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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。
This article aimed to study plasma pharmacokinetics, plasma protein binding, and in vitro metabolic characteristics of small / rat oral and intravenous YZG-331. The pharmacokinetic parameters and bioavailability of YZG-331 were determined by LC-MS / MS after oral and intravenous injection of YZG-331 in small / Human plasma protein binding rate; Comparison of the in vitro stability of YZG-331 in animal and human plasma, liver microsomes, enterobacteria, and artificial gastrointestinal fluids. The results showed that small / rat after oral administration of YZG-331 are absorbed faster, there is the trend of absorption and elimination of saturation. The bioavailability of male mice (51.2%) was significantly higher than that of female mice (27.7%), while that of female rats was significantly higher than that of male rats (78.7%) (27.1%). After oral administration of YZG-331, the mice are widely distributed in vivo and distributed in the brain of the target tissues of the drug, including the thalamus, the hippocampus, the cortex and the striatum. YZG-331 and human and animal plasma proteins highly (93.3% ~ 98.9%), no significant concentration-dependent and species differences. YZG-331 is stable in human and animal plasma, artificial gastrointestinal fluids and in mouse, monkey, dog and human liver microsomes but is metabolized by rat liver microsomes and intestinal flora. YZG-331 in mice, rats plasma pharmacokinetics there is a certain gender differences and species differences; YZG-331 widely distributed in the body, highly associated with the plasma protein, the rat liver microsomal and intestinal bacteria Metabolic transformation.