. Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier

doi:10.1038/aps.2015.64

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	. Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier
	Diao, Xing-xing; Zhong, Kan; Li, Xiu-li; Zhong, Da-fang; Chen, Xiao-yan
刊名	ACTA PHARMACOLOGICA SINICA
	2015-12
卷号	36 期号:12 页码:1520-1527
关键词	3-n-butylphthalide (NBP) 3-OH-NBP 10-OH-NBP blood-brain barrier isomer-selective drug plasma protein binding drug brain protein binding P-gp/BCRP cerebral ischemia
ISSN号	1671-4083
DOI	10.1038/aps.2015.64
文献子类	Article
英文摘要	Aim: To investigate the mechanisms underlying the isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP (3-OH-NBP) and 10-hydroxy-NBP (10-OH-NBP), across the blood brain barrier (BBB). Methods: After oral administration of NBP (20 mg/kg) to rats, the pharmacokinetics of two major hydroxylated metabolites, 3-OH-NBP and 10-OH-NBP, in plasma and brains were investigated. Plasma and brain protein binding of 3-OH-NBP and 10-OH-NBP was also assessed. To evaluate the influences of major efflux transporters, rats were pretreated with the P-gp inhibitor tariquidar (10 mg/kg, iv) and BCRP inhibitor pantoprazole (40 mg/kg, iv), then received 3-OH-NBP (12 mg/kg, iv) or 10-OH-NBP (3 mg/kg, iv). The metabolic profile of NBP was investigated in rat brain homogenate. Results: After NBP administration, the plasma exposure of 3-OH-NBP was 4.64 times that of 10-OH-NBP, whereas the brain exposure of 3-OH-NBP was only 11.8% of 10-OH-NBP. In the rat plasma, 60%+/- 5.2% of 10-OH-NBP was unbound to proteins versus only 22%+/- 2.3% of 3-OH-NBP being unbound, whereas in the rat brain, free fractions of 3-OH-NBP and 10-OH-NBP were 100%+/- 9.7% and 49.9%+/- 14.1%, respectively. In the rats pretreated with tariquidar and pantoprazole, the unbound partition coefficient K-p,K-uu of 3-OH-NBP was significantly increased, while that of 10-OH-NBP showed a slight but not statistically significant increase. Incubation of rat brain homogenate with NBP yielded 3-OH-NBP but not 10-OH-NBP. Conclusion: The isomer-selective distribution of 10-OH-NBP and 3-OH-NBP across the BBB of rats is mainly attributed to the differences in plasma and brain protein binding and the efflux transport of 3-OH-NBP. The abundant 10-OH-NBP is not generated in rat brains.
WOS关键词	CANCER RESISTANCE PROTEIN ; P-GLYCOPROTEIN P-GP/ABCB1 ; TANDEM MASS-SPECTROMETRY ; FOCAL CEREBRAL-ISCHEMIA ; PLASMA-PROTEIN ; CHIRAL 3-N-BUTYLPHTHALIDE ; TISSUE DISTRIBUTION ; DRUG DISCOVERY ; BINDING ; PENETRATION
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5586901
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000366098300015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276308]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiao-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	Diao, Xing-xing,Zhong, Kan,Li, Xiu-li,et al. . Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier[J]. ACTA PHARMACOLOGICA SINICA,2015,36(12):1520-1527.
APA	Diao, Xing-xing,Zhong, Kan,Li, Xiu-li,Zhong, Da-fang,&Chen, Xiao-yan.(2015).. Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier.ACTA PHARMACOLOGICA SINICA,36(12),1520-1527.
MLA	Diao, Xing-xing,et al.". Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier".ACTA PHARMACOLOGICA SINICA 36.12(2015):1520-1527.