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Absorption, distribution, metabolism, and excretion of [14C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats

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Abstract

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) [14C] CVL218 metabolism in rats was traced by a liquid scintillation counter and oxidative combustion. (2) Metabolic profiles and metabolites were identified by UHPLC-β-RAM/UHPLC-Fraction Collector and UHPLC-Q Exactive Plus MS. (3) The partition coefficient Kp,uu,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 Kp,uu,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 Kp,uu,brain value indicated that penetration through the BBB might be mediated by uptake transporters.

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Data availability

The original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author.

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Acknowledgements

This research was funded by the National Natural Science Foundation of China (No. 81903701, No. 82104275). Thanks to all the colleagues and professors from Yunnan Provincial Key Laboratory of Pharmacology, Shanghai Center for Drug Metabolism and Pharmacokinetics, and Fuwai Yunnan Cardiovascular Hospital for their support and encouragement.

Funding

Innovative Research Group Project of the National Natural Science Foundation of China, No. 81903701, XingXing Diao, No. 82104275, Yuan-dong Zheng.

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Author notes

  1. Xin-mei Li and Yuan-dong Zheng contributed equally.

Authors and Affiliations

  1. Yunnan Provincial Key Laboratory of Pharmacology, Kunming Medical University, Kunming, 650000, China

    Xin-mei Li

  2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201210, China

    Xin-mei Li, Yuan-dong Zheng, Yi-fan Zhang, Xia-juan Huan, Chen Yang, Meng-ling Liu, Chun-hao Yang & Xing-xing Diao

  3. Department of Pharmacy, Fuwai Yunnan Cardiovascular Hospital, Kunming, 650000, China

    Xin-mei Li

  4. Convalife (Shanghai) Co., Ltd., Shanghai, 200000, China

    Xiao-kun Shen

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Contributions

XL: designed the study, performed the assays, and wrote the paper; YZ: designed the study and performed the assays; YZ and ML: analyzed the data; XH: designed the pharmacological studies; XS and CY: contributed new reagents and partial financial support; XD: reviewed the manuscript.

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Correspondence to Xing-xing Diao.

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This research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The manuscript has no associated data.

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The study protocol was approved by the Animal Ethics Committee of the Shanghai Institute of Materia Medica, Chinese Academy of Science (Shanghai, China).

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Li, Xm., Zheng, Yd., Zhang, Yf. et al. Absorption, distribution, metabolism, and excretion of [14C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats. Cancer Chemother Pharmacol 90, 499–510 (2022). https://doi.org/10.1007/s00280-022-04485-5

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