Pharmacokinetics Toxicokinetics

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 ^g of hypericin and 526, 1578, or 3156 ^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.

6.1. Absorption

For single doses of 300, 900, or 1800 mg of dried hypericum extract in humans, the median time between administration of the dose and detectable plasma concentration (tag) in hours were as follows:

A difference was observed between the tlag of hypericin compared with pseudohypericin. These differences may be a function of the dosage form given. Pseudohypericin may be released from the dosage form more quickly than hypericin. Also, hypericin and pseudohypericin may be absorbed in different locations in the gastrointestinal tract. Another explanation may be that hypericin may undergo first-pass hepatic metabolism (41).

The median maximum plasma concentrations (Cmax) in g/L for the respective doses were as follows:

The maximum plasma concentrations increased in a nonlinear fashion (41,42).

The median time to peak plasma concentration (Tmax) in hours for the corresponding doses were as follows:

Overall no correlation was observed between dose and Tmax. However, hypericin took longer to reach maximum plasma concentration. This corresponds with the lag time data (41).

After multiple dosing of300 mg of Hypericum extract three times daily, the data for median Cmax and trough plasma concentration (Cmin) were as follows:

a mean.

6.2. Distribution

For oral doses, the volume of distribution appears to be approx 162 L for hypericin and 63 L for pseudohypericum (42).

6.3. Metabolism/Elimination

The median half-lives in hours for single 300, 900, and 1800 mg oral doses were as follows:

After multiple doses of Hypericum extract 300 mg three times daily, median half-lives in hours were:

The data in these two studies differ in regard to the elimination half-life of hypericin. It is difficult to ascertain whether the half-life for either hyperi-cin or pseudohypericin is dose related.

Neither hypericin, pseudohypericin, their glucuronic acid conjugates, nor their sulfate conjugates were detected in the urine (42). The chemical structure and molecular size (>500 Da) of hypericin and pseudohypericin suggest metabolism via hepatic glucuronidization followed by biliary excretion (42).

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