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Identification and characterization of in vitro and in vivo metabolites of steroidal alkaloid veratramine 下载免费PDF全文
Chunming Lyu Wenbin Zhou Yufeng Zhang Shen Zhang Fang Kou Zhong Zuo 《Biopharmaceutics & drug disposition》2015,36(5):308-324
Veratramine, a steroidal alkaloid originating from Veratrum nigrum L., has demonstrated distinct anti‐tumor and anti‐hypertension effects, however, its metabolism has rarely been explored. The objective of the current study was to provide a comprehensive investigation of its metabolic pathways. The in vitro metabolic profiles of veratramine were evaluated by incubating it with liver microsomes and cytosols. The in vivo metabolic profiles in plasma, bile, urine and feces were monitored by UPLC‐MS/MS after oral (20 mg/kg) and i.v. (50 µg/kg) administration in rats. Meanwhile, related P450s inhibitors and recombinant P450s and SULTs were used to identify the isozymes responsible for its metabolism. Eleven metabolites of veratramine, including seven hydroxylated, two sulfated and two glucuronidated metabolites, were characterized. Unlike most alkaloids, the major reactive sites of veratramine were on ring A and B instead of on the amine moiety. CYP2D6 was the major isozyme mediating hydroxylation, and substrate inhibition was observed with a Vmax, Ki and Clint of 2.05 ± 0.53 nmol/min/mg, 33.08 ± 10.13 µ m and 13.58 ± 1.27 µL/min/mg. SULT2A1, with Km, Vmax and Clint values of 19.37 ± 0.87 µ m , 1.51 ± 0.02 nmol/min/mg and 78.19 ± 8.57 µL/min/mg, was identified as the major isozyme contributing to its sulfation. In conclusion, CYP2D6 and SULT2A1 mediating hydroxylation and sulfation were identified as the major biotransformation for veratramine. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
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《Journal of clinical virology》2011,50(4):231-238
Neurocognitive disorders due to human immunodeficiency virus type 1 (HIV-1) infection have been reported in 25–60% of cases,1, 2, 3 despite a sustained viral response in peripheral blood while on highly active anti-retroviral therapy (HAART). A possible reason may be that the central nervous system (CNS) is less accessible for anti-retroviral agents, therefore this sanctuary site can provide a reservoir for ongoing HIV-1 replication. Mutations conferring resistance to anti-retroviral drugs may predominate in compartments where drug levels are suboptimal. This review provides an overview on the literature regarding the development of resistance mutations and the sensitivity for co-receptors in CNS.Mutations caused by the anti-retroviral drugs with the lowest intracerebral penetration would be expected to be found in higher percentages in the CNS than in the periphery of the human body. However, few studies have been performed that can confirm or reject this claim. Zidovudine, the anti-retroviral drug with the best intracerebral penetration, has been studied to some extent. This drug indeed induces resistance mutations in blood as well as the CNS.HAART induces a switch from HIV that uses co-receptor CRR5 to HIV that uses co-receptor CXCR4. This switch may appear later in the CNS compartment compared to the periphery. However, current literature shows conflicting evidence.In conclusion, the current understanding of HIV-strain evolution under drug pressure in sanctuary sites like CNS is incomplete. Therefore, more research is needed in order to establish the role of these sites in the development of drug resistant mutants under adequate HAART. 相似文献
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Zhirong Zhang Qiang Zheng Jing Han Guangping Gao Jie Liu Tao Gong Zhongwei Gu Yuan Huang Xun Sun Qin He 《Biomaterials》2009,30(7):1372-1381
We have synthesized a renal-specific drug carrier, 14-succinyl triptolide-lysozyme (TPS-LZM) conjugate for targeted delivery of TP to the PTECs. TPS-LZM could be taken up by HK-2 cells, free TP would be degraded and released, mainly from basolateral side of the cells. Compared with TP, the overall targeting efficiency (TE) of TPS-LZM was significantly enhanced from 11.74% to 95.54% and its MRT was moderately prolonged from 3.08 h to 4.10 h. At very low concentration, TPS-LZM could significantly reverse the disease progression in renal ischemia-reperfusion (I/R) injury animal models, while the mixture of free TP and LZM was ineffective. Further, TPS-LZM conjugate presented much lower hepatotoxicity (0.78 folds lower than TP) and no adverse effect on the immune (1.13 folds higher than TP) and genital system. Thus, TPS-LZM represents a very effective drug candidate for specific treatment of immunological renal diseases with low adverse side effect. 相似文献
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Chunming Lyu Yufeng Zhang Wenbin Zhou Shen Zhang Fang Kou Hai Wei Ning Zhang Zhong Zuo 《The AAPS journal》2016,18(2):432-444
Veratramine, a major alkaloid from Veratrum nigrum L., has distinct anti-tumor and anti-hypertension effects. Our previous study indicated that veratramine had severe toxicity toward male rats. In order to elucidate the underling mechanism, in vivo pharmacokinetic experiments and in vitro mechanistic studies have been conducted. Veratramine was administrated to male and female rats intravenously via the jugular vein at a dose of 50 μg/kg or orally via gavage at 20 mg/kg. As a result, significant pharmacokinetic differences were observed between male and female rats after oral administration with much lower concentrations of veratramine and 7-hydroxyl-veratramine and higher concentrations of veratramine-3-O-sulfate found in the plasma and urine of female rats. The absolute bioavailability of veratramine was 0.9% in female rats and 22.5% in male rats. Further experiments of veratramine on Caco-2 cell monolayer model and in vitro incubation with GI content or rat intestinal subcellular fractions demonstrated that its efficient passive diffusion mediated absorption with minimal intestinal metabolism, suggesting no gender-related difference during its absorption process. When veratramine was incubated with male or female rat liver microsomes/cytosols, significant male-predominant formation of 7-hydroxyl-veratramine and female-predominant formation of veratramine-3-O-sulfate were observed. In conclusion, the significant gender-dependent hepatic metabolism of veratramine could be the major contributor to its gender-dependent pharmacokinetics. 相似文献
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Hayeon Kim John A. Vargo Kenneth J. Smith Sushil Beriwal 《Clinical breast cancer》2021,21(3):e271-e278
BackgroundCurrently it remains difficult to identify patients most likely to benefit from radiotherapy (RT) for ductal carcinoma-in-situ (DCIS), thus leading to wide variation in practice patterns. The genomic risk assessment tool DCISionRT (PreludeDX) has been validated to prognosticate recurrence risk and predict RT benefit. We aimed to study the cost-effectiveness analysis comparing DCIS treatments based on DCISionRT testing to traditional clinicopathologic risk factors.Patients and MethodsA Markov state transition model was constructed to perform a cost-effectiveness analysis comparing breast-conserving surgery with or without RT using DCISionRT testing vs. traditional clinicopathologic risk factors. Clinical parameters were obtained from clinical trial data and cross-validation studies. Cost data were based on 2019 Medicare reimbursement. Incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained comparing DCIS treatments using DCISionRT testing to traditional clinicopathologic risk factors and evaluated with a willingness-to-pay threshold of US$100,000 per QALY gained. To account for uncertainty, 1-way and probabilistic sensitivity analyses were performed.ResultsBase case analysis showed that DCIS management using DCISionRT testing was a cost-effective strategy, resulting in an ICER of $74,331 per QALY gained compared to clinicopathology-based treatment. Model results were sensitive to a variation of the proportion of genomic-high, low-risk patients receiving RT in DCISionRT testing strategy, and changes in DCISionRT testing cost.ConclusionDCISionRT testing could potentially be a cost-effective strategy compared to traditional decision making for DCIS treatments, optimizing RT benefit based on an accurate recurrence risk assessment. 相似文献
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建立基于96孔板检测的FRAP法和DPPH法及其在橘核抗氧化活性研究中的应用 总被引:1,自引:0,他引:1
目的建立基于96孔板检测的样品消耗小、实验结果准确稳定的改良微型铁离子还原/抗氧化力测定法(ferric reduction ability plasma assay,FRAP)和1,1-二苯基-2-三硝基苯肼自由基清除能力测定法(2,2diphenyl-1-picrylhydrazyl assay,DPPH),并将之应用于橘核抗氧化活性评价。方法首先,分别考察不同反应温度、反应体系以及反应时间对于FRAP法和DPPH法检测抗坏血酸(Aa)抗氧化能力的影响,选择Aa的浓度和抗氧化能力之间线性关系最佳的反应条件作为最适反应条件并建立这两种方法的微量模型。其次,通过精密度、回收率以及标准品对照实验验证微量模型的稳定性及准确性。最后,将微型FRAP,DPPH法应用于橘核提取物(Cse)及其主要活性成分柠檬苦素(Lim)、诺米林(Nom)、橙皮苷(Hes)的抗氧化活性评价。结果微型FRAP法将150μl TPTZ工作液与5μl待测抗氧化剂溶液作为反应体系且选择在30℃温育反应,反应时间为5 min。DPPH法将160μl DPPH溶液与40μl待测抗氧化剂溶液作为反应体系且选择于25℃保温显色,显色时间为30 min。用这2种改良微型法获得的Aa,Cse和Hes的AEAC值分别为1.00,187.42,19.31g·L-1,EC50值分别为0.06,24.83,4.62 g·L-1。结论基于96板检测的微型FRAP,DPPH法样品消耗量小,实验结果稳定可靠且筛选效率高。Aa的抗氧化能力HesCse,而Lim,Nom不具抗氧化能力,故该实验认为橘核中抗氧化作用的主要物质基础为Hes。 相似文献
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