.Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects
.Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects
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DOI：
10.1038/sj.ejcn.1602543
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发表时间：
2007-04-01
影响因子：
4.7
通讯作者：
Niopas, I.
中科院分区：
文献类型：
--
作者：
Kanaze, F. I.;Bounartzi, M. I.;Niopas, I.
背景和目的：橙皮素和柚皮素是橙皮苷和柚皮苷的黄酮苷元，天然存在于柑橘类水果中。它们发挥有趣的药理学特性，如抗氧化剂，抗炎，血脂和胆固醇降低，并被认为有助于人类的健康益处。然而，没有关于柑橘类黄烷酮橙皮素和柚皮素作为纯糖苷配基口服给药后的药代动力学的信息。因此，本研究的目的是评价橙皮素和柚皮素在血浆和尿液中的药代动力学参数，以固体分散体胶囊的形式在人体中单次口服给药后，还通过使用糖苷配基而不是天然存在的糖苷来提高黄烷酮的吸收率。设计：六名健康志愿者在禁食条件下口服135 mg的每种化合物，橙皮素和柚皮素。在12小时内的14个不同时间点采集血样。在24小时内，以五个连续的时间间隔收集尿液。血浆和尿液橙皮素和柚皮素浓度，酶水解后，其结合形式，使用经验证的高压液相色谱法进行测量。橙皮素和柚皮素的药代动力学参数，如C-max、T-max、AUC（0-t）、AUC根据其血浆或尿液浓度计算CL/F、V/F、t（1/2）、MRT、A（e）、A（e（0-24））和R-max。药代动力学分析表明，橙皮素和柚皮素都被迅速吸收，给药后20分钟观察到其血浆浓度，分别在4.0和3.5h达到高峰。橙皮素和柚皮素的平均血浆峰浓度（C-max）为825.78 ± 410.63 ng/ml（2731.8 +/- 1358.4 nmol/l）和2009.51 +/- 770.82 ng/ml橙皮素和柚皮素的平均AUC（0-无穷大）值分别为4846.20 +/- 1675.99 ng h/ml和9424.52 +/- 2960.52 ng h/ml。橙皮素和柚皮素的消除半衰期分别为3.05 +/- 0.91 h和2.31 +/- 0.40 h。平均值的相对累积尿排泄量，作为给药剂量的百分比，橙皮素和柚皮素，被发现是3.26 +/- 0.44和5.81 +/-0.81%，foreign.Conclusions：口服给药的黄烷酮苷元，橙皮素和柚皮素，导致其快速吸收作为其共轭形式。累积的尿液回收数据表明，两种黄烷酮苷元的生物利用度较低，这是由于广泛的首过代谢，部分是由于肠道细菌的酶裂解C环，导致降解产物，如酚酸。
Background and objective: Hesperetin and naringenin, the aglycones of the flavanone glycosides hesperidin and naringin, occur naturally in citrus fruits. They exert interesting pharmacological properties such as antioxidant, anti-inflammatory, blood lipid and cholesterol lowering and are considered to contribute to health benefits in humans. However, no information is available on the pharmacokinetics of the citrus flavanones hesperetin and naringenin after their oral administration to humans as pure aglycones. Therefore, the objective of the present investigation was the evaluation of the pharmacokinetic parameters of hesperetin and naringenin in plasma and urine, after their single oral administration in humans in the form of solid dispersion capsules, and also to improve the absorption rate of flavanones by using aglycones rather than the naturally occurring glycosides.Design: Six healthy volunteers received orally 135 mg of each compound, hesperetin and naringenin, under fasting conditions. Blood samples were collected at 14 different time points over a 12 h period. Urine was collected over 24 h, in five sequential timed intervals. Plasma and urine hesperetin and naringenin concentrations, after enzymatic hydrolysis of their conjugated forms, were measured using validated high-pressure liquid chromatography methods. Pharmacokinetic parameters for hesperetin and naringenin, such as C-max, T-max, AUC(0-t), AUC(0-infinity), CL/F, V/F, t(1/2), MRT, A(e), A(e(0-24)), and R-max were calculated from their plasma or urine concentrations.Results: Pharmacokinetic analysis showed that both hesperetin and naringenin were rapidly absorbed and their concentrations in plasma observed 20 min after dosing and reached a peak in 4.0 and 3.5 h, respectively. The mean peak plasma concentration (C-max) for hesperetin and naringenin were 825.78 +/- 410.63 ng/ml (2731.8 +/- 1358.4 nmol/l) and 2009.51 +/- 770.82 ng/ml (7386.6 +/- 2833.4 nmol/l), respectively and the mean AUC(0-infinity) values were 4846.20 +/- 1675.99 ng h/ml and 9424.52 +/- 2960.52 ng h/ml for hesperetin and naringenin, respectively. The elimination half-life for hesperetin was found to be 3.05 +/- 0.91 h and for naringenin 2.31 +/- 0.40 h, respectively. The mean values of the relative cumulative urinary excretion, as percentage of the administered dose, for hesperetin and naringenin, were found to be 3.26 +/- 0.44 and 5.81 +/- 0.81%, respectively.Conclusions: Oral administration of the flavanone aglycones, hesperetin and naringenin, lead to their rapid absorption as their conjugated forms. The cumulative urinary recovery data indicated low bioavailability for both flavanone aglycones, owing to extensive first-pass metabolism partly by cleavage of the C-ring by the enzymes of intestinal bacteria leading to degradation products such as phenolic acids.