Absorption, distribution, metabolism, and excretion of [C-14]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats
文献类型：期刊论文
| 作者 | Li, Xin-mei2,3,4; Zheng, Yuan-dong3; Zhang, Yi-fan3 ; Huan, Xia-juan3; Yang, Chen3; Liu, Meng-ling3; Shen, Xiao-kun1; Yang, Chun-hao3; Diao, Xing-xing3
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| 刊名 | CANCER CHEMOTHERAPY AND PHARMACOLOGY
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| 出版日期 | 2022-10-25 |
| 页码 | 12 |
| ISSN号 | 0344-5704 |
| 关键词 | [C-14]Mefuparib Mefuparib (CVL218) Blood-brain barrier Mass balance Tissue distribution GastroPlus simulation |
| DOI | 10.1007/s00280-022-04485-5 |
| 通讯作者 | Diao, Xing-xing(xxdiao@simm.ac.cn) |
| 英文摘要 | Introduction Mefuparib (CVL218) is a novel second-generation poly-ADP-ribose polymerase (PARP) inhibitor for cancer treatment. CVL218 can easily enter the brain. However, the transport mechanism by which CVL218 crosses the blood-brain barrier (BBB) is unknown. Methods (1) [C-14] CVL218 metabolism in rats was traced by a liquid scintillation counter and oxidative combustion. (2) Metabolic profiles and metabolites were identified by UHPLC-beta-RAM/UHPLC-Fraction Collector and UHPLC-Q Exactive Plus MS. (3) The partition coefficient K-p,K-uu,K-brain value was simulated by two strategies. One strategy was using ACD and GastroPlus Software based on the results of intravenous administration pharmacokinetics and plasma protein-binding studies. The reliability was confirmed by comparison with another strategy (brain/plasma distribution study). Results (1) Rapid drug elimination was observed 24 h after intragastric administration. The total cumulative excretion in urine and feces within 168 h accounted for 97.15% of the dose. The cumulative radioactive dose recovery in bile was 41.87% within 72 h. The drug-related substances were extensively distributed to the tissues within 48 h. (2) M8 was the major metabolite in plasma, urine, feces and bile. (3) CVL218 exhibited high brain protein-binding rate (88.16%). The K-p,K-uu,K-brain value (8.42) simulated by the simple software strategy was similar to that of the brain/plasma distribution study (7.01). Conclusions CVL218 is a fast-metabolizing drug and is mainly excreted in feces. The B/P ratio prediction and observation data for CVL218 were consistent. Furthermore, the K-p,K-uu,K-brain value indicated that penetration through the BBB might be mediated by uptake transporters. |
| WOS关键词 | PLASMA PARTITION-COEFFICIENTS ; BLOOD-BRAIN-BARRIER ; IN-VIVO ; PHARMACOKINETIC MODELS ; PREDICTION ; BINDING ; CANCER ; OPPORTUNITIES ; MECHANISM ; TRANSPORT |
| 资助项目 | Innovative Research Group Project of the National Natural Science Foundation of China[81903701] ; Innovative Research Group Project of the National Natural Science Foundation of China[82104275] |
| WOS研究方向 | Oncology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | SPRINGER |
| WOS记录号 | WOS:000871816300001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/303235]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Diao, Xing-xing |
| 作者单位 | 1.Convalife Shanghai Co Ltd, Shanghai 200000, Peoples R China 2.Fuwai Yunnan Cardiovasc Hosp, Dept Pharm, Kunming 650000, Yunnan, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201210, Peoples R China 4.Kunming Med Univ, Yunnan Prov Key Lab Pharmacol, Kunming 650000, Yunnan, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Xin-mei,Zheng, Yuan-dong,Zhang, Yi-fan,et al. Absorption, distribution, metabolism, and excretion of [C-14]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats[J]. CANCER CHEMOTHERAPY AND PHARMACOLOGY,2022:12. |
| APA | Li, Xin-mei.,Zheng, Yuan-dong.,Zhang, Yi-fan.,Huan, Xia-juan.,Yang, Chen.,...&Diao, Xing-xing.(2022).Absorption, distribution, metabolism, and excretion of [C-14]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats.CANCER CHEMOTHERAPY AND PHARMACOLOGY,12. |
| MLA | Li, Xin-mei,et al."Absorption, distribution, metabolism, and excretion of [C-14]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats".CANCER CHEMOTHERAPY AND PHARMACOLOGY (2022):12. |
入库方式： OAI收割
来源：上海药物研究所
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