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	Comparative Metabolism of Cinobuafgin in Liver Microsomes from Mouse,Rat,Dog,Pig,Monkey and Human
	Ning J(宁静) ; Ge GB(葛广波) ; Ma XC(马骁驰) ; Liang SC(梁思成) ; Yang L(杨凌)
	2010-05-16
会议名称	18th international symposium on microsomes and drug oxidations
会议日期	2010-5-16
会议地点	中国
页码	115/2
通讯作者	杨凌
中文摘要	cinobufagin (cbg), a major bioactive component of traditional chinese medicine chan-su with digoxin-like structure, has been reported with na+-k+-atpase inhibitory effects and outstanding antitumor activities. in this study, a comprehensive study on in vitro metabolic stability of cbg was first carried out by using liver microsomes from human and five common experimental animals, including mouse, rat, dog, pig and monkey. the results showed significant species differences in in vitro metabolism of cbg between human and rat. the species-specific deacetylation of cbg was found as major in vitro metabolic pathway in rat, while two mono-hydroxylated metabolites of cbg were also detected. in sharp contrast, hydroxylation of cbg was the major in vitro metabolic pathway in human, mouse, dog, pig and monkey. two mono-hydroxylated metabolites of cbg in human and other animal species were identified as 5-hydroxylatedcbg and 12-hydroxylatedcbg by using lc–ms, h-nmr and c-nmr. a combination of chemical inhibition studies and assays with recombinant human cyps indicated that cyp3a4 was assigned as the main hepatic isoform for two hydroxylation reactions of cbg. furthermore, an independent inhibition study showed that two inhibitors of cyp3a (ketoconazole and troleandomycin) can strongly inhibit the hydroxylation of cbg in all species, indicating cyp3a involved in hydroxylation of cbg in all species. the kinetics showed that cbg can be rapid hydrolyzed by esterase in rat liver microsomes, with the km and vmax values were 32.85 µm and 15.77 nmol/min/mg protein, respectively. the kinetic parameters and catalytic efficiency of cbg hydroxylations by liver microsomes from various species were also determined, and the intrinsic clearance values (vmax/ km) for both c-5 and c-12 hydroxylation of cbg in liver microsomes among various species were obey the following sequence, mouse > dog > monkey > minipig > human. in summary, the in vitro metabolic pathways of cbg in various species were revealed and our results strongly suggest that mouse, dog, minipig and monkey could serve as surrogate models for human in toxic and pharmacokinetic studies of cbg. in addition, the knowledge of cbg metabolism also provided vital information for understanding the pharmacokinetic behaviors of cbg containing chinese traditional medicines.
会议主办者	北京大学
学科主题	物理化学
语种	中文
内容类型	会议论文
源URL	[http://159.226.238.44/handle/321008/114352]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
推荐引用方式 GB/T 7714	Ning J,Ge GB,Ma XC,et al. Comparative Metabolism of Cinobuafgin in Liver Microsomes from Mouse,Rat,Dog,Pig,Monkey and Human[C]. 见:18th international symposium on microsomes and drug oxidations. 中国. 2010-5-16.

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