Metabolism and pharmacokinetics of alantolactone and isoalantolactone in rats: Thiol conjugation as a potential metabolic pathway

doi:10.1016/j.jchromb.2017.11.039

	Metabolism and pharmacokinetics of alantolactone and isoalantolactone in rats: Thiol conjugation as a potential metabolic pathway
	Zhou, Bailun 1; Ye, Ji 2; Yang, Niao 2; Chen, Liping 2; Zhuo, Zhiguo 2; Mao, Ling 2; Liu, Qun 2; Lan, Gongcai 1; Ning, Jing 4; Ge, Guangbo 4
刊名	JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
	2018
卷号	1072 页码:370-378
关键词	Alantolactone Isoalantolactone Glutathione Cysteine Conjugation Metabolism
ISSN号	1570-0232
DOI	10.1016/j.jchromb.2017.11.039
文献子类	Article
英文摘要	Alantolactone (AL) and isoalantolactone (IAL), two major active sesquiterpene lactones isolated from Radix Inulae extract, have a wide range of pharmacological activities. The predominant metabolic pathway of AL and IAL observed was glutathione (GSH) conjugation in vitro, which could occur in the absence of metabolic enzymes. Non-enzymatic conjugation with cysteine (Cys) couldalso be observed. Four metabolites (AL-GSH, AL-Cys, IAL-GSH, IAL-Cys) were subsequently isolated and confirmed by nuclear magnetic resonance (NMR). The results indicated that the thiol of GSH or Cys can be reacted with the exomethylene carbon atoms of a, 13 unsaturated carbonyl of AL and IAL. After intravenous administration in rats, AL and IAL were extensively metabolized, and the exposure, as measured by area under the concentration-time curve (AUC), for AL-GSH, AL-Cys, IAL-GSH, and IAL-Cys was approximately 1.54-, 0.96-, 1.50-, and 0.91-fold that of the parent drug, respectively. The AUC ratio of metabolites to parent compounds of oral administration was 3.66-, 9.19-, 12.97-, and 9.92-fold that of the parent drug for the above metabolites, respectively. The bioavailability of AL-total (AL, AL-GSH, AL-Cys) and IAL-total (IAL, IAL-GSH, IAL-Cys) was, respectively, 8.39% and 13.07%, which was 3.62 and 6.95- fold that of AL (2.32%) and IAL (1.88%), respectively. The oral exposure will be underestimated if the parent drugs are tested alone. These findings provide useful information for preclinical safety evaluation, and for predicting AL and IAL metabolism in humans.
WOS关键词	SESQUITERPENE LACTONES ; INULA-HELENIUM ; RADIX-INULAE ; GLUTATHIONE ; CHROMATOGRAPHY ; PLASMA
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000423637600048
内容类型	期刊论文
源URL	[http://cas-ir.dicp.ac.cn/handle/321008/168604]
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
通讯作者	Wang, Shumei; Zhang, Weidong
作者单位	1.Guangdong Pharmaceut Univ, Sch Tradit Chinese Med, Guangzhou, Guangdong, Peoples R China 2.Second Mil Med Univ, Sch Pharm, Dept Nat Prod Chem, Shanghai, Peoples R China 3.Shanghai Inst Pharmaceut Ind, Dept Pharm, Shanghai, Peoples R China 4.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Bailun,Ye, Ji,Yang, Niao,et al. Metabolism and pharmacokinetics of alantolactone and isoalantolactone in rats: Thiol conjugation as a potential metabolic pathway[J]. JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES,2018,1072:370-378.
APA	Zhou, Bailun.,Ye, Ji.,Yang, Niao.,Chen, Liping.,Zhuo, Zhiguo.,...&Zhang, Weidong.(2018).Metabolism and pharmacokinetics of alantolactone and isoalantolactone in rats: Thiol conjugation as a potential metabolic pathway.JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES,1072,370-378.
MLA	Zhou, Bailun,et al."Metabolism and pharmacokinetics of alantolactone and isoalantolactone in rats: Thiol conjugation as a potential metabolic pathway".JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES 1072(2018):370-378.