Hyperforin. in St. John’s wort

Madabushi R, Frank B, Drewelow B, et al. Hyperforin in St. John s wort drug interactions. Eur J Clin Pharmacol 2006 62 225-233. 

Certain CYP enzymes may be induced or inhibited by conventional drugs or by compounds in plants, leading to an increase or decrease in the activity of the enzyme. If a CYP enzyme is induced, plasma levels of drugs metabolized by that enzyme may be decreased, which, in turn, may result in plasma levels too low to be effective. For example, the compound hyperforin in St. John s wort induces CYP3A4 and reduces plasma levels of cyclosporine, a drug used... 

Recent teports from our research groups have demonstrated that neat supercritical CO2 is selective for the extraction of hyperforin and adhyperforin in St. John s wort (24, 33) (Figure 2). Modifiers do not increase toe SFE recoveries of these phloroglucinols, but tend to cause partial extraction of polar compounds in St. John s wort. Thus, extraction with neat CO2 is toe best choice for selective removal of hyperforin and adhyperforin from St. John s wort. 

A commoniy reported drug-dietary suppiement interaction is between St. John s Wort and FiiV protease inhibitors, ieading to drug resistance and treatment faiiure. St. John s wort is a popuiar dietary suppiement often used for depression. Of the two substances found in St. John s wort, hypericin and hyperforin, hyperforin appears to be the main constituent, with in vitro seieotive serotonin reuptake inhibitor (SSRi) activity (see Chapter 21). Hyperforin aiso appears to be the more potent inducer of CYP3A enzymes based on in vitro and in vivo studies. 

In kidney transplant patients orally administered 900 mg daily of a low-hyperforin (0.6 mg hyperforin daily) or regular (42 mg hyperforin daily) St. John s wort preparation in addition to the standard dose of cyclosporine, no clinically relevant changes in cyclosporine levels were observed during the low-hyperforin treatment period. During treatment with the regular St. John s wort extract, a 45% reduction in plasma levels (AUC042) of cyclosporine was observed (Mai et al. 2004). Cyclosporine is metabolized by CYP3A4 (Dresser et al. 2003). 

Hypericin and pseudohypericin (Fig. 21) are naphthodianthrones and occur in St. John s wort Hypericum perforatum, Clusiaceae). These dark-red compounds are accumulated in glands on the margin oiK perforatum leaves and petals. It was assumed for a long time that they represent the antidepressant principle in extracts of St. John s wort. Recently, however, it became evident that the prenylated acylphloroglucinols hyperforin and adhyperforin are responsible for most of the pharmacological effects. 

Hyperforin, the major constituent in Hypericum perforatum (St. John s Wort), inhibits the enzymatic activity of 5-lipoxygenase and COX-1 in platelets, acts as a dual inhibitor of 5-lipoxygenase and COX-1, and might have some potential in inflammatory and allergic diseases connected to eicosanoids (32), Several Hypericum species are of medicinal value in Asia and the Pacific. One of these is Hypericum erectum Thunb., the potential of which as a source of 5-lipoxygenase is given here. 

Dimpfel W, Schober F, Mannel M. (1998). Effects of a methanolic extract and a hyperforin-enriched C02 extract of St. John s Wort (Hypericum perforatum) on intracerebral field potentials in the freely moving rat (Tele-Stereo-EEG). Pharmacopsychiatry. 31(suppl 1) 30-5. 

Laakmann G, Schule C, Baghai T, Kieser M. (1998). St. John s wort in mild to moderate depression the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 31(suppl 1) 54-59. 

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. 

Of particular concern is that this inconsistency in product and active constituent occurs even within the same batch. As part of a clinical study with St. John s wort. Hall et al. analyzed 10 capsules of St. John s wort from the same lot (lot 13207) and found the mean total weight to be 444 mg (4.6% CV) versus 300 mg as stated on the label. In addition, the dosage form was supposed to be standardized to contain 900 pg of hypericin, but the mean content was found to be 840 pg (6.6% CV). There was also variability of the hyperforin content (mean 11 mg and 5.7 /o CV), which was not stated on the label (21). Our experience (Lam YWF, unpublished data) with two random capsules from one batch of kava-kava also showed the same extent of undesirable variance the total content of the pharmacologically active kavalactone was 47.3 mg in one capsule and 39.4 mg in the second one. 

Figure 3 Variability in hyperforin content among commercially available SJW products. Data taken from published studies assessing hyperfortin content of SJW tablets or capsules. Abbreviation SJW, St. John s wort. Source From Refs. 22-26.

---