Objective: Sakurasosaponin, a primary bioactive saponin from Aegiceras corniculatum, shows potential as an anti-cancer agent. However, there is a lack of information on its in vivo metabolism. This study aims to profile the in vivo metabolites of sakurasosaponin in rat feces, urine, and plasma after oral administration. An efficient strategy using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry was developed, which combined metabolic prediction, multiple mass defects filtering, and highresolution extracted ion chromatograms for rapid and systematic analysis.
Methods: Firstly, a theoretical list of metabolites for sakurasosaponin was developed. This was done by considering the metabolic pathways of saponins. Next, the multiple mass defects filtering method was employed to identify potential metabolites in feces and urine, using the unique metabolites of sakurasosaponin as multiple mass defects filtering templates. Subsequently, a high-resolution extracted ion chromatogram was used to quickly determine the metabolites in rat plasma post-identification in feces and urine. Lastly, the analysis of accurate mass, typical neutral loss, and diagnostic ion of the candidate metabolites was carried out to confirm their structural elucidation, and metabolic pathways of sakurasosaponin in vivo were also proposed.
Results: In total, 30 metabolites were provisionally identified in feces, urine, and plasma. Analysis of metabolic pathways revealed isomerization, deglycosylation, oxidation, hydroxylation, sulfate conjugation, glucuronide conjugation, and other related reactions as the primary biotransformation reactions of sakurasosaponin in vivo.
Conclusion: The findings demonstrate that the designed research strategy effectively minimizes matrix interference, prevents the omission of low-concentration metabolites, and serves as a foundation for the discovery of active metabolites of sakurasosaponin.
Background: Remimazolam (RMZ) is a novel ultrashort-acting benzodiazepine used for sedation by intravenous administration. The pharmacophore of RMZ includes a carboxyl ester group sensitive to esterase- mediated hydrolysis, which is the primary path of metabolic elimination. However, for the sake of drug safety, a deeper and broader knowledge of the involved metabolic pathways and the evolving metabolites is required. Information is needed on both humans and experimental animals to evaluate the possibility that humans form harmful metabolites not encountered in animal toxicity studies.
Objective: The current study aimed at identifying the mechanisms of remimazolam's metabolism and any potential clinically significant metabolites.
Methods: Using tissue homogenates from various animals and humans, the liver was identified as the tissue primarily responsible for the elimination of RMZ. CNS7054, the hydrolysis product of remimazolam, was identified as the only clinically relevant metabolite. Using bacterial or eukaryotic over-expression systems, carboxylesterase 1 (CES1) was identified as the iso-enzyme predominantly involved in RMZ metabolism, with no role for carboxylesterase 2. Using a variety of inhibitors of other esterases, the contribution to elimination mediated by esterases other than CES1 was excluded.
Results: Besides tissue carboxylesterases, rodents expressed an RMZ esterase in plasma, which was not present in this compartment in other laboratory animals and humans, hampering direct comparisons. Other pathways of metabolic elimination, such as oxidation and glucuronidation, also occurred, but their contribution to overall elimination was minimal.
Conclusion: Besides the pharmacologically non-active metabolite CNS7054, no other clinically significant metabolite of remimazolam could be identified.
Curcumin is a naturally occurring polyphenolic compound extracted from the rhizomes of Curcuma longa, commonly known as turmeric. It has been used for centuries in traditional medicine and is gaining increasing attention in modern medicine owing to its potential therapeutic benefits. Psoriasis is a chronic inflammatory disease characterized by red scaly patches on the skin. Curcumin has been found to be effective in treating psoriasis by inhibiting the activity of various enzymes and proteins involved in the inflammation and proliferation of psoriatic skin cells. Nanogel preparation of curcumin has been found to be a promising approach for the delivery of compounds to treat psoriasis. Nanogels are composed of biocompatible and biodegradable crosslinked hydrogels. The nanogel formulation of curcumin increases its solubility, stability, and bioavailability, indicating that a lower dose is needed to achieve the same therapeutic effect. This review article suggests that the nanogel preparation of curcumin can be a better alternative for psoriasis treatment as it increases the bioavailability and stability of curcumin and also reduces the required dosage. This study suggests that curcumin nanogel preparations are promising alternatives to traditional psoriasis treatments and could potentially be used as a more effective and safe treatment option. This article highlights the need for further research to fully understand the potential of curcumin nanogel preparations for psoriasis treatment in humans.
Objective: Waiganfengsha Granule, an over-the-counter drug, is commonly used for treating windheat cold and sore throat in clinical settings. However, its material basis of medicinal efficacy is still unclear. In this study, an efficient integrated analytical strategy was established for its chemical and metabolite profiles study.
Methods: Firstly, to avoid the possible false-positive results of structural elucidation, an in-house component library that contains chemical constituents reported in the literature from the six individual medicines of Waiganfengsha Granule was established. Secondary, mass data post-processing techniques, including precursor ion list and neutral loss filtering, were applied to enhance the identification accuracy. Thirdly, for the rapid characterization of those absorbed components after oral administration in rats, the identified chemical constituents were used as candidate components for the serum analysis. By comparing the retention time and analyzing mass data, the metabolites in rat plasma were identified.
Results: As a result, 57 chemical ingredients were identified, including 21 phenolic acids, 9 alkaloids, 2 flavonoids, 5 lignins, 13 saponins, and 7 other compounds. Among these, 12 compounds were unambiguously identified by comparison with reference standards, and 45 were tentatively characterized by analyzing their accurate MS data, MS/MS fragmentation patterns, and also by comparison with those data reported in the literature. Additionally, 46 metabolites were detected and identified in rat plasma.
Conclusion: This study is beneficial for understanding the chemical composition and metabolic profiles of Waiganfengsha Granule, and the results obtained might provide a solid basis for further studies on its functional mechanism.
Background: Cytochrome P450 (CYP) 46A1, also known as cholesterol 24S-hydroxylase, is essential for maintaining the homeostasis of cholesterol in the brain and serves as a therapeutic target of neurodegenerative disorders and excitatory neurotoxicity. N-methyl-d-aspartate receptor (NMDAR) is a prototypical receptor for the excitatory neurotransmitter glutamate and can be specifically regulated by 24S-hydroxycholesterol (24S-HC). Glycyrrhiza is one of the most widely used herbs with broad clinical applications, which has several pharmacological activities, such as clearing heat and detoxifying, moistening the lung and relieving cough, analgesic, neuroprotective outcomes, and regulating a variety of drug activities. Glycyrrhiza is a commonly used herb for the treatment of epileptic encephalopathy. However, whether glycyrrhiza can interfere with the activity of CYP46A1 remains unknown.
Objective: This study aimed to investigate the regulating effects of glycyrrhiza polysaccharides (GP) on CYP46A1-mediated cholesterol conversion, as well as in the modulation of related proteins.
Materials and methods: The effects of glycyrrhiza polysaccharide (GP) on the activity of CYP46A1 were investigated in vivo and in vitro. Moreover, the potential regulatory effects of GP on the expressions of CYP46A1, HMG-CoA reductase (HMGCR), and NMDAR were also detected.
Results: The in vitro results demonstrated that glycyrrhiza polysaccharide (GP), as the main water-soluble active component of glycyrrhiza, remarkably inhibited the activity of CYP46A1 in a non-competitive mode with a Ki value of 0.7003 mg/ml. Furthermore, the in vivo experiments verified that GP markedly decreased the contents of 24S-HC in rat plasma and brain tissues as compared to the control. More importantly, the protein expressions of CYP46A1, GluN2A, GluN2B, and HMG-CoA reductase (HMGCR) in rat brains were all downregulated, whereas the mRNA expressions of CYP46A1 and HMGCR were not significantly changed after treatment with GP.
Conclusion: GP exhibits a significant inhibitory effect on CYP46A1 activity in vitro and in vivo, and the protein expressions of CYP46A1, HMGCR, and NMDAR are also inhibited by GP, which are of considerable clinical significance for GP's potential therapeutic role in treating neurological diseases.
The field of cancer therapy has witnessed a transformative shift with the emergence of biomimetic nanoscale drug delivery systems. These innovative platforms draw inspiration from nature's intricate designs and have the potential to revolutionize cancer treatment by precisely targeting tumor cells while sparing healthy tissues. In this critical appraisal, we explore the current advances in biomimetic nanosystems, examining their principles, diverse natural inspirations, benefits, and challenges. Biomimetic nanoscale systems, including liposomes, exosome-based carriers, virus-mimetic nanoparticles, and cell-membrane-coated nanoparticles, have demonstrated the ability to overcome the complexities of the tumor microenvironment. They offer enhanced target specificity, improved cellular uptake, and prolonged circulation, addressing limitations associated with conventional chemotherapy. We assess recent breakthroughs and discuss the potential impact of biomimetic nanosystems on oncology, emphasizing their versatility in encapsulating various therapeutic payloads, from small molecules to nucleic acids and immunotherapeutics. While these systems hold great promise, we also scrutinize safety concerns, scalability issues, and the necessity for rigorous clinical validation. In conclusion, biomimetic nanoscale drug delivery systems represent a promising avenue in the quest for more effective and targeted cancer therapies. This appraisal provides a comprehensive overview of the current state of the field, highlighting its potential to shape the future of cancer treatment and underscoring the importance of continued research and development efforts in this dynamic and transformative domain.
Background: The simultaneous use of NSAIDs and antibiotics is recommended for bacterial diseases in human and veterinary medicine. Moxifloxacin (MFX) and dexketoprofen (DEX) can be used simultaneously in bacterial infections. However, there are no studies on how the simultaneous use of DEX affects the pharmacokinetics of MFX in rats.
Objectives: The aim of this study was to determine the effect of DEX on plasma and lung pharmacokinetics of MFX in male and female rats.
Methods: A total of 132 rats were randomly divided into 2 groups: MFX (n=66, 33 males/33 females) and MFX+DEX (n=66, 33 females/33 males). MFX at a dose of 20 mg/kg and DEX at a dose of 25 mg/kg were administered intraperitoneally. Plasma and lung concentrations of MFX were determined using the highperformance liquid chromatography-UV and pharmacokinetic parameters were evaluated by noncompartmental analysis.
Results: Simultaneous administration of DEX increased the plasma and lung area under the curve from 0 to 8 h (AUC0-8) and peak concentration (Cmax) of MFX in rats, while it significantly decreased the total body clearance (CL/F). When female and male rats were compared, significant differences were detected in AUC0-8, Cmax, CL/F and volume of distribution. The AUC0-8lung/AUC0-8plasma ratios of MFX were calculated as 1.68 and 1.65 in female rats and 5.15 and 4.90 in male rats after single and combined use, respectively.
Conclusion: MFX was highly transferred to the lung tissue and this passage was remarkably higher in male rats. However, DEX administration increased the plasma concentration of MFX in both male and female rats but did not change its passage to the lung. However, there is a need for a more detailed investigation of the difference in the pharmacokinetics of MFX in male and female rats.
Objective: This study aimed to investigate the effects of clarithromycin and ketoconazole on the pharmacokinetic properties of tacrolimus in different CYP3A4 genotype recombinant metabolic enzyme systems, so as to understand the drug interactions and their mechanisms further.
Method: The experiment was divided into three groups: a blank control group, CYP3A4*1 group and CYP3A4*18 recombinant enzyme group. Each group was added with tacrolimus (FK506) of a series of concentrations. Then 1 umol/L clarithromycin or ketoconazole was added to the recombinant enzyme group and incubated in the NADPH system for 30 minutes to examine the effects of clarithromycin and ketoconazole on the metabolizing enzymes' activity of different genotypes. The remaining concentration of FK506 in the reaction system was determined using UPLC-MS/MS, and the enzyme kinetic parameters were calculated using the software.
Results: The metabolism of CYP3A4*18 to FK506 was greater than that of CyP3А4*1B. Compared with the CYP3A4*1 group, the metabolic rate and clearance of FK506 in the CYP3A4*18 group significantly increased, with Km decreasing. Clarithromycin and ketoconazole inhibit the metabolism of FK506 by affecting the enzyme activity of CYP3A4*1B and CYP3A4*18B. After adding clarithromycin or ketoconazole, the metabolic rate of FK506 significantly decreased in CYP3A4*1 and CYP3A4*18, with Km increasing, Vmax and Clint decreasing.
Conclusion: Compared with CYP3A4*1, CYP3A4*18 has a greater metabolism of FK506, clarithromycin and ketoconazole can inhibit both the enzymatic activities of CYP3A4*1 and CYP3A4*18, consequently affecting the metabolism of FK506 and the inhibitory on CYP3A4*1 is stronger.
Precision dosing is essential in improving drug efficacy and minimizing adverse reactions, especially in liver impaired patients. However, there is no objective index to directly evaluate the body's ability to metabolize specific drugs. Many factors affect the activity of enzymes, and alter the systemic exposure of substrate drugs, like genetic polymorphism, drug-drug interactions and physiological/pathological state. So, quantifying the activities of enzymes dynamically would be helpful to make precision dosing. Recently, some endogenous substrates of enzymes, such as 6β-hydroxycortisol (6β-OH-cortisol)/cortisol and 6β-hydroxycortisone, have been identified to investigate variations in drug enzymes in humans. Clinical data obtained support their performance as surrogate probes in terms of reflecting the activities of corresponding enzyme. Therefore, a group of Monitored endogenous biomarkers in multiple points can address the uncertainty in drug metabolization in the preclinical phase and have the potential to fulfill precision dosing. This review focuses on recent progress in the contribution of endogenous substances to drug precision dosing, factors that influence enzyme activities, and drug exposure in vivo.
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