摘要
目的研究抗肿瘤候选药物DHDK在人和大鼠肝微粒体的代谢动力学特征,比较种属差异,为临床前研究提供依据。方法建立HPLC法测定DHDK在肝微粒体孵育体系中的含量,用于考察DHDK体外代谢稳定性和酶动力学,进而推算其在体内的肝清除率(CLh)与肝提取率(ER)。结果肝微粒体孵育试验表明DHDK在两个种属之间的体外代谢稳定性和酶动力学行为无显著性差异(P>0.05),但在人体内的肝清除率显著低于大鼠(P<0.05)。结论DHDK体外代谢主要依赖于烟酰胺腺嘌呤二核苷酸磷酸和肝微粒体酶,属于中等程度代谢消除。
Objective To conduct in vitro metabolic investigations of DHDK[(1E,4E)-1,7-bis(4-hydroxyphenyl)hepta-1,4-dien-3-one],a newly developed anticancer compound,and interspecies variation to corroborate its preclinical investigations.Methods In vitro metabolic stability and enzyme kinetics study of DHDK were carried out in rat and human liver microsomes of various species,using a stablished and validated HPLC method to quantify DHDK.The study also extrapolated to in vivo intrinsic hepatic clearance(CL_h)in tandem with hepatic extraction ratio(ER)based upon in vitro data.Results The in vitro metabolic stability and kinetic differences were observed with insignificant difference between rat and human(P>0.05).There were significantly lower CL_h in vivo in human compared to rat(P<0.05).Conclusion The metabolism study of DHDK shows moderate eliminated rates in vitro by both human and rat,dependent on cytochrome P450 metabolic enzymes and the cofactor nicotinamide adenine dinucleotide phosphate.
作者
井继雪
宫宁宁
于治国
赵云丽
JING Jixue;GONG Ningning;YU Zhiguo;ZHAO Yunli(School of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,China)
出处
《沈阳药科大学学报》
CAS
CSCD
2024年第2期188-194,共7页
Journal of Shenyang Pharmaceutical University
