Schulz Hans-Ulrich, Schürer Michael, Bässler Dagmar, Weiser Dieter
LAFAA Laboratory for Contract Research in Clinical Pharmacology and Biopharmaceutical Analytics GmbH, Bad Schwartau, Germany.
Arzneimittelforschung. 2005;55(10):561-8. doi: 10.1055/s-0031-1296905.
Hypericins, hyperforin and flavonoids are discussed as the main components contributing to the antidepressant action of St. John's wort (Hypericum perforatum). Therefore, the objective of the two open phase I clinical trials was to obtain pharmacokinetic data of these constituents from a hypericum extract containing tablet: hypericin, pseudohypericin, hyperforin, the flavonoid aglycone quercetin, and its methylated form isorhamnetin. Each trial included 18 healthy male volunteers who received the test preparation, containing 900 mg dry extract of St John's wort (STW 3-VI, Laif 900), either as a single oral dose or as a multiple once daily dose over a period of 14 days. Concentration/time curves were determined for the five constituents, for 48 h after single dosing and for 24 h on day 14 at the end of 2 weeks of continuous daily dosing. After single dose intake, the key pharmacokinetic parameters were determined as follows: Hypericin: Area under the curve (AUC(0-infinity)) = 78.33 h x ng/ml, maximum plasma concentration (Cmax) = 3.8 ng/ml, time to reach Cmax (tmax) = 7.9 h, and elimination half-life (t1/2) = 18.71 h; pseudohypericin: AUC(0-infinity) = 97.28 h x ng/ml, Cmax = 10.2 ng/ml, tmax = 2.7 h, t1/2 = 17.19 h; hyperforin: AUC(0-infinity) = 1550.4 h x ng/ml, Cmax = 122.0 ng/ml, tmax = 4.5 h, t1/2 = 17.47 h. Quercetin and isorhamnetin showed two peaks of maximum plasma concentration separated by about 3-3.5 h. Quercetin: AUC(0-infinity) = 417.38 h x ng/ml, Cmax (1) = 89.5 ng/ml, tmax (1) = 1.0 h, Cma (2) = 79.1 ng/ml, tmax (2) = 4.4 h, t1/2 = 2.6 h; isorhamnetin: AUC(0-infinity) = 155.72 h x ng/ml, Cmax (1) = 12.5 ng/ml, tmax (1) = 1.4 h, Cmax (2) = 14.6 ng/ml, tmax (2) = 4.5 h, t1/2 = 5.61 h. Under steady state conditions reached during multiple dose administration similar results were obtained. Further pharmacokinetic characteristics calculated from the obtained data were the mean residence time (MRT), the lag-time, the peak-trough fluctuation (PTF), the lowest observed plasma concentration (Cmin), and the average plasma concentration (Cav). The data obtained for the five consitituents generally corresponded well with values previously published. The trial preparation was well tolerated.
金丝桃素、贯叶连翘素和黄酮类化合物被认为是贯叶连翘（Hypericum perforatum）发挥抗抑郁作用的主要成分。因此，两项开放性I期临床试验的目的是获取这些成分在一种含贯叶连翘提取物片剂中的药代动力学数据，这些成分包括：金丝桃素、假金丝桃素、贯叶连翘素、黄酮苷元槲皮素及其甲基化形式异鼠李素。每项试验均纳入18名健康男性志愿者，他们接受了含900mg贯叶连翘干提取物（STW 3-VI，Laif 900）的试验制剂，给药方式为单次口服剂量或连续14天每天一次的多次剂量。测定了这五种成分的浓度/时间曲线，单次给药后48小时以及连续每日给药2周结束时第14天的24小时内进行测定。单次剂量摄入后，关键药代动力学参数测定如下：金丝桃素：曲线下面积（AUC(0-∞)）=78.33小时×纳克/毫升，最大血浆浓度（Cmax）=3.8纳克/毫升，达峰时间（tmax）=7.9小时，消除半衰期（t1/2）=18.71小时；假金丝桃素：AUC(0-∞)=97.28小时×纳克/毫升，Cmax=10.2纳克/毫升，tmax=2.7小时，t1/2=17.19小时；贯叶连翘素：AUC(0-∞)=1550.4小时×纳克/毫升，Cmax=122.0纳克/毫升，tmax=4.5小时，t1/2=17.47小时。槲皮素和异鼠李素显示出两个最大血浆浓度峰值，间隔约3 - 3.5小时。槲皮素：AUC(0-∞)=417.38小时×纳克/毫升，Cmax(1)=89.5纳克/毫升，tmax(1)=1.0小时，Cma(2)=79.1纳克/毫升，tmax(2)=4.4小时，t1/2=2.6小时；异鼠李素：AUC(0-∞)=155.72小时×纳克/毫升，Cmax(1)=12.5纳克/毫升，tmax(1)=1.4小时，Cmax(2)=14.6纳克/毫升，tmax(2)=4.5小时，t1/2=5.61小时。在多次给药达到稳态条件下，获得了类似结果。根据所得数据计算的进一步药代动力学特征包括平均驻留时间（MRT）、滞后时间、峰谷波动（PTF）、最低观察到的血浆浓度（Cmin）和平均血浆浓度（Cav）。这五种成分获得的数据总体上与先前发表的值相符。试验制剂耐受性良好。
