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Pharmacokinetics and Disposition of Contezolid in Humans: Resolution of a Disproportionate Human Metabolite for Clinical Development

文献类型：期刊论文

作者Wu, Xiaojie2; Meng, Jian3; Yuan, Hong5; Zhong, Dafang3; Yu, Jicheng2; Cao, Guoying2; Liu, Xingdang4; Guo, Beining1; Chen, Yuancheng2; Li, Yi1
刊名ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
出版日期2021-10-01
卷号65期号:11页码:13
关键词contezolid disposition metabolism pharmacokinetics
ISSN号0066-4804
DOI10.1128/AAC.00409-21
通讯作者Meng, Jian(goodwill_123@163.com) ; Zhong, Dafang(dfzhong@mail.shcn.ac.cn) ; Zhang, Jing(zhang_fudan@aliyun.com)
英文摘要Contezolid (MRX-I), a novel oxazolidinone antibiotic, was recently approved for the treatment of serious Gram-positive infections. The pharmacokinetics and disposition of [C-14]contezolid were investigated in a single-dose human mass balance study. Cross-species comparison of plasma exposure for contezolid and metabolites was performed, and the safety of the disproportionate metabolite in human was evaluated with additional nonclinical studies. After an oral administration of 99.1 mu Ci/602-mg dose of [C-14]contezolid, approximately 91.5% of the radioactivity was recovered in 0 to 168 h postdose, mainly in urine followed by that in feces. The principal metabolic pathway of contezolid in human comprised an oxidative ring opening of the 2,3-dihydropyridin-4-one fragment into polar metabolites MRX445-1 and MRX459, with recovery of approximately 48% and 15% of the dose, respectively, in urine and feces. Contezolid, MRX445-1, and MRX459 accounted for 68.0%, 19.5%, and 4.84% of the plasma exposure of the total radioactivity, respectively. Metabolites MRX445-1 and MRX459 were observed in disproportionately larger amounts in human plasma than in samples from rat or dog, the rodent and nonrodent species, respectively, used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies, wherein the primary metabolite, MRX445-1, was further characterized. The no-observed-adverse-effect level (NOAEL) of MRX445-1 was determined as 360 mg/kg body weight/day in a 14-day repeat-dose test in pregnant and nonpregnant Sprague Dawley rats. Furthermore, MRX445-1 exhibited no antibacterial activity in vitro. Thus, MRX445-1 is not expected to exert clinically relevant pharmacology and toxicity.
WOS关键词MRX-I ; ANTIBACTERIAL OXAZOLIDINONE ; SAFETY
资助项目New Drug Creation and Manufacturing Program of the Ministry of Science and Technology of China[2017ZX09304005] ; National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology, People's Republic of China[2017ZX09304005]
WOS研究方向Microbiology ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000747507200005
出版者AMER SOC MICROBIOLOGY
源URL[http://119.78.100.183/handle/2S10ELR8/300164]  
专题中国科学院上海药物研究所
通讯作者Meng, Jian; Zhong, Dafang; Zhang, Jing
作者单位1.Fudan Univ, Huashan Hosp, Inst Antibiot, Shanghai, Peoples R China
2.Fudan Univ, Huashan Hosp, Phase & Clin Res Ctr, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
4.Fudan Univ, Huashan Hosp, Dept Nucl Med, Shanghai, Peoples R China
5.MicuRx Pharmaceut Inc, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Xiaojie,Meng, Jian,Yuan, Hong,et al. Pharmacokinetics and Disposition of Contezolid in Humans: Resolution of a Disproportionate Human Metabolite for Clinical Development[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2021,65(11):13.
APA Wu, Xiaojie.,Meng, Jian.,Yuan, Hong.,Zhong, Dafang.,Yu, Jicheng.,...&Zhang, Jing.(2021).Pharmacokinetics and Disposition of Contezolid in Humans: Resolution of a Disproportionate Human Metabolite for Clinical Development.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,65(11),13.
MLA Wu, Xiaojie,et al."Pharmacokinetics and Disposition of Contezolid in Humans: Resolution of a Disproportionate Human Metabolite for Clinical Development".ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 65.11(2021):13.

入库方式： OAI收割

来源：上海药物研究所

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