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Stereoselective Glucuronidation of Ornidazole in Humans: Predominant Contribution of UDP-Glucuronosyltransferases 1A9 and 2B7

文献类型：期刊论文

作者Du, Jiangbo2; You, Tiangeng1; Chen, Xiaoyan2; Zhong, Dafang2
刊名DRUG METABOLISM AND DISPOSITION
出版日期2013-07
卷号41期号:7页码:1306-1318
ISSN号0090-9556
DOI10.1124/dmd.113.051235
文献子类Article
英文摘要Ornidazole [R, S-1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol] is a chiral 5-nitroimidazole class antimicrobial agent. This study aimed to investigate the principal metabolic pathway of ornidazole in humans and identify the major enzymes involved. A total of 19 metabolites were identified in human urine collected from patients with hepatobiliary diseases after an intravenous drip infusion of 500 mg of racemic ornidazole. Stereoselective glucuronidation, followed by renal excretion, was the principal metabolic pathway of ornidazole in humans, accounting for 37.3% of the administered dose. Screening assays with 12 available human recombinant UDP-glucuronosyltransferases (UGTs) demonstrated that UGT1A9 was the predominant UGT isoform involved in R-ornidazole glucuronidation, whereas S-ornidazole glucuronidation was almost exclusively catalyzed by UGT2B7. Chemical inhibition study with niflumic acid and flurbiprofen supported these findings. Enzyme kinetic parameters were then determined in human liver microsomes (HLMs), human kidney microsomes (HKMs), UGT1A9, and 2B7. The K-m values for UGT1A9 (15.6 +/- 6 1.6 mM for R-ornidazole) and 2B7 (3.8 +/- 0.9 mM for S-ornidazole) were quite similar to those determined in HLMs and HKMs (20.1 +/- 1.4 and 17.7 +/- 4.0 mM for R-ornidazole; 6.6 +/- 1.3 and 3.2 +/- 0.4 mM for S-ornidazole). The in vitro intrinsic clearance (CLint) ratios of S- to R-ornidazole were approximately 4.3 in HLMs and 6.5 in HKMs, respectively. The hepatic and renal clearances were estimated based on the well-stirred model. Overall, stereoselective glucuronidation was the principal metabolic pathway of ornidazole in humans. Furthermore, UGT1A9 and 2B7 were the predominant UGT isoforms responsible for R- and S-ornidazole glucuronidation in humans, respectively.
WOS关键词IN-VITRO DATA ; BOVINE SERUM-ALBUMIN ; DRUG CLEARANCE ; ANAEROBIC-BACTERIA ; QUANTITATIVE PREDICTION ; VIVO EXTRAPOLATION ; HUMAN KIDNEY ; HUMAN LIVER ; UGT 1A9 ; METRONIDAZOLE
资助项目National Natural Science Foundation of China[81173117]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000320307100003
出版者AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
源URL[http://119.78.100.183/handle/2S10ELR8/277569]  
专题上海药物代谢研究中心
通讯作者Du, Jiangbo
作者单位1.Shanghai East Hosp, Shanghai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China;
推荐引用方式
GB/T 7714		 Du, Jiangbo,You, Tiangeng,Chen, Xiaoyan,et al. Stereoselective Glucuronidation of Ornidazole in Humans: Predominant Contribution of UDP-Glucuronosyltransferases 1A9 and 2B7[J]. DRUG METABOLISM AND DISPOSITION,2013,41(7):1306-1318.
APA Du, Jiangbo,You, Tiangeng,Chen, Xiaoyan,&Zhong, Dafang.(2013).Stereoselective Glucuronidation of Ornidazole in Humans: Predominant Contribution of UDP-Glucuronosyltransferases 1A9 and 2B7.DRUG METABOLISM AND DISPOSITION,41(7),1306-1318.
MLA Du, Jiangbo,et al."Stereoselective Glucuronidation of Ornidazole in Humans: Predominant Contribution of UDP-Glucuronosyltransferases 1A9 and 2B7".DRUG METABOLISM AND DISPOSITION 41.7(2013):1306-1318.

入库方式： OAI收割

来源：上海药物研究所

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