Herb-Drug Interactions: Danshen

Salvia miltiorrhiza Bunge (Lamiaceae)

Synonym(s) and related species

Chinese salvia, Dan-Shen, Red root sage, Tan-Shen.

Constituents

Danshen products may be standardised according to the content of: tanshinones (diterpene quinones), tanshinone IIA and tanshinone IIB; the polyphenolic acid, salvianolic acid B; and the related compound danshensu (3,4-dihydroxy-phenyllactic acid). Other constituents include fatty-acid (oleoyl) derivatives, lithospermic acid B, and salvinal (a benzofuran) and nitrogen-containing compounds such as salvianen.

Use and indications

The dried root of danshen is traditionally used in Chinese medicine for cardiovascular and cerebrovascular diseases, specifically angina pectoris, hyperlipidaemia and acute ischaemic stroke, but also palpitations, hypertension, thrombosis and menstrual problems. It is also used as an anti-inflammatory and for the treatment of cancer and liver disease.

Pharmacokinetics

Limited in vitro and animal studies suggest that danshen extracts affect the activities of various cytochrome P450 isoenzymes. However, these effects do not appear to be clinically relevant. In a study in mice, a commercial pharmaceutical extract of danshen induced the activity of the cytochrome P450 isoenzyme CYP1A2 (assessed by 7-methoxyresorufin O-demethylation) by about 60%. An aqueous extract had no effect, whereas an ethyl acetate extract, which is not used in pharmaceutical preparations, had a very marked four- to eightfold increase in CYP1A2 activity. A purified extract of tanshinone IIA had a similar effect in this study, and in one of two mice models in another study. Conversely, in another study using mice and human liver microsomes, tanshinone IIA (extracted in ethyl acetate) inhibited CYP1A2. Any potent effects of danshen extracts on CYP1A2 therefore appear to be limited to ethyl extracts of danshen, which are not used clinically. The more modest effects found with the commercial pharmaceutical extract may not be clinically relevant, as clinical studies with theophylline, a substrate of CYP1A2 did not find a clinically relevant interaction.

The extracts of danshen that are used pharmaceutically do not appear to have clinically relevant effects on CYP2C9 (see tolbutamide) or CYP3A4 (see calcium-channel blockers).

Some extracts of danshen may inhibit P-glycoprotein, see under digoxin.

Interactions overview

Some case reports and animal data indicate that danshen can, rarely, increase the effects of warfarin, resulting in bleeding. The antiplatelet activity of danshen may be partly responsible, and therefore additive antiplatelet effects might occur if danshen is taken with conventional antiplatelet drugs, which may also increase the risk of bleeding. Danshen can falsify the results of serum immunoassay methods for digoxin, and experimental evidence suggests that danshen could raise digoxin levels. Additive blood-pressure-lowering effects could, in theory, occur if danshen is taken with nifedipine, but no clinically relevant pharmacokinetic interaction appears to occur. Clinical evidence suggests that danshen does not affect the pharmacokinetics of theophylline, and experimental evidence suggests that danshen does not affect the pharmacokinetics of alcohol, or tolbutamide.

Danshen + Alcohol

The interaction between danshen and alcohol is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

An oral danshen extract 200mg/kg inhibited the oral absorption of alcohol in rats. Blood-alcohol levels were reduced by up to 60% in comparison to control rats. Danshen had no effect on blood-alcohol levels when ethanol was injected intraperitoneally. The danshen used in this study was standardised to contain 13% tanshinone IIA.

Mechanism

Unknown.

Importance and management

Evidence for an interaction between alcohol and danshen appears to be limited to one study in rats. Even if these results are replicated in humans, any effect is probably not clinically relevant, and danshen is certainly not proven for use as an aid to reducing alcohol absorption or lowering blood-alcohol levels.

Danshen + Calcium-channel blockers

The interaction between danshen and calcium-channel blockers is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in mice, a commercial pharmaceutical extract and an aqueous extract of danshen had no effect on nifedipme oxidation. In contrast an ethyl acetate extract of danshen (which is not used as a pharmaceutical preparation) caused a threefold increase in nifedipme oxidation. Another study found that purified tanshinone IIA, present in ethyl acetate extracts, caused a decrease in nifedipme oxidation in mice, whereas a third study reported no change in nifedipme oxidation by tanshinone IIA in human liver microsomes.

Studies in the rat femoral artery have shown that danshen extracts cause vasorelaxant effects.

Mechanism

Contradictory findings have been reported on the effect of ethyl acetate danshen extracts on nifedipme oxidation, which is mediated by the cytochrome P450 isoenzyme CYP3A4. This could be increased, decreased or unchanged.

Importance and management

Evidence for an interaction between nifedipine and danshen appears to be limited to experimental studies, which suggest that the type of danshen extract used is important in determining whether or not an interaction may occur. In general an interaction with pharmaceutical extracts seems unlikely. Ethyl acetate extracts may decrease nifedipine metabolism, but as these are not used pharmaceuticalfy, this is of little clinical relevance. A pharmacodynamic interaction may occur, because both nifedipine and danshen have calcium-channel-blocking effects. Until more is known, some caution might be warranted if patients take nifedipine (and possibly any calcium-channel blocker) with danshen, as additive blood pressure-lowering effects could, in theory, occur.

Danshen + Digoxin

The interaction between danshen and digoxin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

Two in vitro studies. have assessed the effects of tanshinone IIA and tanshinone IIB (major constituents of danshen) on the uptake of digoxin by P-glycoprotein. Both extracts exhibited concentration-dependent inhibitor effects on P-glycoprotein. Tanshinone IIA had the greatest effects of the two extracts, inhibiting the P-glycoprotein-mediated transport of digoxin in a similar manner to verapamil, a known clinically relevant P-glycoprotein inhibitor. The effects of tanshinone IIB were modest in comparison.

Mechanism

Tanshinone IIA appears to be a clinically relevant inhibitor of P-glycoprotein, of which digoxin is a substrate.

Importance and management

The available data appear to be from experimental studies in which specific constituents of danshen were used. This makes it difficult to extrapolate the data to the use of the herb in a clinical setting. What is known suggests that danshen may inhibit the transport of digoxin by P-glycoprotein, which could lead to raised digoxin levels. Therefore if danshen is taken by a patient receiving digoxin it may be prudent to be alert for symptoms of raised digoxin levels, such as bradycardia, and consider monitoring levels, should this occur. However, note that danshen may interfere with some of the tests used to assess digoxin levels, see also laboratory tests.

Danshen + Food

No interactions found.

Danshen + Herbal medicines

No interactions found.

Danshen + Laboratory tests

Danshen can falsify the results of serum immunoassay methods for digoxin.

Evidence, mechanism, importance and management

Danshen can falsify some laboratory measurements of digoxin because it contains digoxin-like immunoreactive components. A study found that a fluorescent polarisation immunoassay method (Abbott Laboratories) for digoxin gave falsely high readings in the presence of danshen, whereas a microparticle enzyme immunoassay (Abbott Laboratories) gave falsely low readings. These, or similar findings, have been reported elsewhere. These false readings could be eliminated by monitoring the free (i.e. unbound) digoxin concentrations or by choosing assay systems that are unaffected by the presence of danshen (said to be the Roche and Beckman systems or an enzyme-linked chemiluminescent immunosorbent digoxin assay by Bayer HealthCare.). Similarly, when assaying serum from patients taking digoxin, to which a variety of danshen extracts were added, the use of a fluorescent polarisation immunoassay gave variable results, whereas the results were more consistent with a chemiluminescent assay, the EMIT 2000 digoxin assay and the Randox digoxin assay. It would therefore seem prudent, wherever possible, to use a chemiluminescent assay for digoxin in patients also taking danshen.

Danshen + Salicylates

The interaction between danshen and salicylates is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

(a) Protein binding

In vitro experiments show that danshen can increase free salicylate concentration by displacing salicylate from binding to albumin proteins. In contrast, unexpectedly, salicylate significantly decreased free danshen concentrations at full anti-inflammatory concentrations of salicylate (150 micrograms/mL and above). However, no significant change in free danshen concentrations was observed when salicylate concentrations were less than this (up to 100 micrograms/ mL).

(b) Pharmacodynamic

An active component of danshen (765-3) has been shown to inhibit human platelet aggregation via its effects on platelet calcium.

Mechanism

In vitro many conventional drugs are capable of being displaced by others, but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important. It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised. It is difficult to find an example of a clinically important interaction (with conventional drugs) due to this mechanism alone.

Additive antiplatelet effects might occur, which might increase the risk of bleeding.

Importance and management

In vitro evidence suggests that danshen displaces salicylate from protein-binding sites at high doses, but the clinical relevance of this seems minimal. There may be a more clinically significant interaction with low-dose aspirin, as both it and danshen have antiplatelet activity. Concurrent use may therefore result in additive antiplatelet effects. Bear this possibility in mind if unexpected signs of bleeding, such as bruising, occur.

Danshen + Theophylline

Danshen does not appear to affect the pharmacokinetics of theophylline.

Clinical evidence

In a crossover study, 12 healthy subjects were given a single 100-mg dose of theophylline alone and, after taking four tablets, each containing an extract of danshen 1 g, three times daily, for 14 days. Danshen slightly decreased the time to maximum theophylline levels, but this was not expected to be clinically relevant, and no other pharmacokinetic parameters were altered.

Experimental evidence

No relevant data found.

Mechanism

Alcoholic extracts of danshen may have effects on cytochrome P450 CYP1A2, the isoenzyme by which theophylline is metabolised. See Pharmacokinetics.

Importance and management

The available evidence is limited, but seems to suggest that the dose of theophylline will not need to be altered in patients also taking danshen extract tablets.

Danshen + Tolbutamide

The information regarding the use of danshen with tolbutamide is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in mice, a commercial pharmaceutical extract of danshen had no effect on tolbutamide hydroxylation. Similarly, an aqueous extract had no effect, whereas the ethyl acetate extract (which is not used as a pharmaceutical preparation, and contained the greatest amount of tanshinone IIA) caused a twofold increase in tolbutamide hydroxylation.

However, in vitro, tanshinone IIA did not affect the oxidation of tolbutamide in mouse or human liver microsomes.

Mechanism

Tolbutamide is a substrate of the cytochrome P450 isoenzyme CYP2C9, and is also used as a probe substrate to assess the effects of other substances on this isoenzyme. The evidence suggests that the usual extracts of danshen do not affect tolbutamide metabolism, and therefore would not be expected to have clinically relevant effects on other substrates of CYP2C9.

Importance and management

Evidence appears to be limited to two experimental studies. However, they provide reasonably strong evidence to suggest that danshen will not affect the metabolism of tolbutamide. Therefore no dosage adjustments are expected to be needed if danshen is given to patients also taking tolbutamide. This study also suggests that danshen is unlikely to affect the metabolism of other drugs that are substrates of this isoenzyme.

Danshen + Warfarin and related drugs

Three case reports and some animal data indicate that danshen can increase the effects of warfarin, resulting in bleeding.

Clinical evidence

A woman taking warfarin, furosemide and digoxin, who began to take danshen on alternate days, was hospitalised a month later with anaemia and bleeding (prothrombin time greater than 60 seconds, ENR greater than 5.62). The anaemia was attributed to occult gastrointestinal bleeding and the over-anticoagulation to an interaction with the danshen. She was later restabilised on warfarin in the absence of the danshen with an INR of 2.5, and within 4 months her haemoglobin levels were normal.

A man taking warfarin, digoxin, captopril and furosemide, with an INR of about 3, developed chest pain and breathlessness about 2 weeks after starting to take danshen. He was found to have a massive pleural effusion, and an INR of more than 8.4. He was later discharged on his usual dose of warfarin with an INR stable at 3, in the absence of the danshen.

Over-anticoagulation was investigated in Chinese patients admitted to a medical unit during a 9-month period in 1994/1995. An interaction with warfarin was reported in a patient using a medicated oil product that contained methyl salicylate 15%, and an ‘analgesic balm’ that contained danshen, methyl salicylate 50% and diclofe-nac.

Experimental evidence

In a study in rats, danshen aqueous extract 5 g/kg twice daily given intraperitoneally for 3 days prolonged the prothrombin time and increased the steady-state levels of both isomers of warfarin. Similar findings were reported in another earlier study by the same group. In contrast, in a study in mice, a commercial pharmaceutical extract of danshen had no effect on warfarin 7-hydroxylation (mediated by the cytochrome P450 isoenzyme CYP2C9). Similarly, an aqueous extract had no effect, but an ethyl acetate extract (which is not used as a pharmaceutical preparation, and contained the greatest amount of tanshinone IIA) increased warfarin 7-hydroxylation threefold, which would be expected to lead to a decrease in its anticoagulant effects.

A study in animals found that high doses of Kangen-Karyu (a mixture of peony root, cnidium rhizome, safflower, cyperus rhizome, saussurea root and the root of danshen) 2 g/kg twice daily inhibited the metabolism and elimination of single doses of warfarin, and prolonged bleeding time. There was no interaction at a lower dose of 500 mg/kg, which suggests that a clinical interaction is unlikely at the recommended dose of 90 mg/kg of Kangen-Karyu daily.

Mechanism

Danshen has antiplatelet actions, which may be additive to the anticoagulant effect of warfarin. The mechanism for the increase in warfarin levels is unknown, because the studies suggest that the usual extracts of danshen do not inhibit the cytochrome P450 isoenzyme CYP2C9, the main route of warfarin metabolism. Consider also tolbutamide, and for more information on the antiplatelet effects of danshen, see salicylates.

Importance and management

Evidence appears to be limited to three case studies, which alone would be insufficient to establish an interaction. The pharmacokinetic effects of the usual extracts of danshen seem to suggest that an interaction resulting in raised warfarin levels is unlikely in most patients. However, because danshen may have antiplatelet effects, an interaction between warfarin and danshen, resulting in increased bleeding, is possible. Clinically the use of an antiplatelet drug with an anticoagulant should generally be avoided in the absence of a specific indication. It may therefore be prudent to advise against concurrent use. However, if concurrent use is felt desirable it would seem sensible to warn patients to be alert for any signs of bruising or bleeding, and report these immediately, should they occur.