6-羟基犬尿酸及其结构修饰化合物的药代动力学和脑分布研究,Journal of Pharmacy and Pharmacology

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6-羟基犬尿酸及其结构修饰化合物的药代动力学和脑分布研究
Journal of Pharmacy and Pharmacology ( IF 2.8 ) Pub Date : 2021-08-17 , DOI: 10.1093/jpp/rgab132
Zhuowei Shen ₁ , Haihong Hu ₂ , Jie Pan ₂ , Mingcheng Xu ₂ , Fengting Ou ₂ , Kaifeng He ₂ , Kui Zeng ₂ , Jianbiao Yao ₃ , Ruwei Wang ₃ , Yan Lou ₁ , Su Zeng ₂

Affiliation

目的 6-羟基犬尿酸 (6-HKA) 是银杏叶提取物中的一种有机酸成分，是神经修复作用的主要贡献者，但其口服生物利用度较低。因此，采用前药方法提高6-HKA的生物利用度和脑含量具有重要意义。方法合成了3种6-HKA结构修饰化合物，建立了对大鼠血浆和大鼠脑匀浆中这些结构修饰化合物进行定量的超高效液相色谱-串联质谱方法，并进行了综合验证。该方法有效地应用于研究结构修饰对细胞表观通透系数、药代动力学和大鼠脑分布的影响。主要发现结果表明，酯化可以大大提高 6-HKA 的表观渗透系数和生物利用度。与直接口服 6-HKA 相比，异丙酯的生物利用度显着提高（从 3.96 ± 1.45% 提高到 41.8 ± 15.3%），大鼠脑中 6-HKA 的含量（49.7 ± 9.2 ng/g 脑）口服后显着升高。结论前药法可提高6-HKA的生物利用度和脑含量。在三种结构改性化合物中，异丙基酯化 6-HKA 是最有希望的处理方法。口服给药后大鼠脑中6-HKA的含量（49.7±9.2 ng/g脑）显着升高。结论前药法可提高6-HKA的生物利用度和脑含量。在三种结构改性化合物中，异丙基酯化 6-HKA 是最有希望的处理方法。口服给药后大鼠脑中6-HKA的含量（49.7±9.2 ng/g脑）显着升高。结论前药法可提高6-HKA的生物利用度和脑含量。在三种结构改性化合物中，异丙基酯化 6-HKA 是最有希望的处理方法。

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Pharmacokinetics and brain distribution studies of 6-hydroxykynurenic acid and its structural modified compounds

Objectives 6-Hydroxykynurenic acid (6-HKA) is an organic acid component in extracts of Ginkgo biloba leaves and acts as a major contributor to neurorestorative effects, while its oral bioavailability was low. Therefore, using prodrug method to improve the bioavailability and brain content of 6-HKA is significant. Methods Three structural modified compounds of 6-HKA were synthesized, and ultra performance liquid chromatography-tandem mass spectrometry methods for quantification of these structural modified compounds in rat plasma and rat brain homogenate were established and comprehensively validated. The methods were effectively applied to investigate the effects of structural modification on apparent permeability coefficients in cells, the pharmacokinetics and the brain distribution in rats. Key findings The results illustrated that esterification can greatly improve the apparent permeability coefficient and bioavailability of 6-HKA. Comparing with direct oral administration of 6-HKA, the bioavailability of isopropyl ester was greatly improved (from 3.96 ± 1.45% to 41.8 ± 15.3%), and the contents of 6-HKA in rat brains (49.7 ± 9.2 ng/g brain) were significantly higher after oral administration. Conclusions The bioavailability and the brain content of 6-HKA can be improved by the prodrug method. Among three structural modified compounds, isopropyl-esterified 6-HKA was the most promising treatment.

更新日期：2021-08-17

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