Pharmacokinetic characteristics of YZG-331, a promising sedative-hypnotic candidate agent
10.16438/j.0513-4870.2017-0513
- VernacularTitle:新型镇静催眠化合物YZG-331药代动力学特征的研究
- Author:
Ya-kun YANG
1
;
Zhi-hao LIU
2
;
Li SHENG
1
;
Yan LI
1
Author Information
1. Department of Drug Metabolism, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116000, China
- Publication Type:ORIGINAL ARTICLES
- Keywords:
N6-substituted adenosine derivatives;
preclinical pharmacokinetics;
metabolic stability;
species difference;
gender difference
- From:
Acta Pharmaceutica Sinica
2017;52(12):1910-1917
- CountryChina
- Language:Chinese
-
Abstract:
The purpose of this article was to study the pharmacokinetic characteristics of YZG-331, plasma protein binding and metabolic stability in vivo and in vitro. Plasma and tissue concentrations of YZG-331 were determined in mice and rats after administration by LC-MS/MS analysis orally or intravenously. The plasma protein binding of YZG-331 with human, dog, monkey, rat and mouse were measured by ultrafiltration method. The stability of YZG-331 in animal and human plasma, liver microsomes, intestinal bacteria and artificial gastrointestinal fluid was also investigated in vitro. The results show that YZG-331 was absorbed rapidly in both mice and rats after oral administration, while the absorption and elimination saturation YZG-331 were also observed. The bioavailability of YZG-331 was much higher in male mice (51.2%) than that in female mice (27.7%), however, the bioavailability in male rats (27.1%) was lower than that in female rats (78.7%). YZG-331 was widely distributed in different tissues of mice, especially in certain regains of brain, including thalamus, hippocampi, cortical and striatal. YZG-331 was found to bind to human, dog, monkey, rat and mouse plasma protein in vitro (93.3%-98.9%) without significant concentration dependences and species differences. YZG-331 was stable in animal and human plasma, simulated gastric/intestinal fluid and liver microsomal incubations, except rat liver microsomes and intestinal flora. Therefore, we concluded that:the pharmacokinetics of YZG-331 in mice and rats have gender and species differences; YZG-331 was widely distributed in vivo including brain, the targets of the agent; YZG-331 had a high affinity to plasma protein and was metabolized by rat liver microsomes and intestinal flora.
