NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
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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产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2012
·Vol. 67
·期 9
·804-808
·
IF 1.006
Liu Xiao-You,Fang Zhong-Ze,Dong Pei-Pei,Shi Xiang-Hua,Sun Xu-Yong,Teng Yan-Jie
The objective of the present study is to clearly evaluate the inhibitory effects of tacrolimus (tacro) on important UGT isoforms in human liver, including determination of inhibition kinetic type and calculation of inhibition kinetic parameters. An in vitro incubation system
was used to investigate the inhibitory effect of tacro on UGT isoforms. The recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. Among the tested UGT isoforms, UGT1A1, UGT1A3, UGT2B7 and UGT2B15 were strongly
inhibited by tacro in a concentration-dependent manner. Dixon and Lineweaver-Burk plots showed that the inhibition of UGT1A1, UGT1A3, and UGT2B7 was all best fit to competitive inhibition type, and the inhibition of UGT2B15 was best fit to noncompetitive type. The inhibition kinetic parameters
(Ki) were determined to be 4.7, 1.3, 1.9, and 4.3 M for UGT1A1, UGT1A3, UGT2B7, and UGT2B15, respectively. Inhibition of these important UGT isoforms in human liver might be an important reason for clinically frequent drug-drug interaction between tacro and other drugs.
研究领域:
药理学
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生物化学
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临床医学
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DOI
高影响因子
International Journal of Nanomedicine
·
2016
·
IF 4.32
Wenhui Pan,Mengyao Qin,Guoguang Zhang,Yueming Long,Wenyi Ruan,Jingtong Pan,Zushuai Wu,Tao Wan,Chuanbin Wu,Yuehong Xu
Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm2) and penetration through the skin (13.38±2.26 μg/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.
研究领域:
药剂学
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皮肤科学
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生物材料学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Nan Hu,Minyan Qian,Yanru Liu,Zhenwei Jiang,Caomei Xu,Wenting Zhang,Jingting Jiang
Backgroud Immunosuppressant tacrolimus (TAC) induces glucose metabolism disorder and diabetes mellitus (DM) closely associated with intestinal microbiota dysbiosis and reduced bile acid levels, and this study aimed to explore the ameliorative effect and underlying mechanism of hyodeoxycholic acid (HDCA) on TAC-induced DM in rat models. Methods We first verified the critical role of intestinal microbiota and bile acids in the pathogenesis of TAC-induced DM via antibiotic-induced gut microbiota depletion, then orally administered HDCA (100 mg/kg) to TAC-induced diabetic rats to evaluate its protective efficacy, detecting glycolipid metabolism indices, targeted bile acid omics, FXR/TGR5 protein expression, serum and ileal GLP/FGF15 levels, and mRNA levels of key metabolic genes including Cyp7a1, Cyp27a1, Cyp7b1, Cyp8b1, Fgfr4, Creb1 and Ppargc1a . Results Antibiotic treatment significantly reduced BSH-active gut microbiota such as Bacteroides and Lactobacillus , disrupting the serum bile acid pool and exacerbating diabetic symptoms by altering the gut microbiota-bile acid axis; while HDCA administration markedly improved glucose tolerance and reshaped bile acid profiles in TAC-induced diabetic rats, specifically lowering serum and fecal 12-OH/Non-12-OH BAs ratio via downregulating hepatic Cyp7a1 and upregulating hepatic Cyp8b1 expression. HDCA also suppressed enteroendocrine cell-derived GLP-1 secretion, decreased serum and ileal FGF15 levels, and reduced the expression of ileal FXR as well as hepatic Creb1 and Ppargc1a. Conclusions Collectively, HDCA exerts a significant ameliorative effect on TACinduced DM by regulating metabolic enzymes and altering bile acid profiles, with the core mechanism involving inhibited enterohepatic FXR-FGF15 axis, increased GLP-1 secretion and suppressed hepatic gluconeogenesis, all of which play key regulatory roles in this protective process.
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产品关联
DOI
PubMed
高影响因子
CHINESE CHEMICAL LETTERS
·
2025
·
IF 8.9
Wenke Liu,Di Zhang,Ziyu Qu,Keke Yi,Shumin Wan,Zihong Ye,Xinhua Dai,Jie Xie,You Jiang,Xiang Fang
Precise assessment of tacrolimus (TAC) concentrations is critical in clinical diagnostics, and liquid chromatography–mass spectrometry (LC-MS/MS) is the preferred approach due to its high specificity and sensitivity. However, classic LC-MS/MS systems are frequently enormous, costly, and need expert operation, which restricts its applicability in numerous industries. In this paper, a liquid chromatography–miniature mass spectrometry (LC-MiniMS) system was designed and developed. The miniature linear ion trap spectrometer had a footprint of 59 × 38 × 27 cm 3 , which substantially reduced the instrument size and cost while maintaining quantitative performance. The LC-MiniMS system’s circuit boards were integrated and the software automation was optimized, so it was more convenient to use and maintain. Results demonstrated excellent linearity over the range of 0.5–50 ng/mL with R 2 > 0.99. The limit of detection and limit of quantification were 0.1 and 0.3 ng/mL, respectively. The accuracy ranged from 99.67% to 106.10%, intraday precision was between 0.70% and 2.61%, and interday precision was between 0.90% and 2.90%, all within acceptable limits, and matrix effects were negligible. The method was successfully applied to quantify TAC in 32 clinical whole-blood samples, and the results strongly agreed with those from a conventional LC-MS/MS system (QTRAP 6500+). The LC-MiniMS system can efficiently quantify TAC in whole blood and provide a tiny, cost-effective, and uncomplicated option for therapeutic drug monitoring in clinical settings, especially in decentralized or resource-limited scenarios.
研究领域:
分析化学
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临床化学
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质谱分析
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治疗药物监测
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产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Gao Ping,Du Xiaoyi,Liu Lili,Xu Hua,Liu Maochang,Guan Xinlei,Zhang Chengliang
Tacrolimus-induced chronic nephrotoxicity (TIN) hinders its long-term use in patients. However, there are no drugs available in the clinic to relieve it at present. Astragaloside IV (AS-IV) is a saponin extract of the Astragalus which is widely used in the treatment of kidney disease. This study aimed to investigate the effect of AS-IV on TIN and its underlying mechanism. Herein, C57BL/6 mice were treated with tacrolimus and/or AS-IV for 4 weeks, and then the renal function, fibrosis, oxidative stress and p62-Keap1-Nrf2 pathway were evaluated to ascertain the contribution of AS-IV and p62-Keap1-Nrf2 pathway to TIN. Our results demonstrated that AS-IV significantly improved renal function and alleviated tubulointerstitial fibrosis compared with the model group. The expression of fibrosis-related proteins, including TGF-β1, Collagen I and α-SMA, were also decreased by AS-IV. Furthermore, AS-IV relieved the inhibition of tacrolimus on antioxidant enzymes. The data in HK-2 cells also proved that AS-IV reduced tacrolimus-induced cell death and oxidative stress. Mechanistically, AS-IV markedly promoted the nuclear translocation of Nrf2 and the renal protective effects of AS-IV were abolished by Nrf2 inhibitor. Further researches showed that phosphorylated p62 was significantly increased after AS-IV pretreatment. Moreover, AS-IV failed to increase nuclear translocation of Nrf2 and subsequent anti-oxidative stress in HK-2 cells transfected with p62 siRNA. Collectively, these findings indicate that AS-IV relieve TIN by enhancing p62 phosphorylation, thereby increasing Nrf2 nuclear translocation, and then alleviating ROS accumulation and renal fibrosis.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Xinhang Meng,Minfeng Shi,Jinfeng Qian,Yujie Luo,Liyuan Cui,Dajin Li,Songcun Wang
The establishment of placentation and maternal-fetal tolerance are important determinants of a successful pregnancy. Tacrolimus, also known as FK506, is a calcineurin inhibitor that has often been used for pregnant women after solid organ transplantation. Previous therapeutic interventions have shown the benefits of using the immuno-suppressive agent FK506 in improving clinical pregnancy and live birth rates and reducing the risk of spontaneous miscarriage. However, the mechanism(s) by which FK506 is involved in these processes have not been fully elucidated. To further characterize its function in early pregnancy, we explored the effect of FK506 on the human-derived first trimester extravillous trophoblast cells (HTR8/SVneo cells) and found that FK506 promoted invasion, tube formation and proliferation, but inhibited apoptosis of HTR8/SVneo cells. Based on the integrated metabolomics and transcriptomics analyses, the present study provided the cellular and molecular cues evidently showing that FK506 had positive effects on the placentation and maternal-fetal tolerance through modulating FASN-CEACAM1 pathway. The spontaneous-abortion-prone model gave further evidence that FK506 exerted a protective effect on pregnancy by regulating the FASN-CEACAM1 axis. These findings might provide a new fundamental mechanism and promising potential of low-dose FK506 in preventing pregnancy loss.
研究领域:
妇产科学
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免疫学
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生殖生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2020
·
IF 7.727
Yang Yang,Yuan Ding,Bo Fan,Yi Wang,Zhengwei Mao,Weilin Wang,Jindan Wu
Sepsis is a complex disorder with very high morbidity and mortality; it can occur when an immune disorder triggers an invasion of pathogens in the host. Although many potential anti-infective and immunosuppressive treatments have been reported, we still do not have effective means of treating sepsis in clinic. The aim of this study is to develop a nanomaterial system that targets the site of inflammation and carries a combination of multiple drugs to better treat sepsis and alleviate its symptoms. We selected poly(lactide- co -glycolide acid) (PLGA) with good biocompatibility and degradability to prepare the nanoparticles (NPs) loaded with broad-spectrum antibiotic Sparfloxacin (SFX) and anti-inflammatory immunosuppressant Tacrolimus (TAC) by an emulsion-solvent evaporation method. The targeting ability of the NPs toward inflammatory sites is endowed by grafting of the γ3 peptide (NNQKIVNLKEKVAQLEA) that can specifically bind to the intercellular adhesion molecule-1 (ICAM-1), which is highly expressed on the surface of inflammatory endothelial cells. The drug loaded γ3-PLGA NPs have excellent cytocompatibility, low hemolysis ratio, and systemic toxicity. The drug loaded γ3-PLGA NPs also have excellent antibacterial property to both Gram-positive and Gram-negative bacteria and can effectively reduce the inflammation and immune response in acute lung infection mice. This study provides a simple and robust nanoplatform to treat lung infection induced sepsis, which may pave a way to design multifunctional nanomedicine for clinical translation.
研究领域:
药学
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纳米技术
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免疫学
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传染病学
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材料科学
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DOI
PubMed
高影响因子
JCI Insight
·
2025
·
IF 6.1
Ping Gao,Xinwei Cheng,Maochang Liu,Hui Peng,Guodong Li,Tianze Shang,Jianqiao Wang,Qianyan Gao,Chenglong Zhu,Zhenpeng Qiu,Chengliang Zhang
Tacrolimus-induced chronic nephrotoxicity (TICN) hinders its long-term use, but its mechanism remains unclear. Tacrolimus exerts its pharmacological effect by inhibiting calcineurin and its substrate NFAT. Whether the inhibition of other calcineurin substrates is related to TICN remains to be explored. Transcription factor EB (TFEB), a substrate of calcineurin, plays a crucial role in various homeostasis. Herein, we found that tacrolimus inhibited TFEB nuclear translocation and activity in mouse kidneys and HK-2 cells. Then, TFEB gain- and loss-of-function rescued the effect of tacrolimus in HK-2 cells. Furthermore, TFEB activation both by phosphorylation sites mutation and agonist rescued TICN in mice. To elucidate the mechanism of TFEB, we analyzed ChIP-seq data. Growth arrest and DNA damage-inducible 45α (GADD45α) was identified as a transcriptional target of TFEB via chromatin immunoprecipitation and dual luciferase reporter assays. And then we revealed that GADD45α overexpression rescued DNA damage and kidney injury caused by tacrolimus or TFEB knockdown in vitro, and vise versa. The protective effect of GADD45α against TICN and DNA damage was further demonstrated by overexpressing it in mice. In conclusion, the persistent inhibition of TFEB-GADD45α pathway by tacrolimus contributes to TICN. This study identifies a specific target for intervention of TICN.
研究领域:
药理学
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肾病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2024
·
IF 5.5
Yan Liu,Xin-Xin Liu,Si-yu Wang,Xin-Yang Pan,Zi-Han Wang,Yu-Xin Wei,Zhi-Min Zhou,Kaihui Nan,Jing-Jie Wang
In situ gelling eye drops of tacrolimus (FK506 Gel) were developed to address the formulation challenge of tacrolimus for anterior ocular inflammatory diseases. Both in silico and in vitro investigations were conducted to screen a suitable cyclodextrin species to increase the drug solubility. Guanosine was employed as the gelator and combined with inclusion complexes of tacrolimus in the presence of borate anions to obtain FK506 Gel, which gelated when came into contact with cations in tear fluid and led to the formation of a nanofibrous hydrogel. The versatility of our design to improve the solubility and ocular retention of the hydrophobic drug was demonstrated in vivo with coumarin 6 as a model drug. A mouse dry eye model was used to evaluate the therapeutic effects of FK506 Gel, which, in combination with the biocompatibility study, suggested that FK506 Gel served as a superior treatment for anterior ocular inflammatory diseases.
研究领域:
药剂学
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眼科医学
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生物材料
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Bo Zhu,Jie Shi,Huanchao Sun,Lixin Xia,Weisen Fang,Hongjian Li,Wanshun Liu,Baoqin Han
Chitosan and its water-soluble derivatives have been widely used in biomaterials, but their disadvantages have hindered their widespread application. In this study, butyryl chitosan, a liposoluble chitosan derivative, was prepared by introducing butyryl groups into chitosan molecules through an acylation reaction. The synthesis conditions were optimised, the reaction was more efficient and simpler than previously reported strategies. Two butyryl chitosan with degrees of substitution greater than two were synthesised. Chemical characterisations confirmed that the hydroxyl and primary amine groups in the backbone of chitosan were converted into amide and ester groups, respectively. The butyryl chitosan films have advantages such as high mechanical properties, long biodegradation time, proper surface charge, good cytocompatibility, and histocompatibility. Butyryl chitosan was used as carrier to prepare an implantable tacrolimus sustained release film. Characterization results showed that tacrolimus existed in an amorphous state in the release film. This work embodies an innovative formulation using tacrolimus-loaded carboxymethyl chitosan amorphous solid dispersions embedded butyryl chitosan film with added advantage of sustained release, an effective blood concentration in vivo for 11 days and a systemic exposure but lower intrapatient variability in tacrolimus trough levels. This work merits sustainable tacrolimus release use by providing application-based proofs and qualifies as a potential formulation for sustainable tacrolimus release system. We expect an improvement in terms of therapeutic compliance with positive effects on allograft outcomes.
研究领域:
生物材料
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药学
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药物递送系统
·
聚合物化学
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产品关联
DOI
高影响因子
Journal of Materials Chemistry B
·
2023
·Vol. 11
·期 20
·4464-4474
·
IF 7
Xiaoqian Jiang,Xinxin Xu,Hua Kuang,Liqiang Liu,Liguang Xu,Aihua Qu,Chuanlai Xu
Tacrolimus is a macrolide immunosuppressant widely used in organ transplantation. Due to the narrow treatment window, therapeutic drug monitoring of the clinical application of tacrolimus is necessary. In this study, a carboxyl group introduced at the hydroxyl or carbon positions of tacrolimus was used to couple with carrier protein to synthesize complete antigens. After screening different immunogens and coating antigens, a highly-sensitive and specific monoclonal antibody (mAb) 4C5 was obtained, with a half inhibitory concentration (IC50) value of 0.26 ng mL−1 determined by indirect competitive enzyme-linked immunosorbent assay (ic-ELISA). A colloidal gold-based immunochromatographic strip (CG-ICS) was established to monitor tacrolimus in human whole blood based on the mAb 4C5. Through visual observation, it was found that the visual limit of detection (vLOD) and cut-off value of qualitative detection were 1.0 and 20.0 ng mL−1, respectively. The calculated LOD (cLOD) value of quantitative detection was 0.16 ng mL−1, and the linear range was 0.48–7.57 ng mL−1. In addition, the results of the CG-ICS for analyzing real positive samples of human whole blood were basically consistent with those of LC-MS/MS. Therefore, the CG-ICS was suitable for rapid and accurate clinical monitoring of tacrolimus.
研究领域:
药理学
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免疫学
·
分析化学
·
临床医学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）