ORAL BIOAVAILABILITY OF HYPERFORIN FROM HYPERICUM EXTRACTS IN RATS AND HUMAN VOLUNTEERS

Validated analytical methods suitable for determining hyperforin in pl asma after administration of alcoholic Hypericum perforatum extracts c ontaining hyperforin are described. After oral administration of 300 m g/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats max imum plasma levels of approximately 370 ng/ml (approx. 690 nM) were re ached after 3 h, as quantified by a HPLC and UV detection method. Esti mated half-life and clearance values were 6 h and 70 ml/min/kg respect ively. Since therapeutic doses of Hypericum extracts are much lower th an 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 th is method, plasma levels of hyperforin could be followed for up to 24 h in healthy volunteers after administration of film coated tablets co ntaining 300 mg hypericum extracts representing 14.8 mg hyperforin. Th e maximum plasma levels of approximately 150 ng/ml (approx. 280 nM) we re reached 3.5 h after administration. Half-life and mean residence ti me were 9 and 12 h respectively. Hyperforin pharmacokinetics were line ar up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower C-max and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentrat ion 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 reg imen, was approximately 100 ng/ml (approx. 180 nM).