St. John’s Wort and Herb-Drug interactions. Evaluation of studies demonstrating a dose-dependant effect of hyperforin and the implications for using low hyperforin extracts to avoid HDI’s

 

Reference: Mueller SC, et al. No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers. Eur J Clin Pharmacol. 2009 Jan;65(1);81-7

Commentary: by Linda Ryan, RH (AHG), ND (Australia)

Design: Clinical trial. Open-label one-sequence crossover, single-dose (midazolam) multiple-dose (St. John’s wort) drug-drug interaction study. On the day before starting St. John’s wort medication, baseline pharmacokinetics of midazolam were evaluated. On day 14 of the St. John’s wort medication period, a second midazolam pharmacokinetic characterization was performed.

Participants: 20 healthy male volunteers

Study Medication and Dosage: 7.5 mg Midazolam co-administered with two capsules per day of 500 mg SJW low-hyperforin powder capsules. One 500 mg capsule in the morning and one capsule in the evening for 14 days. Total hyperforin 0.06 ± 0.001 mg per capsule.

Main Outcome Measure: Evaluate extent to which low levels of hyperforin effects plasma concentrations of a medication (midazolam) metabolized by the CYP3A enzyme. Blood samples were taken through a venous catheter before administration of midazolam and at 5, 10, 15, 20, 30, and 50 min and 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 h after ingestion of midazolam.

Key Findings: Slight decrease in midazolam from baseline representing a mean 11.3% decrease, which indicated only a mild induction of CYP3A not considered clinically relevant.

Practical Implications: For many years, St. John’s wort (SJW) has been identified as an herb that interacts with an extensive list of drugs. Studies indicate that SJW potently induces the cytochrome P450 enzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp), resulting in an increase in the breakdown and excretion of a number of pharmaceutical drugs, resulting in reduced plasma concentration of the conventional drugs. (Markowitz JS, et al 2003; Zhou S, et al 2004))

More recent pharmacokinetic investigations have identified hyperforin as the constituent of SJW that is primarily responsible for the herb-drug interactions (Komoroski BJ, et al, 2004; Mueller, et al, 2006 and 2009). Two independent research teams (Moore, et al 2000 and Wentworth, et al, 2000) have further identified hyperforin as a potent activator of the pregnane X receptor (PXR) in mice. Its human counterpart is the steroid X receptor (SXR). The PXR is known to increase transcription of the gene which encodes P-gp.

Studies indicate that herb-drug interactions (HDI’s) involving hyperforin are also dose-dependant, with low levels of hyperforin having clinically insignificant HDI activity. (Mueller SC, et al, 2009). Pharmacokinetic interaction between low hyperforin SJW extracts and several drugs, including alprazolam, caffeine, tolbutamide, digoxin and low dose oral contraceptive pill have been studied with no significant differences in bioavailability after serum testing. (Bone KM, MediHerb Clinical e-Monitor No. 11, 2006).

Hyperforin is a highly unstable phytochemical and significant degradation is observed in acidic aqueous solutions as well as under exposure to light (Ang, CYW, Hu L, Heinze TM et al, 2004). This degradation in an acidic aqueous solution continues for several months, resulting in a preparation that contains no hyperforin at all (Bone KM, MediHerb Clinical e-Monitor No. 11, 2006).

Traditional (galenical) preparations of St. John’s wort include hydroethanolic extractions. Therefore, a gently-aged fluid extract would be low-hyperforin and possibly hyperforin-free without subjecting the raw plant material to harsh processing measures.

Questions have arisen evaluating whether the antidepressant activity of SJW is entirely attributed to its hyperforin content, as once believed, and studies are suggesting that it is more likely that other phytochemical constituents are responsible (Madabushi R, 2006).

Well designed studies and proper analysis will help reach convincing conclusions in our future understanding of HDI’s involving St. John’s wort and promote medical confidence in using specific St. John’s wort preparations that are safe and appropriate for individual applications, such as antidepressant indications, in cases involving co-administration of SJW and pharmaceutical medications.

About Linda Ryan, RH (AHG), ND (Aus)
After more than 20 years experience as a traditional herbalist, Linda Ryan, RH (AHG), ND (Australia), moved to Australia in 1989 to pursue formal studies in Herbal Medicine and Naturopathy. There she received her Bachelor’s of Health Science in Complementary Medicine from Charles Stuart University. She has been in private practice for 12 years in both Australia and America. She is a Clinical Support Consultant with MediHerb Pty. Ltd. and also tutors practitioners studying herbal medicine in America for the Australian College of Phytotherapy.

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