新型镇静催眠化合物YZG-331药代动力学特征的研究

发布时间：2018-04-19 22:16

本文选题：N-取代-腺苷衍生物 + 临床前药代动力学　；参考：《药学学报》2017年12期

【摘要】：本文旨在研究小/大鼠口服和静脉注射YZG-331后的血浆药代动力学、血浆蛋白结合以及体外代谢特征。通过LC-MS/MS方法测定小/大鼠口服和静脉注射YZG-331后血浆药物浓度变化及组织分布,计算药代动力学参数和生物利用度;应用超滤法测定YZG-331与动物和人血浆蛋白的结合率;比较YZG-331在动物和人血浆、肝微粒体、肠菌以及人工胃肠液中的体外稳定性。结果表明,小/大鼠口服YZG-331后均吸收较快,存在吸收与消除饱和趋势。雄性小鼠的生物利用度(51.2%)明显高于雌鼠(27.7%),而雌性大鼠的生物利用度(78.7%)明显高于雄鼠(27.1%)。小鼠口服YZG-331后体内分布广泛,在药效靶组织脑中也有分布,包括丘脑、海马、皮层、纹状体。YZG-331与人和动物血浆蛋白高度结合(93.3%~98.9%),无明显浓度依赖和种属差异。YZG-331在人和动物血浆、人工胃肠液以及小鼠、猴、狗和人肝微粒体中稳定,但可经大鼠肝微粒体和肠道菌群代谢。YZG-331在小鼠、大鼠体内的血浆药代动力学存在一定性别差异和种属差异;YZG-331在体内分布广泛,与血浆蛋白高度结合,可经大鼠肝脏微粒体和肠道菌群代谢转化。
[Abstract]:The aim of this study was to study the plasma pharmacokinetics, plasma protein binding and in vitro metabolic characteristics after oral and intravenous injection of YZG-331 in small / rats. The plasma drug concentration and tissue distribution after oral and intravenous YZG-331 were measured by LC-MS/MS method, and the pharmacokinetic parameters and bioavailability were calculated. The ultrafiltration method was used to measure the plasma drug concentration and the bioavailability. The binding rate of YZG-331 with animal and human plasma protein was determined, and the stability of YZG-331 in animal and human plasma, liver microsomes, intestinal bacteria and artificial gastrointestinal fluid was compared. The results showed that the absorption and elimination of saturation were found in the small / rat mice after oral YZG-331, and the bioavailability (51.2%) of the male rats was significantly higher than that of the female rats (27.7%). The bioavailability of female rats (78.7%) was significantly higher than that of male rats (27.1%). After oral YZG-331, mice were widely distributed in vivo and distributed in the brain of drug target tissues, including thalamus, hippocampus, cortex,.YZG-331 of striatum and human and animal plasma protein (93.3%~ 98.9%), without significant concentration dependence and species difference.YZG-331 in human and movement. Plasma, artificial gastrointestinal fluid and mice, monkeys, dogs and human liver microsomes are stable, but the rat liver microsomes and intestinal microflora metabolize.YZG-331 in mice, the plasma pharmacokinetics of rats in rats, there are certain gender differences and species differences; YZG-331 is widely distributed in the body, and the plasma protein is highly combined with rat liver microsomes. Metabolic transformation of intestinal flora and intestinal microflora.

【作者单位】：中国医学科学院北京协和医学院药物研究所药物代谢室创新药物非临床药代/药效北京市重点实验室活性物质发现与适药化研究北京市重点实验室;大连医科大学药学院临床药理学室;
【基金】：国家自然科学基金青年科学基金项目(81603190) 中国医学科学院医学与健康科技创新工程经费资助(2016-I2M-3-011)
【分类号】：R965

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