Absorption, distribution, metabolism, and excretion of [14C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats
Absorption, distribution, metabolism, and excretion of [14C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats
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DOI：
10.1007/s00280-022-04485-5
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发表时间：
2022-10
影响因子：
3
通讯作者：
Xin-mei Li;Yuandong Zheng;Yi-fan Zhang;Xia-juan Huan;Cheng Yang;Meng-ling Liu;Xiao-kun Shen
中科院分区：
文献类型：
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作者：
Xin-mei Li;Yuandong Zheng;Yi-fan Zhang;Xia-juan Huan;Cheng Yang;Meng-ling Liu;Xiao-kun Shen
前言Mefuparib（CVL 218）是一种新型的第二代多聚腺苷二磷酸核糖聚合酶（PARP）抑制剂，用于肿瘤治疗。CVL 218很容易进入大脑。方法（1）用液体闪烁计数器和氧化燃烧法追踪[14 C] CVL 218在大鼠体内的代谢。(2)UHPLC-β-RAM/UHPLC-Fraction Collector和UHPLC-Q Exactive Plus MS鉴定代谢产物。（3）采用两种策略模拟分配系数Kp、uu、brainvalue。一种策略是基于静脉给药药代动力学和血浆蛋白结合研究的结果，使用ACD和GastroPlus软件。结果（1）灌胃给药后24 h内药物消除迅速，给药后24 h内药物在脑/血浆中的分布与给药前无明显差异。168 h内尿、粪中累积排泄量占给药剂量的97.15%。72 h内胆汁中累积放射性回收率为41.87%。药物有关物质在48 h内广泛分布于组织中。(2)M8是血浆、尿液、粪便和胆汁中的主要代谢产物。(3)CVL 218具有较高的脑蛋白结合率（88.16%）。结论CVL 218是一种快速代谢药物，主要经粪便排泄。CVL 218的B/P比值预测值与观测值基本一致。此外，Kp、uu、brainvalve的测定结果表明，脑血屏障的穿透可能是由摄取转运蛋白介导的。
IntroductionMefuparib (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 coefficientKp,uu,brainvalue 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%). TheKp,uu,brainvalue (8.42) simulated by the simple software strategy was similar to that of the brain/plasma distribution study (7.01).ConclusionsCVL218 is a fast-metabolizing drug and is mainly excreted in feces. TheB/Pratio prediction and observation data for CVL218 were consistent. Furthermore, theKp,uu,brainvalue indicated that penetration through the BBB might be mediated by uptake transporters.