetic interaction between simvastatin and verapamil which can be helpful in prediction of rhabdomyolysis in patients with concurrent use of these drugs.

This study aimed to demonstrate that the dose of a CYP3A substrate (simvastatin) can be adapted individually on the basis of CYP3A activity as assessed by midazolam metabolic clearance. In 18 healthy participants individual CYP3A activity was quantified using midazolam metabolic clearance both alone and during CYP3A inhibition with 40 mg ritonavir. Thereafter, simvastatin acid exposure was determined after a simvastatin standard dose (40 mg) and doses adapted to individual CYP3A activity at baseline and during CYP3A inhibition. Interindividual variability of CYP3A activity and simvastatin acid AUC0-24 was large and both correlated (r(2)  = 0.745, P < .001). The adapted simvastatin doses ranged from 25 to 80 mg and their administration reduced simvastatin variability fivefold. Despite the low adapted simvastatin dose of 12 mg during CYP3A inhibition with ritonavir, exposure increased (point estimate of 4.2 [90% CI: 3.15-5.61]) probably caused by additional OATP1B1 inhibition. CYP3A activity-based dose adaptation can be used to reduce interindividual variability in simvastatin exposure., (© 2013, The American College of Clinical Pharmacology.)

1. Ginkgo biloba extract (GBE) is one of the most commonly used herbal remedies worldwide. It is usually concomitantly administrated with statins to treat diseases in geriatric patients. We aim to determine the influence of GBE on the pharmacokinetics (PK) and pharmacodynamics of simvastatin, which is currently unknown. 2. An open-label, randomized, two-period, two-treatment, balanced, crossover study was performed in 14 healthy volunteers. Subjects received simvastatin 40 mg once daily, co-treated with placebo or GBE 120 mg twice daily. Each treatment was administered for 14 d, separated by a wash-out period of 1 month. Simvastatin, simvastatin acid and lipoprotein concentrations were assessed. 3. GBE administration reduced mean simvastatin area under the curve (AUC)0-24, AUC0-∞ and Cmax by 39% (p = 0.000), 36%(p = 0.001) and 32% (p = 0.002), respectively, but did not cause significant differences in simvastatin acid PK or its cholesterol-lowering efficacy. 4. GBE consumption decreased simvastatin system exposure, but did not affect simvastatin acid PK. However, we cannot rule out the possibility for a pharmacodynamic interaction between GBE and simvastatin in vivo.

The absorption, distribution, metabolism, and excretion (ADME) of drugs in vivo are to a large extent dependent on different transport and metabolism routes. Elucidation of this complex transport-metabolism interplay is a major challenge in drug development and at present no in vitro models suitable for this purpose are at hand. The aim of this study was to develop flexible, well-controlled, easy-to-use, integrated cell models, where drug transport and drug metabolism processes could be studied simultaneously. HEK293 cells stably transfected with the organic anion transporting polypeptide 1B1 (OATP1B1) were subjected to either transient transfection or adenoviral infection to introduce the genes expressing cytochrome P450 3A4 (CYP3A4), NADPH cytochrome P450 oxidoreductase (POR), cytochrome b5 (CYB5A), and multidrug resistance protein 1 (MDR1), in different combinations. Thereafter, the time and concentration-dependent transport and metabolism of two well-characterized statins, atorvastatin (acid and lactone forms) and simvastatin (acid form), were determined in the different models. The results show that CYP3A4-dependent metabolism of the more hydrophilic atorvastatin acid was dependent on OATP1B1 uptake and influenced by MDR1 efflux. In contrast, the metabolism of the more lipophilic atorvastatin lactone was not affected by active transport, whereas the metabolism of simvastatin acid was less influenced by active transport than atorvastatin acid. Our results, together with the models being applicative for any combination of drug transporters and CYP metabolizing enzymes of choice, provide proof-of-concept for the potential of the new integrated cell models presented as valuable screening tools in drug discovery and development.

Osteogenic/osteoinductive systems combine simvastatin, poloxamine Tetronic 908 (T908) and α-cyclodextrins (αCDs) in a supramolecular network that enhances the solubility/stability of the simvastatin hydroxy acid form and synergistically promotes osteoblast differentiation. Incorporation of 5% αCD transforms dilute T908 solutions (as low as 2% copolymer) into gels, enhances the osteoinductive activity of T908, and provides simvastatin sustained release for more than one week, which results in higher and more prolonged alkaline phosphatase (ALP) activity. The performance of the intrinsically osteoinductive polypseudorotaxane scaffold can be easily tuned by modifying the concentrations of T908, αCD, and simvastatin in a certain range of values. Moreover, the use of affordable, stable materials that can be sterilized applying a conventional method make the supramolecular gels advantageous candidates as scaffolds to be applied in the critical defect using minimally invasive techniques., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)