Pharmacokinetic evaluation of the anticancer prodrug simmitecan in different experimental animals

doi:10.1038/aps.2013.74

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	Pharmacokinetic evaluation of the anticancer prodrug simmitecan in different experimental animals
	Hu, Zhe-yi; Li, Xiu-xue; Du, Fei-fei; Yang, Jun-ling; Niu, Wei; Xu, Fang; Wang, Feng-qing; Li, Chuan; Sun, Yan
刊名	ACTA PHARMACOLOGICA SINICA
	2013-11
卷号	34 期号:11 页码:1437-1448
关键词	pharmacokinetics distribution metabolism excretion L-P L-2-Z carboxylesterase species difference prodrug
ISSN号	1671-4083
DOI	10.1038/aps.2013.74
文献子类	Article
英文摘要	Aim: To investigate the pharmacokinetics and disposition of simmitecan (L-P) that was a water-soluble ester prodrug of chimmitecan (L-2-Z) with potent anti-tumor activities in different experimental animals, and to assess its drug-drug interaction potential. Methods: SD rats were injected with a single iv bolus doses of L-P (3.75, 7.5 and 15 mg/kg). The pharmacokinetics, tissue distribution, excretion and metabolism of L-P and its active metabolite L-2-Z were studied through quantitative measurements and metabolite profiling with LC/MS. The binding of L-P and L-2-Z to rat plasma proteins was examined using an ultrafiltration method. Systemic exposures of beagle dogs to L-P as well as drug distribution in tumors of the nude mice xenograft model of human hepatic cancer SMMC-7721 cells were also examined. The metabolism of L-P by liver mcirosomal carboxylesterase in vitro was investigated in different species. The effects of L-P and L-2-Z on cytochrome P450 enzymes were examined using commercial screening kits. Results: The in vivo biotransformation of L-P to L-2-Z showed a significant species difference, with a mean elimination half-life t1/2 of approximately 1.4 h in rats and 1.9 h in dogs. The systemic exposure levels of L-P and L-2-Z were increased in a dose-dependent manner. In rats, approximately 66% of L-P and 79% of L-2-Z were bound to plasma proteins. In rats and the nude mice bearing human hepatic cancers, most organ tissues had significantly higher concentrations of L-P than the corresponding plasma levels. In the tumor tissues, the L-P levels were comparable to those of plasma, whereas the L-2-Z levels were lower than the L-P levels. In rats, L-P was eliminated mainly via biliary excretion, but metabolism played an important role in elimination of the intact L-P. Finally, L-P and L-2-Z exerted moderate inhibition on the activity of CYP3A4 in vitro. Conclusion: L-P and L-2-Z have relatively short elimination half-lives and L-P is mainly eliminated via biliary excretion. The species difference in the conversion of L-P to L-2-Z and potential drug-drug interactions due to inhibition of CYP3A4 should be considered in further studies.
资助项目	National Science & Technology Major Project of China "Key New Drug Creation and Manufacturing Program"[2009ZX09304-002] ; National Science & Technology Major Project of China "Key New Drug Creation and Manufacturing Program"[2009ZX09301-001] ; National Science & Technology Major Project of China "Key New Drug Creation and Manufacturing Program"[2009ZX09102-020] ; National Natural Science Foundation of China[30873120] ; Chinese National Natural Science Foundation for Distinguished Young Scholars[30925044]
WOS关键词	NERVOUS-SYSTEM TOXICITY ; IN-VITRO ; IRINOTECAN CPT-11 ; CAMPTOTHECIN ; METABOLISM ; PLASMA ; SN-38 ; CARBOXYLESTERASES ; CHIMMITECAN ; DISPOSITION
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4966498
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000326680500010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277399]
专题	上海药物代谢研究中心
通讯作者	Sun, Yan
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Hu, Zhe-yi,Li, Xiu-xue,Du, Fei-fei,et al. Pharmacokinetic evaluation of the anticancer prodrug simmitecan in different experimental animals[J]. ACTA PHARMACOLOGICA SINICA,2013,34(11):1437-1448.
APA	Hu, Zhe-yi.,Li, Xiu-xue.,Du, Fei-fei.,Yang, Jun-ling.,Niu, Wei.,...&Sun, Yan.(2013).Pharmacokinetic evaluation of the anticancer prodrug simmitecan in different experimental animals.ACTA PHARMACOLOGICA SINICA,34(11),1437-1448.
MLA	Hu, Zhe-yi,et al."Pharmacokinetic evaluation of the anticancer prodrug simmitecan in different experimental animals".ACTA PHARMACOLOGICA SINICA 34.11(2013):1437-1448.