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排序方式: 共有266条查询结果,搜索用时 31 毫秒
1.
《Drug metabolism and pharmacokinetics》2020,35(6):563-570
Minesapride is a novel 5-hydroxytryptamine 4 (5-HT4) receptor partial agonist that is expected to show efficacy in patients with irritable bowel syndrome with predominant constipation and functional constipation. An open-label study was conducted to evaluate pharmacokinetics (PK) and safety of minesapride. Japanese subjects, 12 elderly and 12 young, received a single oral dose of minesapride 40 mg/day in the fasted state. Metabolite profiles were also investigated in this clinical study and in an in vitro study using cryopreserved hepatocytes. Clinical results showed that minesapride was rapidly absorbed (Cmax: 2302.1 ng/mL in the elderly group, 2117.5 ng/mL in the young group), and the plasma concentration then decreased with half-life of approximately 7 h. There were no notable PK differences between elderly and young groups. No serious adverse events (AEs) were observed. The only AE that occurred in 2 or more subjects was diarrhea. Metabolite profiles in plasma and urine were similar between elderly and young groups. No major metabolites exceeded 10% of unchanged minesapride, and results of the in vitro study suggested that there were no human-specific metabolites. From the viewpoints of PK and metabolite profiling, no dose adjustment of minesapride is warranted in elderly population without renal or hepatic impairment. 相似文献
2.
Ames试验检测三硝基甲苯及其还原代谢产物的诱变性 总被引:1,自引:1,他引:0
应用Ames试验检测系统观察了三硝基甲苯及其还原代谢产物4-羟氨基-2,6-二硝基甲苯(4-HA),4-氨基-2,6-二硝基甲苯(4-A),2-氨基-4,6-二硝基甲苯(2-A)和2,4-二氨基-6-硝基甲苯(2,4-DA)的诱变活性,实验结果显示,三硝基甲苯及其代谢产物具有明显的致突变作用,4-A的直接诱变活性最强,而且移码型诱变性更为显著,在微粒体酶系统的参与下,TNT的诱变活性增强,其代谢产 相似文献
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本文报告了2,4,6-三硝基甲苯(TNT)的代谢物,2-氨基-4,6-二硝基甲苯2和2,4-二氨基-6-硝基甲苯3的合成。以邻甲基苯甲酸为原料,经硝化(HNO_3-H_2SO_4)和Schmidt反应(NaN_3-H_2SO_4)得到2,用NaHS还原TNT的方法合成化合物3。 相似文献
5.
Activation of the reticulothalamic cholinergic pathway by the major metabolites of aniracetam 总被引:3,自引:0,他引:3
The aim of the study was to further investigate the effects of aniracetam, a cognition enhancer, and its metabolites on the brain cholinergic system. We measured choline acetyltransferase activity and acetylcholine release using in vivo brain microdialysis in stroke-prone spontaneously hypertensive rats (SHRSP). The enzyme activity in the pons–midbrain and hippocampus, and basal acetylcholine release in the nucleus reticularis thalami were lower in SHRSP than in age-matched Wistar Kyoto rats, indicating central cholinergic deficits in SHRSP. Repeated treatment of aniracetam (50 mg/kg p.o.×11 for 6 days) preferentially increased the enzyme activity in the thalamus, whereas decreased it in the striatum. Among the metabolites of aniracetam, local perfusion of N-anisoyl-γ-aminobutyric acid (GABA, 0.1 and/or 1 μM) and p-anisic acid (1 μM) into the nucleus reticularis thalami, dorsal hippocampus and prefrontal cortex of SHRSP produced a significant but delayed increase of acetylcholine release. We failed, however, to find any effect of aniracetam itself. A direct injection of N-anisoyl-GABA (1 nmol) into the pedunculopontine tegmental nucleus of SHRSP enhanced the release in the nucleus reticularis thalami. Thus, these data prove that aniracetam can facilitate central cholinergic neurotransmission via both metabolites. Based on its pharmacokinetic profile, N-anisoyl-GABA may contribute to the clinical effects of aniracetam, mainly by acting on the reticulothalamic cholinergic pathway. 相似文献
6.
地西泮代谢物的结合物水解条件研究 总被引:2,自引:0,他引:2
目的:考察β 葡萄糖醛酸苷酶水解尿液中地西泮代谢物的结合物的酶解条件.方法: 实验设计采用正交表L9(34).取尿样2 mL,加内标,再加不同量的β 葡萄糖醛酸苷酶,在不同温度、不同酶解时间下水解,然后用正己烷 二氯甲烷(5∶3)5 mL提取,挥干提取液后用50 μL甲醇溶解,10 μL进样,采用高效液相色谱法检测.结果:对水解产物峰面积与内标物峰面积的比值进行方差分析,发现水解尿液中去甲地西泮、替马西泮、奥沙西泮的葡萄糖醛酸苷结合物的最佳酶解条件分别为55℃,5 h,5 000 U酶量;55℃,2 h,1 000 U酶量;55℃,2 h,5 000 U酶量.结论:水解2 mL尿液中地西泮代谢物的结合物的最佳条件为55℃,5 h,5 000 U酶量. 相似文献
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8.
Precocious puberty (PP) refers to the appearance of physical and hormonal signs of pubertal development at an abnormally early age. Urinary steroid signatures obtained from 42 patients with central PP and 40 patients with peripheral PP were assessed to compare metabolic changes. Levels of androgens such as testosterone, androstenedione, androstenediol, 16α-hydroxy-dehydroepiandrosterone, and 5α-androstenedione tended to be high in both PP groups, and the level of 17β-estradiol was higher in the central-PP group (P < 0.01) than in the peripheral-PP and 32 age-matched healthy girls. Altered steroid metabolism was also associated with urinary BPA levels, and levels of testosterone, 17β-estradiol, and pregnenolone were significantly increased among individuals with high BPA levels. In particular, a correlation was observed between estrogen metabolism and BPA levels irrespective of the type of PP. These findings suggest that in girls, BPA exposure causes metabolic changes in steroidogenesis, but not the early onset of PP. 相似文献
9.
《Nanotoxicology》2013,7(6):783-794
AbstractProtein coronas on nanoparticles (NPs) affect their physicochemical properties, cellular uptake, and toxicity, and have been described extensively. To date, studies of the occurrence of small molecule (metabolite) coronas are limited. We sought to determine whether a metabolite corona forms on NPs, using high-sensitivity metabolomics combined with a model system for freshwater ecotoxicology (Daphnia magna feeding on Chlorella vulgaris). Using amino-functionalized polystyrene NPs (NH2-pNPs), we showed the impact of this material on Daphnia feeding to provide a rationale for the detailed molecular investigations. We then employed a targeted LC-MS/MS approach for sodium dodecyl sulfate (SDS) as an analog to signaling molecules known to occur in our freshwater model system and optimized a corona extraction method for this representative metabolite. Next, we performed an untargeted discovery-based metabolomics study – using high-sensitivity nanoelectrospray direct infusion mass spectrometry (DIMS) – to enable an unbiased assessment of the metabolite corona of NH2-pNPs in the freshwater model system. Our results demonstrate that SDS was successfully recovered from NH2-pNPs, confirming that the extraction protocol was fit-for-purpose. Untargeted DIMS metabolomics reproducibly detected 100?s of small molecule peaks extracted from NH2-pNPs exposed to conditioned media from the D. magna–C. vulgaris model system. Attempts to annotate these extracted metabolites, including by using van Krevelen and Kendrick Mass Defect plots, indicate a diverse range of metabolites that were not clustered into any particular class. Overall we demonstrate the existence of an ecologically relevant metabolite corona on the surface of NPs through application of a high-sensitivity, untargeted mass spectrometry metabolomics workflow. 相似文献
10.
Quinocetone (QCT) is a new feeding antibacterial agent in the QdNOs family. The mechanism of its adrenal toxicity is far from clear. This study was conducted to estimate the adrenal cell damage induced by QCT and its bidesoxy-quinocetone (B-QCT) metabolite and to further investigate their mechanisms. Following doses of QCT increasing from 5 to 50 μM, cell apoptosis and necrosis, mitochondrial dysfunction and redox imbalance were observed in porcine adrenocortical cells. The mRNA levels of the six components of intermediary enzymes and the adrenal renin-angiotensin-aldosterone system (RAAS) displayed a dysregulation induced by QCT, indicating that QCT might influence aldosterone secretion not only through the upstream of the production but also through the downstream of the adrenal RAAS pathway. In contrast, B-QCT had few toxic effects on the cell apoptosis, mitochondrial dysfunction and redox imbalance. Moreover, LCMS-IT-TOF analysis showed that no desoxy metabolites of QCT were found in either cell lysate or supernatant samples. In conclusion, we reported on the cytotoxicity in porcine adrenocortical cells exposed to QCT via oxidative stress, which raised awareness that its toxic effects resulted from N→O groups, and its toxic mechanism might involve the interference of the steroid hormone biosynthesis pathway. 相似文献