Herb-Drug Interactions: Schisandra

Schisandra chinensis K.Koch (Schisandraceae)

Synonym(s) and related species

Gomishi (Japanese), Magnolia vine, Wu-Wei-Zi (Chinese).

Kadsura chinensis Turcz.

Schisandra sphenanthera Rehder & EH Wilson is often used with, or substituted for, Schisandra chinensis. Other species of Schisandra are also used medicinally in China.

Constituents

The major active components of the fruits of Schisandra chinensis are dibenzocyclooctene lignans. The identity and nomenclature are confusing, because, when originally isolated by different researchers, the same compounds were given different names. The main groups of compounds are the schisandrins (schizandrins) and the gomisins (some of which were originally called wuweizu esters) and their derivatives. Schisandrin is also referred to in the literature as schisandrol A, gomisin A as schisandrol B, deoxyschisandrin as schisandrin A or wuweizu A, and schisantherin B as gomisin B or wuweizu B, for example. An essential oil contains borneol, 1,8-cineole, citral, sesquicarene and other monoterpenes. Extracts of Schisandra sphenanthera are reported to have a fairly similar chemical composition.

Use and indications

Schisandra is a very important herb in Chinese medicine. It is used as a tonic and restorative and considered to have liver-protecting, cardiotonic, hypotensive, immunomodulating, expectorant, hypnotic and sedative effects. It is used in the treatment of asthma, hyperproliferative and inflammatory skin diseases, night sweats, urinary disorders, chronic diarrhoea, insomnia and many other conditions.

Pharmacokinetics

The effects of extracts of schisandra on cytochrome P450 isoenzymes are reasonably well studied. The gomisins B, C, G and N, and gamma-schisandrin have all demonstrated inhibition of CYP3A4 in vitro. Gomisin C was the most potent and competitive inhibitor and was even stronger than that of ketoconazole. It has also been suggested that gomisin C irreversibly inactivates CYP3A4. In contrast, schisandrol B (gomisin A), schisandrin A and schisandrin B (gomisin B) induced CYP3A4 in another in vitro study. The conflicting effects found with gomisin B are unclear, but it has been suggested that, due to confusion over the naming and identification of these compounds, studies may have been carried out with constituents with the same names but different structures. Furthermore, the clinical effects of these extracts on CYP3A4 are unclear, as in vitro inhibition has not been replicated in rats, see nifedipine8.

Schisandra may also induce the cytochrome P450 isoenzyme CYP2C9, see warfarin8.

In vitro studies using schisandrins A and B, schisandrols A and B (gomisin A) and schisantherin A (gomisin C), suggest that these constituents are inhibitors of P-glycoprotein, although schisandrols A and B (gomisin A) had only weak effects in one study.

It has also been demonstrated that schisandrins A and B, schisandrols A and B (gomisin A) and schisantherin A (gomisin C) are inhibitors of MDR1, which is a multidrug resistance-associated protein.

A study in rats given schisandrin, an aqueous extract of Schisandra chinensis, or Sheng-Mai-San (a traditional Chinese medicine containing Radix ginseng, Radix ophiopogonis and Fructus schisandrae) found that schisandrin was detectable in the plasma after each preparation, but after the aqueous extract or Sheng-Mai-San was given, the half-life and AUC of schisandrin were greater than when schisandrin alone was given. It is therefore possible that components of these products could alter the metabolism of schisandrin. This may be important when extrapolating the effects of multi-constituent herbal preparations to the use of schisandra.

Interactions overview

Schisandra may modestly induce the metabolism of warfarin and greatly increase the absorption of tacrolimus, but it appears to have little effect on the metabolism of nifedipine.

Schisandra + Food

No interactions found.

Schisandra + Herbal medicines

No interactions found.

Schisandra + Nifedipine

The interaction between schisandra and nifedipine is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a single-dose study, rats were given nifedipine 2mg/kg 30 minutes after a 50-mg/kg dose of Shoseiryuto. The effects of Shoseiryuto were also studied in vitro in rats. Although the in vitro study found that Shoseiryuto inhibited CYP3A4, the study in rats found that the pharmacokinetics of nifedipine were not affected by the preparation. Shoseiryuto contains schisandra fruit, ephedra herb, cinnamon bark, peony root, processed ginger, asiasarum root, pinellia tuber and glycyrrhiza.

Mechanism

Schisandra has been shown in vitro to have an inhibitory effect on the cytochrome P450 isoenzyme CYP3A4, which is involved in the metabolism of nifedipine. This animal study does not support the in vitro findings.

Importance and management

Evidence appears to be restricted to experimental studies involving rats, and the findings, which cannot be directly extrapolated to humans, suggest that the in vitro effects do not seem to be clinically relevant in vivo. Because of the nature of the evidence, it is difficult to make recommendations on the concurrent use of nifedipine and Shoseiryuto until human studies are conducted; however, a clinically relevant interaction appears unlikely.

Schisandra + Tacrolimus

Schisandra greatly increases tacrolimus levels and its adverse effects.

Clinical evidence

In a pharmacokinetic study, 12 healthy subjects were given an extract of Schisandra sphenanthera (containing 33.75 mg schizandrin) twice daily for 14 days, with a single 2-mg oral dose of tacrolimus on day 14. The extract of Schisandra sphenanthera increased the AUC and maximum plasma concentrations of tacrolimus by 164% and 227%, but did not alter its half-life. Six of the 12 subjects experienced indigestion, and burning hands and feet, one hour after both medicines were given. These symptoms resolved over 10 hours.

Experimental evidence

No relevant data found.

Mechanism

Not established. P-glycoprotein is involved in the intestinal absorption of tacrolimus. It is therefore possible that the inhibition of P-glycoprotein by schizandrin, and possibly other related compounds, may have resulted in increased absorption of tacrolimus. The authors also suggest that the metabolism of tacrolimus, which is a substrate of the cytochrome P450 isoenzyme CYP3A4, may have been inhibited by schisandra. However, studies with nifedipine, see above, suggest that this effect may not be clinically relevant.

Importance and management

An interaction between schisandra and tacrolimus seems fairly well established, although the mechanism is not fully elucidated. Concurrent use appears to result in a large rise in tacrolimus levels, accompanied by an increase in tacrolimus adverse effects. If the use of both medicines is considered desirable it would seem prudent to monitor the outcome of concurrent use closely, adjusting the tacrolimus dose as necessary. It is important to note that, although the schisandra product used in the study was standardised for schisandrin content, this constituent has not been established as the cause of the interaction. Therefore the extent of the interaction may vary between different schisandra products, and different batches of the same schisandra product. This may make this interaction difficult to standardise for, and therefore it may be prudent to avoid concurrent use where tacrolimus blood levels are critical, such as in organ transplantation.

Schisandra + Warfarin and related drugs

The interaction between schisandra and warfarin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in rats, pretreatment with schisandra aqueous extract 500 mg/kg daily by gastric lavage for 6 days reduced the AUC of a single 2-mg/kg dose of intravenous warfarin by 29%, and increased warfarin clearance by 37%. The half-life of warfarin was also reduced from 13.1 hours to 11.6 hours.

Mechanism

The authors of the study suggest that schisandra increases the metabolism of warfarin by inducing the cytochrome P450 isoenzyme CYP2C9, the most important isoenzyme involved in the metabolism of warfarin.

Importance and management

Evidence is limited to this one experimental study in rats, which suggests that schisandra extracts may modestly increase the metabolism of warfarin. If similar effects occur in humans there may be a slight decrease in the anticoagulant effects of warfarin, although note that a decrease in the AUC of 29% is fairly modest and only small effects would be expected. If schisandra extracts are given to any patient taking warfarin, it may be prudent to consider monitoring the INR within the first week of treatment, if this is not already planned. All coumarin anticoagulants are metabolised by CYP2C9 to a greater or lesser extent, and therefore they may interact similarly. It would seem prudent to use similar precautions if these drugs are given with schisandra.