•  https://doi.org/10.1111/bph.14936
• First published: 19 November 2019

P. D. Karkos, ^{1 ,*} S. C. Leong, ¹ C. D. Karkos, ² N. Sivaji, ¹ and D. A. Assimakopoulos ³

Abstract

The first clinically relevant reports of preparations of St. John’s wort (SJW), a herbal medicine with anti-depressant effects, interacting with other drugs, altering their bioavailability and efficacy, were published about 20 years ago. In 2000, a pharmacokinetic interaction between SJW and cyclosporine caused acute rejection in two heart transplant patients. Since then, subsequent research has shown that SJW altered the pharmacokinetics of drugs such as digoxin, tacrolimus, indinavir, warfarin, alprazolam, simvastatin, or oral contraceptives. These interactions were caused by pregnane-X-receptor (PXR) activation. Preparations of SJW are potent activators of PXR and hence inducers of cytochrome P450 enzymes (most importantly CYP3A4) and P-glycoprotein. The degree of CYP3A4 induction correlates significantly with the hyperforin content in the preparation. Twenty years after the first occurrence of clinically relevant pharmacokinetic drug interactions with SJW, this review revisits the current knowledge of the mechanisms of action and on how pharmacokinetic drug interactions with SJW could be avoided.

1 INTRODUCTION

Preparations of St. John’s wort (SJW; Hypericum perforatum L.; Clusiaceae) enjoy a long history of use in traditional or folk medicine for treating a diverse range of disorders that includes bacterial and viral infections, respiratory impairment, skin wound, peptic ulcers, and inflammation (Nathan, 2001; Robbers & Tyler, 1999; Schwarz & Cupp, 2000). However, the most common reason for using herbal preparations of SJW is to alter mood for relieve of symptoms associated with mild to moderate depressive episodes or major depression respectively (International Classification of Diseases of the WHO, Version 10 F32 F33, DSM-V). Several clinical trials have demonstrated mood enhancement with an efficacy that is at least comparable to widely prescribed synthetic antidepressants, such as fluoxetine (Behnke, Jensen, Graubaum, & Gruenwald, 2002; Schrader, 2000), paroxetine (Szegedi, Kohnen, Dienel, & Kieser, 2005), sertraline (Brenner, Azbel, Madhusoodanan, & Pawlowska, 2000; Gastpar & Zeller, 2005), or imipramine (Philipp, Kohnen, & Hiller, 1999; Woelk, 2000) and superior to placebo (Gastpar, Singer, & Zeller, 2006; Kasper, Anghelescu, Szegedi, Dienel, & Kieser, 2006; Lecrubier, Clerc, Didi, & Kieser, 2002; Schrader, Meier, & Brattström, 1998; Uebelhack, Gruenwald, Graubaum, & Busch, 2004).

SJW extracts contain numerous constituents belonging to at least 10 biologically active chemical classes (Nahrstedt & Butterweck, 2010). Major compounds are naphthodianthrones (such as hypericin), phloroglucinol derivatives (such as hyperforin), and flavonoids (such as quercetin, hyperoside, rutoside, miquelianin, and quercitrin; Figure 1). Numerous SJW preparations are commercially available, and manufacturers employ various methods to produce and maintain uniformity for their products. However, the extraction process determines the composition of the final product. Hydroalcoholic extracts may contain up to 6% hyperforin (Pharm Eur, 01/2017:1874) which is not chemically stable and can degrade rapidly. In the past, the amount of hyperforin was neglected during the extraction process because of its instability, generating hydroalcoholic extracts that usually contained just 0.5–2% hyperforin. However, at the end of the 1990s, some manufacturers modified the extraction method to obtain extracts with hyperforin amounts of 4–5%, because, at that time, hyperforin was thought to be one of the main active compounds in SJW extracts. When the recommended daily dose of SJW is 900 mg (3 × 300 mg) is taken, this amount of the extract is equivalent to a daily dose of approximately 40 mg of hyperforin. Interestingly, along with the modified extraction method producing extracts with a high hyperforin content, first reports of clinically relevant drug interactions occurred. As extracts of natural product, in general, are of complex composition, it is likely that the analytical profile of SJW preparations will vary with the extraction method used. Hyperforin, hypericin, and flavonoids have been demonstrated to be present in very different concentrations in various commercial products. For example, a German study that analysed 33 different SJW products showed that the hyperforin content varied from <0.5 mg per unit (<0.2% of extract) to 13 mg per unit (approx. 4.3% of extract) while hypericin varied between 0.1% and 0.3% (Wurglics et al., 2001a; Wurglics et al., 2001b). Similar results were reported by Länger (2010), who compared the hyperforin and hypericin content of several commercial SJW extracts that were used in relevant clinical studies. The hyperforin content in these extracts varied from 0% to 6%; hypericin varied between 0.1% and 0.3%. In a recent study, Schäfer, Potterat, Seibert, Fertig, & Meyer zu Schwabedissen (2019) tested several commercial SJW extracts currently marketed in Switzerland and observed a clear association between the hyperforin content and the influence on their transactivating activity. Importantly, no such correlation was observed for hypericin content and pregnane X receptor (PXR)-mediated transactivation.

Reference:

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14936