口服新型 5-脂氧合酶激活蛋白抑制剂 Atuliflapon 在健康参与者体内的分布情况。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI:10.1002/prp2.70029
Xue-Qing Li, Bo Lindmark, Carl Amilon, Kristin Samuelsson, Lars Weidolf, Karin Nelander, Jane Knöchel, Maria Heijer, Ryan A Bragg, Malin Gränfors, Eva-Lotte Lindstedt, Sharan Sidhu, Pavlo Garkaviy, Hans Ericsson
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引用次数: 0

摘要

本研究调查了健康男性受试者体内新型 5-脂氧合酶激活蛋白抑制剂阿托利夫拉朋(atuliflapon)的质量平衡、药代动力学(PK)和代谢情况。六名健康男性受试者单次口服 200 毫克 [14C]atuliflapon 悬浮液。采用放射性监测和液相色谱-质谱分析法对阿托利福平的质量平衡、PK 和代谢物谱进行了分析。研究期间还对阿托利夫拉朋的安全性进行了评估。阿托利夫拉朋吸收迅速,中位tmax为1.5小时,随后血浆暴露量呈双相下降,最终半衰期约为20小时。未发生变化的阿托利夫拉朋是血浆中最主要的放射性成分,占药物相关总暴露量(DRE)的40.1%,而直接N-葡萄糖醛酸是唯一超过DRE 10%的代谢物,占20.9%。在健康男性受试者中,肾脏排泄的完整阿托利夫拉蓬占 14C]atuliflapon 悬浮液总排泄量的 10%,耐受性良好。所获得的人体代谢和处置数据将支持阿托利夫拉朋今后作为治疗心血管、心肾和呼吸系统疾病的潜在候选药物进行开发和申报。
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Disposition of orally administered atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor in healthy participants.

In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half-life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug-related exposure (DRE), while a direct N-glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications.

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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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