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1.
《Drug metabolism and pharmacokinetics》2019,34(1):87-94
The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with Ki values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with Km values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CLR) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CLR (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CLR of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates. 相似文献
2.
Galanin-like immunoreactivity has been visualized in nerve fibers in the islets of Langerhans, suggesting an involvement of
galanin in the neural regulation of islet function. In this study, we investigated the effects of galanin on basal and stimulated
insulin and glucagon secretion by infusing the peptide at three different dose rates in rats. We also studied the direct effect
of galanin on insulin secretion from freshly isolated rat islets. At 320 pmol/kg/min, but not at 20 or 80 pmol/kg/min, galanin
lowered basal plasma insulin levels. In contrast, basal plasma glucagon levels were lowered by galanin already at 20 and 80
pmol/kg/min. Furthermore, galanin inhibited both glucose- and arginine-induced insulin release at all three dose levels, whereas
arginine-induced glucagon release was not affected by galanin. Glucose-stimulated insulin secretion from isolated rat islets
was dose-dependently suppressed by galanin (10-6-10-8M). Therefore, it is concluded that galanin in rats inhibits insulin secretion, both in vivo and in vitro, and that at lower
dose levels, the peptide also inhibits basal glucagon release. 相似文献
3.
T B Vree Y A Hekster M W Tijhuis E F Termond J F Nouws 《Biopharmaceutics & drug disposition》1986,7(3):239-252
Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half-lives of sulfatroxazole and its metabolites 5-hydroxysulfatroxazole and N4-acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N4-acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half-life of N4-acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation-deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5-hydroxy- and N4-acetylsulfatroxazole. Inhibition of the N4-acetyl metabolite favours the deacetylation, which results in an increase of the T 1/2 of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4-acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes. 相似文献
4.
5.
KYOSUKE YAMAMOTO NOBUHIRO FUKUDA LEI ZHANG TAKAHIRO SAKAI 《Pharmacological research》1996,33(6):337-342
The aim of this study was to examine the effects of dietary fenofibrate (0.05% in the diet) on ketone body production and lipid secretion in isolated perfused rat liver. Feeding with fenofibrate for 7–9 days caused an increased liver weight. Ketone body production was significantly greater in the livers perfused with oleic acid than in those perfused without fatty acid, with the elevation of the ratio ofβ-hydroxybutyrate:acetoacetate indicating an increased redox potential in mitochondrial compartments by exogenous fatty acid. On the other hand, fenofibrate feeding caused a further stimulation of ketone body production from both endogenous and exogenous fatty acid substrates, respectively, with a decreased ratio ofβ-hydroxybutyrate:acetoacetate as compared to respective control livers, indicating a decreased redox potential. Hepatic secretion of triglyceride, but not of cholesterol, was decreased markedly in the fenofibrate-fed rats, especially when oleate was provided, suggesting an inverse relationship between rates of ketogenesis and triglyceride secretion. These results suggest that the altered hepatic metabolism of long-chain fatty acids between oxidation and esterification caused by fenofibrate may thus be a factor responsible for the decreased secretion of triglyceride, hence leading to hypotriglyceridaemiain vivo. 相似文献
6.
天蚕素A-蛙皮肽杂合肽基因的表达及产物抗菌活性测定 总被引:5,自引:0,他引:5
目的 研究天蚕素A-蛙皮肽杂合肽基因[CA(1-8)-MA(1-12)]抗菌肽的抗菌活性。方法 将天蚕素A-蛙皮肽杂合肽基因抗菌肽的人工基因克隆到具有自切割功能的表达载体pTYB12上,并在大肠杆菌(E.coli)BL21(DE3)中进行表达,表达产物用几丁质树脂进行了亲和吸附,自切割后洗脱得到抗菌肽,进行透析以去除盐类物质,最后用大肠杆菌与金黄色葡萄球菌进行活性检测。结果 天蚕素A-蛙皮肽杂合肽[CA(1-8)-MA(1-12)]对大肠杆菌与金黄色葡萄球菌均有一定的抗菌活性。结论 天蚕素A-蛙皮肽杂合肽具有抗菌活性。其抑瘤活性的研究还有待于进一步研究。 相似文献
7.
A. Tentorio G. Ghilardi A. Pedroncelli R. Benco S. Stroppa S. Adib D. Gianola G. Pagani 《European journal of clinical pharmacology》1989,36(3):311-313
Summary The effect of nifedipine 40 mg·day–1 for 3 months on glucose tolerance, insulin and C-peptide secretion after an oral glucose tolerance test (OGTT), intra-venous glucose tolerance test (IVGTT) and glucagon stimulatory test, has been studied in 8 moderately hypertensive women suffering from non-insulin dependent diabetes mellitus (NIDDM).No significant variation in glucose metabolism was noted after nifedipine treatment, except for a slight improvement in insulin secretion after OGTT at the end of the study. There was an increase in cholesterol as a collateral effect. 相似文献
8.
Visfatin was expressed in rat anti mouse islets,as well as in MIN6 cells. The visfatin expression was affected by various concentrations of environmental glucose (5.5 and 33.3 mmoL/L) and palmitate(0.5 mmol/L). As compared with low-level glucose medium (5.5 mmol/L, 1.0±0.11) , visfatin expression increased in media with high glucose and palmitate (1.32 ±0. 18, 1. 33±0. 15,1.72±0.27, all P<0. 05). The result suggests that visfatin seems to be involved in the regulation of insulin secretion. 相似文献
9.
明胶降解物对大鼠真皮成纤维细胞增殖及Ⅰ型胶原蛋白分泌的影响 总被引:1,自引:0,他引:1
目的 探讨组织工程心瓣膜常用人工基质材料--明胶发生降解后的产物对大鼠真皮成纤维细胞增殖及Ⅰ型胶原蛋白分泌的影响. 方法 利用酶组合技术制备明胶降解物(gelatin hydrolysate, GH),采用超滤的方法分离出低分子量明胶降解物组分(gelatin hydrolysate fraction, GHF),用于5只SD大鼠真皮成纤维细胞的体外培养.采用CCK-8活细胞计数试剂盒(Cell Counting Kit-8)检测细胞的增殖情况,ELISA试剂盒检测细胞I型胶原蛋白的分泌情况. 结果 ①GHF对细胞增殖作用的浓度效应:在0.125~1.0 mg/ml浓度范围内,GHF对细胞的促增殖作用呈现先增强后减弱的趋势,在0.25 mg/ml时,细胞增殖率最大,达到(47.54±16.35)%;②GH与GHF对细胞增殖影响比较:GH与GHF均具有促进细胞增殖的作用,且在浓度为0.25 mg/ml时,促细胞增殖作用无显著差异[(27.04±15.21)% vs (39.22±15.55)%, P=0.177];③GH与GHF对细胞分泌Ⅰ型胶原蛋白影响比较:GHF组第3天时Ⅰ型胶原分泌量为(28.06±5.60)pg/105,与空白对照的(18.24±4.52)pg/105相比,有显著差异(P=0.006),而GH组直至第6天时Ⅰ型胶原蛋白分泌量,与空白对照相比,无统计学意义(P=0.103). 结论 分子量大小不同的明胶降解物GH与GHF均具有促进大鼠真皮成纤维细胞增殖的作用,且分子量较小的GHF还具有促进细胞I型胶原分泌的功能. 相似文献
10.
James Herrington 《Toxicon》2007,49(2):231-238
Pancreatic beta-cells depolarize in response to glucose and fire calcium-dependent actions potentials that trigger insulin secretion. The major current responsible for action potential repolarization in these cells is a delayed rectifier and Kv2.1 subunits are thought be a major contributor of the delayed rectifier channels. Hence, blockers of Kv2.1 channels might prolong action potentials and enhance calcium influx and insulin secretion. However, the lack of specific small molecule Kv2.1 inhibitors has hindered the testing of this mechanism. Importantly, several gating modifier peptides inhibit Kv2.1 channels in a relatively specific fashion. Hanatoxin (HaTX) and guangxitoxin-1 (GxTX-1) are examples that have been used to probe the role of Kv2.1 channels in beta-cell physiology. Both HaTX and GxTX-1 strongly inhibit the Kv current of beta-cells from various species, arguing that Kv2.1 subunits contribute significantly to the beta-cell delayed rectifier. GxTX-1 prolongs glucose-triggered action potentials, enhances glucose-dependent intracellular calcium elevations and augments glucose-dependent insulin secretion. Taken together, these data suggest that blockers of Kv2.1 channels may be a useful approach to the design of novel therapeutic agents for the treatment of type 2 diabetes. These studies highlight the utility of gating modifier peptides in the study of physiological systems. 相似文献