For some time, the possibility that co-administration of Hypericum extracts may reduce the plasma concentrations of other drugs has been under discussion. So far, the mode of action and the ingredients involved in producing this effect have been unclear. A study has now been published in the British Journal of Pharmacology which demonstrates for the first time that Hypericum extract stimulates the action of P-glycoprotein (P-gp). The St. John's Wort ingredient hypericin appears to be at least co-responsible for this effect.

Two hypotheses on how St. John's Wort extract could reduce the bioavailability of certain drugs have been proposed to date:

1. Increased production of P-glycoprotein (P-gp), a transport molecule, which removes certain substances (e.g. digoxin) from the cells.
   
   
   
2. Increased expression of cytochrome P-450, which would lead to an accelerated break-down of certain drugs.

Is hypericin responsible for P-gp induction?

Which Hypericum ingredients are responsible for these effects has so far been unclear. The recent publication from David Greenblatt's Boston team shows that Hypericum extract induces the expression of P-gp to a significant extent in vitro. This effect appears to be caused mainly by the St. John's Wort ingredient hypericin.

The team incubated intestinal carcinoma cells with a methanolic extract of Hypericum or pure hypericin over 72 hours. P-gp expression was then determined by Western Blot, a procedure for assaying protein. Compared to controls, both extract and pure hypericin led to a clear and dose-dependent increase in cell P-gp protein.

Rhodamine removal is increased.

A second study showed that the increased expression of P-gp also had functional consequences. In these experiments, the research workers could demonstrate that Hypericum extract reduces intra-cellular accumulation of rhodamine 123, a typical P-gp substrate. If P-gp was blocked by the addition of a P-gp inhibitor, the effect of Hypericum was reversed. These results show that Hypericum extract causes a more rapid removal of rhodamine 123 due to an increase in P-gp.

This publication demonstrates for the first time that hypericin in therapeutically relevant concentrations leads to a clear, statistically significant increase in P-gp. From their results, the authors conclude that hypericin and pseudohypericin are at least co-responsible for the clinical P-gp induction observed in man.

The publication "Saint John's wort: An in vitro analysis of P-glycoprotein induction due to extended exposure" by Michael D. Perloff, Lisa L. von Moltke, Elke Stürmer, Richard I. Shader & David J. Greenblatt appeared in the British Journal of Pharmacology (2001) 134, 1601-1608.

Contact

Dr. Willmar Schwabe Pharmaceuticals
Research and Development
Dr. Michael Nöldner
info@schwabepharma.com