Simvastatin (SV), a cholesterol-lowering agent, has been widely used in the treatment of hypercholesterolemia, dyslipidemia and coronary heart disease, but SV shows the low oral bioavailability due ...to its poor aqueous solubility and extensive metabolism by cytochrome-3A system in intestinal guts and liver. In this work, SV loaded lipid nanoparticles (SLNs) with different components were designed to enhance its oral bioavailability, and the plasma concentration of SV and its active metabolite (simvastatin acid, SVA) was determined by LC–MS–MS method. The experimental results showed that SLNs were spherical nano-sized particles with high encapsulation efficiency (>95%). The in situ intestinal absorption indicated that the absorption of SLNs was greatly improved compared with that of free SV, and the absorption was changed with the site of the intestinal segments. SLNs could be uptaken into the enterocytes through both clathrin and caveolae mediated endocytosis pathways. The oral bioavailability of SV after its incorporation into the lipid nanoparticles was improved by 3.37-fold for SLNs I and 2.55-fold for SLNs II compared with that from free SV in rats, and that of the SVA was significantly enhanced as well. As a result, lipid nanoparticles could be a promising delivery system to enhance the oral bioavailability of simvastatin.
ABSTRACT
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.
Organic anion transporting polypeptide 1B1 (OATP1B1) is an uptake transporter located at the sinusoidal membrane of human hepatocytes. This study aimed to investigate the effects of genetic ...polymorphism in the SLCO1B1 gene encoding OATP1B1 on the pharmacokinetics of simvastatin.
Four healthy volunteers with the homozygous SLCO1B1 c.521CC genotype, 12 with the heterozygous c.521TC genotype and 16 with the homozygous c.521TT genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of simvastatin. Plasma concentrations of simvastatin (inactive lactone) and its active metabolite simvastatin acid were measured for 12 h.
The AUC0-infinity of simvastatin acid was 120 and 221% higher in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TC and c.521TT (reference) genotypes, respectively (P<0.001). The Cmax of simvastatin acid was 162 and 200% higher in participants with the c.521CC genotype than in those with the c.521TC and c.521TT genotypes (P<0.001). The Cmax of simvastatin acid occurred earlier in participants with the c.521CC and c.521TC genotypes than in those with the c.521TT genotype (P<0.05). No association existed between the SLCO1B1 genotype and the elimination half-life of simvastatin acid. Moreover, no statistically significant association was seen between the SLCO1B1 genotype and the pharmacokinetics of simvastatin lactone.
SLCO1B1 polymorphism markedly affects the pharmacokinetics of active simvastatin acid, but has no significant effect on parent simvastatin. Raised plasma concentrations of simvastatin acid in patients carrying the SLCO1B1 c.521C variant allele may enhance the risk of systemic adverse effects during simvastatin treatment. In addition, reduced uptake of simvastatin acid by OATP1B1 into the liver in patients with the c.521C allele could reduce its cholesterol-lowering efficacy.
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This study aims to formulate and optimize simvastatin loaded chitosan-tripolyphosphate nanoparticles (SIM CS-TPP NPs) using ionic gelation method to provide a local delivery system ...that controls and sustains the release of simvastatin in the desired dose to promote bone regeneration. Box-Behnken design was adopted for optimization of the formulation variables of the prepared nanoparticles namely, CS percentage, TPP percentage and homogenization time. The optimized formula was selected and characterized by transmission electronic microscopy, in-vitro release, swelling index and storage stability. The ability of the optimum formula to stimulate bone regeneration upon implantation in bone defect generated in rabbits was also evaluated. The optimum SIM CS-TPP NPs had particle size of 106 nm, zeta potential of 43.3 mv, polydispersity index of 0.295 and entrapment efficiency of 98.78% and also showed good storage stability over the first month in addition to controlled and steady release over 2 weeks that effectively delivered simvastatin in a therapeutic dose needed for bone regeneration. Cone beam computed tomography 3D images, bone density measurements and histopathological analysis confirmed the high potential of SIM CS-TPP NPs in promoting bone regeneration in the generated defects compared to both the non-medicated formula and untreated groups after 6 weeks of implantation.
Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, ...unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe
O
@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe
O
@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe
O
@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe
O
have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe
O
@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.
Previously we developed and characterized a novel hydrogel film wound dressing containing Sodium Alginate and Pectin loaded with Simvastatin with multi-functional properties. This study investigated ...the in-vivo efficacy of the developed wound dressing on type I diabetic wound model. Experiments were performed on male Wistar rats for the period of 21-days. Animals developed diabetes after intraperitoneal injection (50 mg/kg) of Streptozotocin then randomly divided into different groups. On days 7, 14, and 21 of post-wounding, animals were euthanized and the wounds tissue were harvested for analysis. The wound healing rate, hematology and histological analysis, hydroxyproline assay, and Vascular Endothelial Growth Factor A measurements were noted. The results revealed that the wound dressing healed the wounded area significantly (p < 0.05) higher than the control after 21-day treatment and wound closure was ~99% without any adverse systemic reactions. Histological analysis qualitatively revealed an enhanced re-epithelialization and collagen deposition. Moreover, results also showed an improved rate of collagen synthesis and angiogenesis in the group treated with the hydrogel film loaded with Simvastatin. Thus, the present study demonstrated that developed film holds great potential for the acceleration of diabetic wound healing by its pro-angiogenic effect, faster re-epithelialization and increased collagen deposition.
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single‐nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to ...simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin‐induced myopathy.
Clinical Pharmacology & Therapeutics (2014); 96 4, 423–428. doi:10.1038/clpt.2014.125
Simvastatin (SS) is an effective cholesterol-lowering medicine, and is hydrolyzed to simvastatin acid (SSA) after oral administration. Due to SS and SSA inter-conversion and its pH and temperature ...dependence, SS and SSA quantitation is analytically challenging. Here we report a high-throughput salting-out assisted liquid/liquid extraction (SALLE) method with acetonitrile and mass spectrometry compatible salts for simultaneous LC–MS/MS analysis of SS and SSA. The sample preparation of a 96-well plate using SALLE was completed within 20
min, and the SALLE extract was diluted and injected into an LC–MS/MS system with a cycle time of 2.0
min/sample. The seamless interface of SALLE and LC–MS eliminated drying down step and thus potential sample exposure to room or higher temperature. The stability of SS and SSA in various concentration ratios in plasma was evaluated at room and low (4
°C) temperature and the low temperature (4
°C) was found necessary to maintain sample integrity. The short sample preparation time along with controlled temperature (2–4
°C) and acidity (pH 4.5) throughout sample preparation minimized the conversion of SS
→
SSA to ≤0.10% and the conversion of SSA
→
SS to 0.00% The method was validated with a lower limit of quantitation (LLOQ) of 0.094
ng
mL
−1 for both SS and SSA and a sample volume of 100
μL. The method was used for a bioequivalence study with 4048 samples. Incurred sample reproducibility (ISR) analysis of 362 samples from the study exceeded ISR requirement with 99% re-analysis results within 100
±
20% of the original analysis results.
Silica-lipid hybrid (SLH) microparticles are a solidified lipid-based drug delivery system under investigation for their aptitude to enhance the oral bioavailability of poorly water-soluble drugs. ...The cholesterol-lowering agent, simvastatin (SIM), is poorly water-soluble and undergoes extensive first pass metabolism, resulting in a low oral bioavailability of approximately 5%. Hence, the current pre-clinical studies investigated the application of SLH technology to SIM with a supersaturation approach, aiming to enhance bioavailability and drug loading capacity. Additionally, the effect of silica was explored by evaluating the performance of SLH fabricated with silica of different particle geometries. SLH microparticles with supersaturated SIM loading levels ranging from 100% to 400% above the equilibrium solubility were successfully fabricated using either Aerosil® 300 or Syloid® 244 silica. All SLH formulations existed as white free-flowing powders, consisting of spherical porous microparticles for Aerosil® 300, and aggregated irregular microparticles for Syloid® 244. During in vitro dissolution in pH 7.0 media, the SLH formulations performed up to 4.4-fold greater than pure SIM powder. Furthermore, in vivo oral pharmacokinetics in male Sprague-Dawley rats revealed that the SLH formulations enhanced the oral bioavailability of SIM up to 6.1-fold and 2.9-fold, in comparison to pure SIM powder and a commercially available formulation (Simvastatin Sandoz®), respectively. The greatest in vivo performance enhancement was observed for the SLH formulation manufactured with Syloid® 244 silica with a supersaturation level of 200%. SLH technology demonstrated to be a successful formulation strategy to significantly improve the oral bioavailability of SIM in rodents and therefore, has a strong potential to also improve the oral bioavailability of SIM in humans.
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