DRUG METABOLISM AND DISPOSITION
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2022
·Vol. 50
·期 6
·809-818
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IF 3.579
Zitao Guo,Mengling Liu,Jian Meng,Yaru Xue,Qi Huang,Yuandong Zheng,Yali Wu,Zhendong Chen,Jinghua Yu,Dafang Zhong,Guangze Li,Xiaoyan Chen,Xingxing Diao
Excretion of [14C]HR011303-derived radioactivity showed significant species difference. Urine (81.50% of dose) was the main excretion route in healthy male subjects, whereas feces (87.16% of dose) was the main excretion route in rats. To further elucidate the underlying cause for excretion species differences of HR011303, studies were conducted to uncover its metabolism and excretion mechanism. M5, a glucuronide metabolite of HR011303, is the main metabolite in humans and rats. Results of a rat microsome incubation study suggested that HR011303 was metabolized to M5 in the rat liver. According to previous studies, M5 is produced in both human liver and kidney microsomes. We found that M5 in the human liver can be transported to the blood by multidrug resistance-associated protein (MRP) 3, and then the majority of M5 can be hydrolyzed to HR011303. HR011303 enters the human kidney or liver through passive diffusion, whereas M5 is taken up through organic anion transporter (OAT) 3, organic anion-transporting polypeptide (OATP) 1B1, and OATP1B3. When HR011303 alone is present, it can be metabolized to M5 in both sandwich-cultured rat hepatocytes (SCRH) and sandwich-cultured human hepatocytes (SCHH) and excreted into bile as M5 in SCRH. Using transporter inhibitors in sandwich-cultured model and membrane vesicles expressing MRP2 or Mrp2, we found that M5 was a substance of MRP2/Mrp2, and the bile efflux of M5 was mainly mediated by MRP2/Mrp2. Considering the significant role of MRP3/Mrp3 and MRP2/Mrp2 in the excretion of glucuronides, the competition between them for M5 was possibly the determinant for the different excretion routes in humans and rats.
研究领域:
药理学
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毒理学
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药物代谢动力学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
·
IF 3.466
Jiaqi Zhang,Qingzhong Jia,Jinlong Qi,Hailin Zhang,Yaru Wu,Xiaowei Shi
QO-58 lysine (QO-58L) as a new potassium channel opener , reported to have a potential activity to cure neuropathic pain . The aim of this research is to develop and validate a high-performance liquid chromatography with tandem spectrometry (LC-MS/MS) method for the quantification of QO-58L in rat urine, feces and bile. In addition, analyze and identify the metabolites in urine and bile. The assay for this compound in samples detected with multiple reaction monitoring mode (MRM), and take nimodipine as internal standards (IS). To better understand the biotransformation of QO-58L, metabolites in urine and bile were identified by using ultra high performance liquid chromatography tandem quadrupole/time of flight mass spectrometry (UHPLC-Q-TOF-MS) in the positive and negative ion mode. Urine, feces and bile were quantified by three new methods. The results showed that: QO-58L was mainly eliminated through fecal route (92.94%), a small amount of it via biliary excretion (2.05%), and rarely through urinary excretion (0.024%). As a result, there are 11 metabolites were identified, including 8 phase I metabolites resulting from elimination, hydroxylation and dihydroxylation, and 3 phase II metabolites originating from sulfation, N -acetylcysteine conjugation and glucuronidation. Furthermore, the newly discoveries of excretion and metabolism significantly expanded our understanding and was going to be greatly helpful for QO-58L's further pharmacokinetic study in vivo.
研究领域:
药理学
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分析化学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Wubuli Abudukahaer,Chai Junwei,Liu Haoqiang,Nijat Dilaram,Li Jianmin,Xia Guoyu,Cao Qi,Zhang Saidan,Huang Weidong,Aipire Adila,Li Jinyao
Glycyrrhiza uralensis polysaccharides (GUPS) are widely applied in biomedicine and functional food due to their multiple pharmacological activities and low toxicity. Despite their widespread use, the in vivo metabolic profile of GUPS remains poorly understood. To address this gap, we developed a quantitative analysis method that involves labeling GUPS with visible fluorescein (5-DTAF) and near-infrared (NIR) fluorescein (Cy7), resulting in stable conjugates with substitution degrees of 0.81% for 5-DTAF and 0.39% for Cy7. The pharmacokinetic studies showed a biphasic elimination pattern in the blood concentration-time curve following both intravenous and oral administration, consistent with a two-compartment model. Using fluorescence quantification and NIR imaging, we observed that GUPS was distributed to various tissues, exhibiting higher concentrations particularly in liver, kidney and lung. Excretion studies indicated that feces were the major excretion pathway of GUPS after oral administration (60.98%), whereas urine was the main pathway after intravenous administration (31.16%). Notably, GUPS could be absorbed rapidly by gut (Tmax 1 ± 0.61 h) and showed a biological half-time t1/2 26.4 ± 7.72 h after oral administration. Furthermore, the Caco-2 cells uptake studies illustrated that macropinocytosis and clathrin-mediated endocytosis were participated in the transport of GUPS in intestine epithelium. This comprehensive analysis of the in vivo pharmacokinetics of GUPS not only enhances our understanding of its metabolic pathways but also establishes a foundational basis for its clinical application, optimizing its therapeutic potential and safety profile.
研究领域:
药理学
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生物医学工程
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生物化学
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产品关联
DOI
PubMed
高影响因子
Small
·
2021
·Vol. 17
·期 43
·2103584
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IF 13.281
Jinsong Tao,Zhengjie Wei,Meng Xu,Long Xi,Yaxin Cheng,Simon Ming-Yuen Lee,Wei Ge,Ying Zheng
Polymeric nanocarriers have high biocompatibility for potential drug delivery applications. After entering bloodstream, nanocarriers will circulate, interact with proteins, dissociate, or be cleared by reticuloendothelial system. Zebrafish as a visual animal model, can serve as a tool for screening nanomedicines and monitoring nanocarrier behaviors in vivo. However, a comprehensive correlation between zebrafish and rodent models is currently deficient. Here, different-sized poly(caprolactone) nanocarriers (PCL NCs) are fabricated with or without PEGylation to investigate correlation between zebrafish and mice regarding their biofate via Förster resonance energy transfer technique. Results show that PEGylated PCL NCs have higher integrity in both zebrafish and mice. Small PEG-PCL NCs have longer circulation, while large PEG-PCL NCs have dramatically higher macrophage sequestration in zebrafish and mice spleen, leading to poor circulation. PCL NCs dissociate rapidly with less macrophage sequestration. Moreover, in 7 days postfertilization (dpf) zebrafish, polymers are eliminated via hepatobiliary pathway, which is not fully functional at earlier stages of development. The effects of nanocarrier integrity on macrophage sequestration in zebrafish and good correlation with mice spleen are pioneered to be demonstrated. The findings suggest that 7 dpf zebrafish are suitable as an in vivo screening model of nanocarriers and predict their biofate in rodents.
研究领域:
药剂学
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纳米医学
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生物材料
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药物递送
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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）