Identification and Characterization of Human UDP-glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Salvianolic Acid A

被引：10
作者：
Han, De-en [1 ,2 ,3 ]
Zheng, Yi [3 ]
Chen, Xijing [3 ]
He, Jiake [3 ]
Zhao, Di [3 ]
Yang, Shuoye [3 ]
Zhang, Chunfeng [1 ]
Yang, Zhonglin [1 ]
机构：
[1] China Pharmaceut Univ, State Key Lab Nat Prod & Funct, Minist Educ, Nanjing 210009, Jiangsu, Peoples R China
[2] Henan Univ Tradit Chinese Med, Coll Pharm, Zhengzhou, Henan, Peoples R China
[3] China Pharmaceut Univ, Ctr Drug Metab & Pharmacokinet, Nanjing 210009, Jiangsu, Peoples R China
来源：
DRUG METABOLISM AND PHARMACOKINETICS | 2012年 / 27卷 / 06期
关键词：
salvianolic acid A; UDP-glucuronosyltransferanses; human liver microsomes; UGT1A1; UGT1A9; HUMAN LIVER-MICROSOMES; DRUG GLUCURONIDATION; MASS-SPECTROMETRY; RAT PLASMA; UGT; 1A9; PERMEABILITY; SPECIFICITY; SELECTIVITY; METABOLISM; MECHANISM;
D O I：
10.2133/dmpk.DMPK-12-RG-023
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
Glucuronidation is an important pathway in the elimination of salvianolic acid A (Sal A); however the mechanism of UDP-glucuronosyltransferases (UGTs) in this process remains to be investigated. In this study, the kinetics of Sal A glucuronidation by pooled human liver microsomes (HLMs), pooled human intestinal microsomes (HIMs) and 12 recombinant UGT isozymes were investigated. The glucuronidation of Sal A can be shown both in HLMs and HIMs with K-m values of 39.84 +/- 3.76 and 54.04 +/- 4.36 mu M, respectively. Among the 12 human UGTs investigated, UGT1A1 and UGT1A9 were the major isoforms that catalyzed the glucuronidation of Sal A (K-m values of 29.72 +/- 2.20 and 24.40 +/- 2.60 mu M). UGT1A9 showed the highest affinity of Sal A glucuronidation. Furthermore, a significant correlation between Sal A glucuronidation and propofol glucuronidation (a typical UGT1A9 substrate) was observed. The chemical inhibition study showed that the IC50 for phenylbutazone inhibition of Sal A glucuronidation was 50.3 +/- 4.3 and 39.4 +/- 2.9 mu M by HLMs and UGT1A9, respectively. Mefenamic acid inhibited Sal A glucuronidation in UGT1A1 and HLMs with IC50 values of >200 and 12.4 +/- 2.2 mu m, respectively.
引用
收藏
页码：579 / 585
页数：7
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