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Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [14C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

文献类型：期刊论文

作者Zheng, Yuandong4,5; Zhang, Hua2,3; Liu, Mengling4,5; Li, Guangze1; Ma, Sheng2,3; Zhang, Zhe1; Lin, Hongda1; Zhan, Yan4,5; Chen, Zhendong4,5; Zhong, Dafang4
刊名DRUG METABOLISM AND DISPOSITION
出版日期2022-06-01
卷号50期号:6页码:798-808
ISSN号0090-9556
DOI10.1124/dmd.121.000581
通讯作者Diao, Xingxing(xxdiao@simm.ac.cn)
英文摘要HR011303, a promising selective urate transporter 1 inhibitor, is currently being studied in a phase III clinical trial in China for the treatment of hyperuricemia and gout. In the current study, the pharmacokinetics, mass balance, and metabolism of HR011303 were examined in six healthy Chinese male subjects who received a single oral dose of 10 mg of [14C]HR011303 (80 mCi). The results showed that HR011303 was rapidly absorbed with a median time to reach Cmax of 1.50 hours postdose, and the arithmetic mean halflife of total radioactivity was approximately 24.2 hours in plasma. The mean blood-to-plasma radioactivity concentration ratio was 0.66, suggesting the preferential distribution of drug-related components in plasma. At 216 hours postdose, the mean cumulative excreted radioactivity was 91.75% of the dose, including 81.50% in urine and 10.26% in feces. Six metabolites were identified, and the parent drug HR011303 was the most abundant component in plasma and feces, but a minor component in urine. Glucuronidation of the carboxylic acid moiety of HR011303 was the primary metabolic pathway in humans, amounting to 69.63% of the dose (M5, 51.57% of the dose; M5/2, 18.06% of the dose) in the urine; however, it was not detected in plasma. UDP-glucuronosyltransferase (UGT) 2B7 was responsible for the formation of M5. Overall, after a single oral dose of 10 mg of [14C]HR011303 (80 mCi), HR011303 and its main metabolites were eliminated via renal excretion. The major metabolic pathway was carboxylic acid glucuronidation, which was catalyzed predominantly by UGT2B7.
WOS关键词URIC-ACID ; DRUG-METABOLISM ; GOUT ; GLUCURONIDATION ; INVOLVEMENT ; PREVALENCE ; MECHANISMS ; EXCRETION ; DISCOVERY ; POTENT
资助项目Jiangsu Hengrui Medicine Co., Ltd. ; National Natural Science Foundation of China[81903701] ; National Key New Drug Creation Special Programs[2017ZX09304-021]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000811854900007
出版者AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
源URL[http://119.78.100.183/handle/2S10ELR8/301632]  
专题中国科学院上海药物研究所
通讯作者Diao, Xingxing
作者单位1.Jiangsu Hengrui Med Co Ltd, Shanghai, Peoples R China
2.Soochow Univ, Inst Interdisciplinary Drug Res & Translat Sci, Suzhou, Peoples R China
3.Soochow Univ, Dept Clin Pharmacol, Affiliated Hosp 1, Suzhou, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Chinese Acad Sci, Shanghai Ctr Drug Metab & Pharmacokinet, Shanghai Inst Mat Med, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zheng, Yuandong,Zhang, Hua,Liu, Mengling,et al. Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [14C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase[J]. DRUG METABOLISM AND DISPOSITION,2022,50(6):798-808.
APA Zheng, Yuandong.,Zhang, Hua.,Liu, Mengling.,Li, Guangze.,Ma, Sheng.,...&Diao, Xingxing.(2022).Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [14C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase.DRUG METABOLISM AND DISPOSITION,50(6),798-808.
MLA Zheng, Yuandong,et al."Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [14C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase".DRUG METABOLISM AND DISPOSITION 50.6(2022):798-808.

入库方式： OAI收割

来源：上海药物研究所

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