Oral Bioavailability of Hyperforin from Hypericum Extracts in Rats and Human Volunteers

Abstract

Validated analytical methods suitable for determining hyperforin in plasma after administration of alcoholic Hypericum perforatum extracts containing hyperforin are described. After oral administration of 300 mg/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats maximum plasma levels of approximately 370 ng/ml (approx. 690 nM) were reached after 3 h, as quantified by a HPLC and UV detection method. Estimated half-life and clearance values were 6 h and 70 ml/min/kg respectively. Since therapeutic doses of Hypericum extracts are much lower than that used in rats, a more sensitive LC/MS/MS method was developed. The lower limit of quantification of this method was 1 ng/ml. Using this method, plasma levels of hyperforin could be followed for up to 24 h in healthy volunteers after administration of film coated tablets containing 300 mg hypericum extracts representing 14.8 mg hyperforin. The maximum plasma levels of approximately 150 ng/ml (approx. 280 nM) were reached 3.5 h after administration. Half-life and mean residence time were 9 and 12 h respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed. Using the observed AUC values from the repeated dose study, the estimated steady state plasma concentrations of hyperforin after 3 x 300 mg/day of the extract, i.e., after normal therapeutic dose regimen, was approximately 100 ng/ml (approx. 180 nM).

Hyperforin Inhibits Cancer Invasion and Metastasis

“…22). This observation substantiates the clinical relevance of our findings and prompts a study of the cancer epidemiology of patients following this antidepressant treatment.…”

“…20). Although a full assessment of the clinical potential of these compounds is not yet possible and must await clarification of issues like absorption, bioavailability, and metabolic fate (21), the pharmacokinetics of Hyp has been thoroughly investigated, revealing that the compound is available upon oral ingestion, with antidepressive therapeutic doses of St. John's wort leading to serum levels of Hyp reaching 0.45 mol/L (22).…”

Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John’s wort: an [11C]-harmine PET study

“…The second scan took place 2-4 hours after the last dose (t max for moclobemide was about 2 h, 26 and t max for compounds of St. John's wort formulation was 2-4 h 27,28 ).…”

Effects of Standardized Extracts of St. John's Wort on the Single-Unit Activity of Serotonergic Dorsal Raphe Neurons in Awake Cats Comparisons with Fluoxetine and Sertraline

“…Pharmacokinetic experiments in humans have shown that after a single therapeutic dose of hypericum extract (300 mg, 5% hyperforin), plasma hyperforin levels reach a peak of about 280 nM, with steady-state plasma levels estimated to be approximately 180 nM after a standard treatment regimen (i.e., 300 mg, t.i.d.) (Biber et al 1998). In rats, peak plasma levels of about 690 nM of hyperforin were found after oral administration of 300 mg/kg of the same hypericum extract (Biber et al 1998).…”

“…(Biber et al 1998). In rats, peak plasma levels of about 690 nM of hyperforin were found after oral administration of 300 mg/kg of the same hypericum extract (Biber et al 1998). Reported IC 50 values for hyperforin as an inhibitor of synaptosomal uptake of serotonin have ranged from 120 nM to 3,300 nM Gobbi et al 1999;Singer et al 1999;Jensen et al 2001).…”