NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2025
·
IF 3.1
Huang Lulu,Ning Chen,He Jiake,Wang Mingcheng,Chen Xijing,Guo Xiaohui,Zhong Lin
Multimorbidity, therapeutic complexity, and polypharmacy, which greatly increases the risk of drug-drug interactions (DDIs) and adverse medical outcomes, have become important and growing challenges in clinical practice. Statins are frequently prescribed to manage post-transplant dyslipidemia and reduce overall cardiovascular risk in solid organ transplant recipients. This study aimed to determine whether rosuvastatin has significant DDIs with tacrolimus (the first-line immunosuppressant) and to evaluate the risk of hepatotoxicity associated with concomitant therapy. We first studied whether a rat model could be established to assess the magnitude of rosuvastatin-tacrolimus DDI. The liver function index and histopathological examination were performed to investigate the characteristics of hepatotoxicity in the presence and absence of DDI. The clinical DDI potential between rosuvastatin and tacrolimus was also explored. Single-dose intravenous administration of tacrolimus did not significantly affect the area under the plasma concentration–time curve (AUC 0-∞ ), clearance (CL), and volume of distribution at steady-state ( V ss ) of rosuvastatin in rats, despite a 96.7% increase in the rosuvastatin maximum plasma concentration ( P = 0.024). Multiple doses of intravenous tacrolimus had no effect on the systemic disposition of rosuvastatin, but significantly increased aspartate transaminase (AST) by 42.6% ( P = 0.043). Multiple doses of intravenous tacrolimus and rosuvastatin significantly altered the disposition of rosuvastatin, reducing alanine aminotransferase (ALT) and AST by 38.3% ( P = 0.040) and 31.6% ( P = 0.019), respectively. Histological evaluation of the liver specimens revealed patterns of drug-induced liver injury in rats. At clinically relevant doses, tacrolimus was predicted to be unable to cause pharmacokinetic interactions with rosuvastatin through basic models. The concomitant administration of tacrolimus and rosuvastatin has a minor impact on rosuvastatin pharmacokinetics; however, mild hepatotoxicity has been observed in rats.
研究领域:
药理学
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毒理学
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临床医学
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DOI
PubMed
高影响因子
Journal of Analytical Methods in Chemistry
·
2024
·
IF 2.3
Yajie Hao,Guang Yin,Xuemei Wang,Juan Fu,Qihui Cao,Qinyong Sun,Guimin Zhang,Zhong Feng
Rosuvastatin calcium is a widely used 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. To establish a control strategy for the elemental impurities, a new digestion method combined with an inductively coupled plasma-mass spectrometer (ICP-MS) was developed and validated by our team to determine elements Cd, Pb, As, Hg, Co, V, and Ni in rosuvastatin calcium tablets, which digest the sample perfectly even in the presence of a large number of excipients, especially titanium dioxide. The measurement mode was collision cell mode with kinetic energy discrimination (KED). 209Bi+, 115In+, and 89Y+ were chosen as internal standard elements. The recoveries of the limit of quantitation (LOQ) ranged from 90.5% to 106.4%, concentrations of the abovementioned elements in LOQ were 0.25 µg·L−1, 0.25 µg·L−1, 0.75 µg·L−1, 1.5 µg·L−1, 2.5 µg·L−1, 5 µg·L−1, and 8 µg·L−1 , respectively, linear correlation coefficients were above 0.9997, the recoveries in accuracy item ranged from 91.8% to 103.6%, and relative standard deviations (RSDs) of recovery in precision were not more than 1.8%, reflecting a reliable method of high sensitivity, strong anti-interference capacity, and good precision, and that it was suitable for the determination of elemental impurities in drugs.
研究领域:
药学
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分析化学
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DOI
PubMed
高影响因子
NEUROTOXICOLOGY
·
2026
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IF 3.8
Xianzheng Sang,Yichao Ye,Chengzi Yang,Xiaoxiang Hou,Yangu Guo,Hantong Shi,Chunhui Wang,Wen Chen,Danfeng Zhang,Lijun Hou
Background Hydroxymethylglutaryl-coenzyme A (HMGCR) inhibitors, known as statins, as first-line lipid-lowering therapies for cardiovascular diseases. Despite their widespread use, concerns persist regarding potential cognitive adverse effects, although a definitive causal relationship remains elusive. Methods To investigate the underlying mechanisms, this study integrated network toxicology, in vitro experiments, public RNA-sequencing data, computational simulations, and Mendelian randomization analysis. Rosuvastatin was chosen as a representative statin, with human as the focused species and the HMC3 human microglial cell line as the in vitro model. Results Network toxicology initially identified microglia as a critically involved cell type. A multi-method approach then demonstrated that rosuvastatin alters microglial functions—including cell viability, migration, phagocytosis, and inflammatory responses—potentially by the JAK-STAT signaling pathway. Conclusions These findings suggest that rosuvastatin-induced disruption of microglial function may contribute to cognitive impairment. Our study elucidates potential pathways for this adverse effect and provides novel insights for developing preventive and therapeutic strategies.
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高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Qing Sun,Li Li,Quan Zhou
Purpose Wuzhi capsule (WZ) is a proprietary Chinese medicine prepared from the ethanolic extract of Schisandra sphenanthera that is commonly used to treat liver injury. Statins are widely used in patients with hyperlipidemia, coronary heart disease, metabolic syndrome, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Co-administration of statins with WZ is possible in clinical practice. WZ has obvious inhibitory effects on the bioavailability of atorvastatin and simvastatin; however, the drug–herb interactions between WZ and rosuvastatin have not been addressed. We explored the effects of WZ on the pharmacokinetics of rosuvastatin in Sprague-Dawley rats to promote a rational use of statins.Methods Eighteen male rats were randomly and evenly divided into three groups: control group (gavage feeding of rosuvastatin 10 mg·kg−1), single dose group (gavage feeding of a single dose of WZ 150 mg·kg−1 followed by rosuvastatin 10 mg·kg−1) and multiple doses group (gavage feeding of WZ 150 mg·kg−1 for 7 days followed by rosuvastatin 10 mg·kg−1 on the seventh day). Plasma samples were collected at different times before and after rosuvastatin administration. The other 18 female rats were tested the same way as the male rats. All samples were analyzed by a validated LC-MS/MS method, and the pharmacokinetic parameters were calculated using a non-compartmental model.Results In both male and female rats, there were no statistically significant differences in rosuvastatin pharmacokinetic parameters between the control group, the single dose group, and the multi-dose group.Conclusion Acute or long-term intake of WZ had no obvious effect on the pharmacokinetics of rosuvastatin, and therefore rosuvastatin could be used as an alternative to atorvastatin and simvastatin when WZ is clinically required in conjunction with statins. An appropriate pharmacodynamic study is needed to encourage the safe use of this combination.
研究领域:
药理学
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药剂学
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中医药
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DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
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2024
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IF 6.1
Dayue Liu,Anning Yang,Yulin Li,Zhenxian Li,Peidong You,Hongwen Zhang,Shangkun Quan,Yue Sun,Yaling Zeng,Shengchao Ma,Jiantuan Xiong,Yinju Hao,Guizhong Li,Bin Liu,Huiping Zhang,Yideng Jiang
Rosuvastatin (RVS) is an excellent drug with anti-inflammatory and lipid-lowering properties in the academic and medical fields. However, this drug faces a series of challenges when used to treat atherosclerosis caused by hyperhomocysteinemia (HHcy), including high oral dosage, poor targeting, and long-term toxic side effects. In this study, we applied nanotechnology to construct a biomimetic nano-delivery system, macrophage membrane (Møm)-coated RVS-loaded Prussian blue (PB) nanoparticles (MPR NPs), for improving the bioavailability and targeting capacity of RVS, specifically to the plaque lesions associated with HHcy-induced atherosclerosis. In vitro assays demonstrated that MPR NPs effectively inhibited the Toll-like receptor 4 (TLR4)/hypoxia-inducible factor-1α (HIF-1α/nucleotide-binding and oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) signaling pathways, reducing pyroptosis and inflammatory response in macrophages. Additionally, MPR NPs reversed the abnormal distribution of ABCA1/ABCG1 caused by HIF-1α, promoting cholesterol efflux and reducing lipid deposition. In vivo studies using apolipoprotein E knockout ( ApoE −/− ) mice confirmed the strong efficacy of MPR NPs in treating atherosclerosis with favorable biosecurity, the mechanism behind this efficacy is believed to involve the regulation of serum metabolism and the remodeling of gut microbes. These findings suggest that the synthesis of Møm-coated RVS-loaded PB NPs provides a promising nanosystem for the targeted therapy of HHcy-induced atherosclerosis.
研究领域:
纳米技术
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药理学
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心血管疾病
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分子生物学
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免疫学
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PubMed
高影响因子
BIOPROCESS AND BIOSYSTEMS ENGINEERING
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2019
·Vol. 43
·期 1
·21-31
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IF 2.371
Zhang Xiao-Jian,Wang Wen-Zhong,Zhou Rong,Liu Zhi-Qiang,Zheng Yu-Guo
Abstract tert -Butyl (3 R ,5 S ) - 6-chloro-3,5-dihydroxyhexanoate [(3 R ,5 S )-CDHH] is the key chiral intermediate to synthesize the side chain of the lipid-lowering drug rosuvastatin. Carbonyl reductases showed excellent activity for the biosynthesis of (3 R ,5 S )-CDHH. The requirement of cofactor NADH/NADPH leads to high cost for the industrial application of carbonyl reductases. In this study, a self-sufficient biocatalyst based on carbonyl reductase and NADP + co-immobilization strategy was developed on an amino resin carrier LX-1000HAA (SCR-NADP + @LX-1000HAA). The self-sufficient biocatalyst achieved in situ cofactor regeneration and showed the activity recovery of 77.93% and the specific activity of 70.45 U/g. Asymmetric synthesis of (3 R ,5 S )-CDHH using SCR-NADP + @LX-1000HAA showed high enantioselectivity (> 99% e.e.) and yield (98.54%). Batch reactions were performed for ten cycles without extra addition of NADP + , and the total yield of (3 R, 5 S )-CDHH achieved at 10.56 g/g biocatalyst. The present work demonstrated the potential of the self-sufficient biocatalyst for the asymmetric biosynthesis of rosuvastatin intermediate. Graphic abstract
研究领域:
生物化学
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酶工程
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药物合成
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
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IF 8.5
Tao Guo,Yuxin Wang,Muhammad Abid Hayat,Yu Si,Yining Ni,Jingwen Zhang,Yun Qiu,Yu Zeng,Yudie Cao,Yancheng Hong,Bo Chen,Jiabo Hu
Intracerebral hemorrhage (ICH) is a severe form of stroke with high mortality and disability rates, largely due to its complex pathology. Currently, no effective therapies exist. Rosuvastatin has shown neuroprotective effects, but its low bioavailability and poor targeting to hemorrhagic sites limit its therapeutic efficacy. To overcome these challenges, this study developed rosuvastatin-loaded human H-ferritin nanoparticles (Rsv@HFn) as a brain-targeting nanoplatform. This nanoplatform enhances the drug's ability to cross the blood-brain barrier, increasing its accumulation at the injury site and improves its therapeutic efficacy. Rsv@HFn also facilitates the translocation of Nrf-2 to the nucleus, increasing HO-1 and CD91 expression and promoting the shift of M1 microglia to the M2 phenotype and reducing neuroinflammation and oxidative stress. Additionally, Rsv@HFn improves blood-brain barrier integrity, reduced brain edema, and alleviated neuropathological damage in ICH mice. Overall, this study introduces a promising therapeutic strategy for ICH by improving drug delivery and targeting, reducing inflammation, and enhancing recovery. These findings provide new avenues for future clinical research in treating ICH.
研究领域:
神经科学
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药理学
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纳米技术
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卒中研究
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治疗学
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产品关联
DOI
PubMed
高影响因子
Lipids in Health and Disease
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2024
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IF 3.9
Xue Ran,Ying-jie Wang,Shi-gang Li,Chi-bing Dai
Background/aims Research has indicated that treatment with rosuvastatin can improve liver pathology in metabolic-associated fatty liver disease (MAFLD) patients and that treatment with Bifidobacterium can improve MAFLD. Therefore, the effects of Bifidobacterium , rosuvastatin , and their combination on related indices in a rat model of diet-induced MAFLD need to be investigated. Methods Forty rats were divided into five groups: the normal diet group (N), high-fat diet (HFD) model group (M), HFD + probiotic group (P), HFD + statin group (S), and HFD + probiotic + statin group (P-S). To establish the MAFLD model, the rats in Groups M, P, S, and P-S were fed a HFD for 8 weeks. The treatments included saline in Group N and either Bifidobacterium , rosuvastatin , or their combination in Groups P, S, and P-S by intragastrical gavage. After 4 weeks of intervention, the rats were euthanized, and samples were harvested to analyze gastrointestinal motility and liver function, pathological changes, inflammatory cytokine production, and the expression of proteins in key signaling pathways. Results HFD feeding significantly increased the body weight, liver index, and insulin resistance (IR) index of the rats, indicating that the MAFLD model was successfully induced. Bifidobacterium reduced the liver of MAFLD rats, while Bifidobacterium with Rosuvastatin decreased the liver index, IR index, and levels of aspartate aminotransferase and alanine aminotransferase in MAFLD rats. The MAFLD model showed altered expression of proteins in signaling pathways that regulate inflammation, increased production of inflammatory cytokines, an elevated MAFLD activity score (MAS), and pathological changes in the liver. The MAFLD model also showed reduced relative counts of intestinal neurons and enteric glial cells (EGCs), altered secretion of gastrointestinal hormones, and slowed gastrointestinal emptying. Bifidobacterium , rosuvastatin , or their combination inhibited these various changes. HFD feeding changed the rats’ gut microbiota, and the tested treatments inhibited these changes. These results suggest that the gastrointestinal motility disorder and abnormal liver function in MAFLD rats may be related to a reduction in Escherichia-Shigella bacteria and an increase in Asticcacaulis bacteria in the gut microbiota and that the improvement in liver function induced by Bifidobacterium plus rosuvastatin may be related to increases in Sphingomonas and Odoribacter bacteria and a decrease in Turicibacter bacteria in the gut microbiota. Conclusions The combined use of Bifidobacterium and rosuvastatin could better regulate the gut microbiota of MAFLD model rats, promote gastrointestinal emptying, and improve liver pathology and function than single treatment with Bifidobacterium or rosuvastatin . This provides a better strategy for the treatment of MAFLD.
研究领域:
胃肠病学
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肝病学
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微生物学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2021
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IF 5.811
Ning Chen,Su Shengdi,Li Jiaming,Kong Dexuan,Cai Hui,Qin Zhiying,Xing Han,Chen Xijing,He Jiake
Purpose: The combination therapy of rosuvastatin (RSV) and the platelet inhibitor clopidogrel (CP) is widely accepted in the management of cardiovascular diseases. The objective of the present study was to identify the mechanism of RSV–CP DDI and evaluate the risk of hepatotoxicity associated with the concomitant use of CP.Methods: We first studied the effect of CP and its major circulating metabolite, carboxylic acid metabolite (CPC), on RSV transport by overexpressing cells and membrane vesicles. Second, we investigated whether a rat model could replicate this DDI and then be used to conduct mechanistic studies and assess the risk of hepatotoxicity. Then, cytotoxicity assay in hepatocytes, biochemical examination, and histopathology were performed to measure the magnitude of liver injury in the presence and absence of DDI.Results: CP inhibited OATP1B1-mediated transport of RSV with an IC50 value of 27.39 μM. CP and CPC inhibited BCRP-mediated RSV transport with IC50 values of <0.001 and 5.96 μM, respectively. The CP cocktail (0.001 μM CP plus 2 μM CPC) significantly inhibited BCRP-mediated transport of RSV by 26.28%. Multiple p.o. doses of CP significantly increased intravenous RSV plasma AUC0-infinity by 76.29% and decreased intravenous RSV CL by 42.62%. Similarly, multiple p.o. doses of CP significantly increased p.o. RSV plasma AUC0-infinity by 87.48% and decreased p.o. RSV CL by 43.27%. CP had no effect on cell viability, while RSV exhibited dose-dependent cytotoxicity after 96 h incubation. Co-incubation of 100 μM CP and RSV for 96 h significantly increased intracellular concentrations and cell-to-medium concentration ratios of RSV and reduced hepatocyte viability. Histological evaluation of liver specimens showed patterns of drug-induced liver injury. Cholestasis was found in rats in the presence of DDI.Conclusion: CP is not a clinically relevant inhibitor for OATP1B1 and OATP1B3. The primary mechanism of RSV–CP DDI can be attributed to the inhibition of intestinal BCRP by CP combined with the inhibition of hepatic BCRP by CPC. The latter is likely to be more clinically relevant and be a contributing factor for increased hepatotoxicity in the presence of DDI.
研究领域:
药理学
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毒理学
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临床医学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
·
2023
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IF 3.8
Wanbing Rao,Lijun Li,Yuting Liu,Chenxia Zhang,Xiaofang Wei,Zeyi Wu,Meiyan Qiu,Shuming Wu,Chunhui Qi,Jinfu Zheng,Shaoyu Cai,Zhongqing Wang
During the development of headspace gas chromatography (HSGC) method for assessing residual solvents in rosuvastatin calcium (RSV) drug substance, acetaldehyde (AA) was detected in obtained chromatograms, with a calculated concentration of up to 226 ppm. After a series of experiments, it was established that acetaldehyde originates from matrix interference due to direct degradation of Imp-C, which is accompanied by the formation of impurity at relative retention time (RRT) 2.18, without the involvement of impurity at RRT 2.31. The thermal instability of Imp-C also results in the formation of impurity at RRT 2.31 through dehydration and decarboxylation. In addition, cyclization reaction of degradant at RRT 2.18 further resulted in the generation of impurity at RRT 2.22. The structure of these three degradants, were confirmed by liquid chromatography-mass spectrometry (LC-MS), 1D and 2D nuclear magnetic resonance (NMR) measurement. In order to minimize the said matrix interference, a simple precipitation procedure was proposed as a pretreatment to mitigate the impact of Imp-C. Subsequently, an HSGC method was developed for the simultaneous determination of the degradant AA and the other five residual solvents used in RSV synthetic process. The final method was validated concerning precision, limit of detection (LOD) and limit of quantitation (LOQ), linearity, and accuracy.
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PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2021
·Vol. 35
·期 7
·e5093
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IF 1.902
Wei Wu,Rui Cheng,Zhenzhou Jiang,Luyong Zhang,Xin Huang
A rapid and specific UPLC–MS/MS method with a total run time of 3.5 min was developed for the determination of pravastatin, fexofenadine, rosuvastatin, and methotrexate in rat primary hepatocytes. After protein precipitation with 70% acetonitrile (containing 30% H 2 O), these four analytes were separated under gradient conditions with a mobile phase consisting of 0.03% acetic acid (v/v) and methanol at a flow rate of 0.50 mL/min. The linearity, recovery, matrix effect, accuracy, precision, and stability of the method were well validated. We evaluated drug–drug interactions based on these four compounds in freshly suspended hepatocytes. The hepatic uptake of pravastatin, fexofenadine, rosuvastatin, and methotrexate at 4°C was significantly lower than that at 37°C, and the hepatocytes were saturable with increased substrate concentration and culture time, suggesting that the rat primary hepatocyte model was successfully established. Triptolide showed a significant inhibitory effect on the hepatic uptake of these four compounds. In conclusion, this method was successfully employed for the quantification of pravastatin, fexofenadine, rosuvastatin, and methotrexate and was used to verify the rat primary hepatocyte model for Oatp1, Oatp2, Oatp4, and Oat2 transporter studies. Then, we applied this model to explore the effect of triptolide on these four transporters.
研究领域:
药理学
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分析化学
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肝脏病学
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PubMed
高影响因子
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