Hypericum pharmacokinetics

A. Johne, J. Brockmoller, S. Bauer, A. Maurer, M. Langheinrich, and I. Root, Pharmacokinetic interaction of digoxin with an herbal extract from St. John s wort (Hypericum perforatum). Clin. Pharmacol. Ther., 66, 338-345 (1999). 

The pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

The pharmacokinetics of hypericin and pseudohypericin piasma have been studied as weii (Brockmoiier et ai. 1997). Human subjects receiving piacebo, or 900, 1800, or 3600 mg of a standardized hypericum extract (LI 160), which contained 0, 2.81, 5.62, and 11.25 mg of totai hypericin and pseudohypericin, achieved maximum total plasma concentrations at 4 hours (0.028, 0.061, and 0.159 mg/L, respectively). The half-lives of absorption, distribution, and elimination were 0.6, 6.0, and 43.1 hours, respectively, using 750 pg of hypericin, and are slightly different for 1578 pg of pseudohypericin (1.3, 1.4, and 24.8 hours, respectively) (Kerb et ai. 1996). The systemic availability of the hypericum extract LI 160 is between 14 and 21%. Comparable results are found in another study using LI 160 (Staffeldt et ai. 1994). Long-term dosing of 3 x 300 mg per day showed that steady-state levels of hypericin are reached after 4 days. 

The oral bioavailability of hypericum may be altered and improved by a combination of its constituents. A hypericum extract containing naphthodianthrones is inactive in a water suspension, but very effective when another constituent, procyanidin, is present. Procyanidin had the effect of increasing the water solubility of naphthodianthrones, and thus increasing their pharmacokinetic availability (Butterweck et ai. 1997). Further, the facilitative effect of procyanidin exhibited an inverted U curve. 

A review of case reports, clinical trials, post-marketing surveillance, and drug monitoring studies concurrently showed that the most common side effects were gastrointestinal, dizziness/confusion, and sedation (Ernst et al. 1998). Importantly, the side effects of hypericum in this study were comparable to placebo levels. A pharmacokinetic study showed that plasma levels of up to 300 ng/ml were well tolerated. Headache occured in one subject who was taking 1200 mg extract (59 mg hyperforin, plasma cone. >400 ng/ml) (Biber et al. 1998). 

Thus, the long tradition of hypericum as a treatment for depression has been well supported by modern scientific research. Several active constituents have been identified, including naphthodianthrones (e.g., hypericin), phloroglucinols (e.g., hyperforin) and flavonoids (amentoflavone). Research has delineated its pharmacokinetic properties, and many of its neurochemical mechanisms have been identified enhancing monoamine... 

Staffeldt B, Kerb R, Brockmoller J, Ploch M, Roots I. (1994). Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J Geriatr Psychiatry Neurol. 7(suppl 1) S47-53. 

It is not possible to discuss pharmacokinetics when the active compound or compounds of St. John s wort are not known. The half-life of hypericin and hyperforin have been estimated at between 6 and 9 hours, with peak plasma concentrations at about 2-3 hours after administration. Some of the ingredients of Hypericum extracts are metabolized in the liver. 

Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John s Wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 2004 44(l) 89-94. 

Stock S, Hoelzl J. Pharmacokinetic tests of (14C)-labeled hypericin and pseudohypericin from Hypericum perforatum and serum kinetics of hypericin in man. Planta Med 1991 57 A61. 

St. John s wort (Hypericum perforatum) had no effect on the pharmacokinetics of digoxin after a single dose in 25 healthy volunteers, but during steady-state therapy it reduced the AUC of digoxin by 25% (296). There were also significant reductions in C ax and (26% and 33% respectively). This effect was attributed to induction of P glycoprotein. 

Mai I, Kruger H, Budde K, Johne A, BrockmoUer J, Neumayer HH, Roots I. Hazardous pharmacokinetic interaction of Saint John s wort (Hypericum perforatum) tvith the immunosuppressant cyclosporin. Int J Chn Pharmacol Ther 2000 38(10) 500-2. 

Two pharmacokinetic studies have examined the pharmacokinetics of hypericin and pseudohypericin (41,42). Standardized hypericum extract LI 160 (Jarsin 300 , Lichtwer Pharma GmbH, Berlin) was used in both trials. In Part I of the studies, subjects in both trials were administered a single dose of either 300, 900, or 1800 mg of the extract (one, three, or six coated tablets) at 10- to 14-day intervals. Each dose contained 250, 750, or 1500 p.g of hypericin and 526, 1578, or 3156 p,g of pseudohypericin, respectively. The doses were administered on an empty stomach in the morning after a 12-hour fast. Subjects fasted for an additional 2 hours after administration. Multiple plasma levels of hypericin and pseudohypericin were measured for up to 120 hours after administration. In addition, urine samples were collected in the study performed by Kerb and colleagues. After a 4-week washout from Part I, subjects were given one coated tablet containing 300 mg of hypericum extract three times a day (8 am, 1 pm, and 6 pm) before meals for 14 days. Blood samples were obtained over the 2-week dosing period. 

Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with anherbal extractfrom St. John s wort Hypericum perforatum). Clin Pharmacol Ther 1999 66(4) 338-345. 

Mai, I., Kruger, H., Budde, K., Johne, A., Brockmoller, J., Neumeyer, H.H., Roots, I. (2000) Hazardous pharmacokinetic interaction of St. John s wort (Hypericum perforatum) with the immunosuppressant cyclosporin. Int. J. Clin. Pharmacol. Then 38, 500-502. 

Portoles, A., Terleira, A., Calvo, A., Martinez, I., and Resplandy, G. (2006) Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers an open-label, pharmacokinetic interaction clinical trial. J. Clin. Pharmacol. 46, 1188-1194. 

Due to their complex composition the pharmacokinetic assessment of herbal medications generally imposes serious technical and regulatory problems. As the active principle(s) of plant extracts are often not known it is difficult to decide which constituent(s) should actually be studied [218]. In the absence of a well defined therapeutically relevant chemical entity, characteristic constituents of herbal preparations are frequently employed for the purpose of standardization. Correspondingly, pharmacokinetic evaluations of Hypericum extracts have almost exclusively been based on the analysis of the naphthodianthrones hypericin 1 and pseudohypericin 2 which represent typical products of members of the genus Hypericum and are considered to be involved in some of their clinical effects. 

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