Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species
Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species
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DOI：
10.3389/fphar.2020.00364
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发表时间：
2020-03-27
影响因子：
5.6
通讯作者：
Su, Weiwei
中科院分区：
文献类型：
--
作者：
Bai, Yang;Peng, Wei;Su, Weiwei
背景药代动力学为药品设计、剂量方案规划、了解人体对药物的作用以及将药物在体内的时间过程与其药效学和/或毒性作用联系起来提供科学依据。近日，天然黄酮类化合物柚皮苷凭借其非临床止咳、化痰功效和低毒功效，被国家食品药品监督管理局作为一类新药产品批准进入临床试验。以往的报道主要集中在柚皮苷或其活性代谢物柚皮素在大鼠体内的药代动力学研究，但由于柚皮苷与草药、水果和其他传统药物等混合物共同给药，这些研究分散且不足。本研究的目的是评估大鼠、狗和人口服和静脉注射柚皮苷后柚皮苷和柚皮素的药代动力学和代谢，这可能有益于新药开发。方法开发并验证了单独的生物分析方法，以确定从大鼠、狗和人获得的生物样品中柚皮苷及其活性代谢物柚皮素的浓度。使用综合的非临床和临床数据来估计柚皮苷和柚皮素的药代动力学参数。实验包括单剂量研究（口服和静脉注射）、多剂量研究以及食物影响评估。此外，在大鼠和人的肝脏和肾脏微粒体中研究了柚皮苷和柚皮素的代谢。所有生物样品均采用液相色谱-串联质谱法进行分析。结果计算了柚皮苷和柚皮素的药代动力学参数，结果显示高脂饮食影响不显着，多次给药后药物蓄积不显着。在大鼠和人类的肝脏和肾脏微粒体中检测到 12 种代谢物；柚皮苷代谢是一个由多种人类酶同时催化的复杂过程。所有评估的物种都表现出柚皮苷和柚皮素的药代动力学和代谢差异。结论结果可用于设计剂量方案、加深对机制的理解并加速新药开发。
BackgroundPharmacokinetics provides a scientific basis for drug product design, dosage regimen planning, understanding the body's action on the drug, and relating the time course of the drug in the body to its pharmacodynamics and/or toxic effects. Recently, naringin, a natural flavonoid, was approved for clinical trials as a first-class new drug product by the China Food and Drug Administration, owing to its nonclinical efficacy in relieving cough, reducing sputum, and low toxicity. Previous reports focused on the pharmacokinetic studies of naringin or its active metabolite naringenin in rats, which were scattered and insufficient because naringin was coadministered with mixtures such as herbs, fruits, and other traditional medicines. The purpose of this study was to evaluate the pharmacokinetics and metabolism of naringin and naringenin, following oral and intravenous administration of naringin in rats, dogs, and humans, which can be beneficial for new drug development.MethodsSeparate bioanalytical methods were developed and validated to determine the concentrations of naringin and its active metabolite naringenin in biological samples obtained from rats, dogs, and humans. Comprehensive nonclinical and clinical data were used to estimate the pharmacokinetic parameters of naringin and naringenin. Experiments included single-dose studies (oral and intravenous administration), multiple-dose studies, and an assessment of food-effects. Furthermore, the metabolism of naringin and naringenin was studied in rat and human liver and kidney microsomes. All biological samples were analyzed using liquid chromatography-tandem mass spectrometry.ResultsThe pharmacokinetic parameters of naringin and naringenin were calculated and the results show an insignificant influence of high-fat diet and insignificant accumulation of the drugs after multiple dosing. Twelve metabolites were detected in the liver and kidney microsomes of rats and humans; naringin metabolism was a complex process simultaneously catalyzed by multiple human enzymes. All evaluated species demonstrated differences in the pharmacokinetics and metabolism of naringin and naringenin.ConclusionThe results can be used to design a dosage regimen, deepen understanding of mechanisms, and accelerate new drug development.