Herb-Drug Interactions: Chinese angelica

Angelica sinensis (Oliv.) Diels (Apiaceae)

Synonym(s) and related species

Dang Gui (Chinese), Danggui, Dong quai.

Angelica polymorpha van sinensis.

Other species used in oriental medicine include Angelica dahurica.

Not to be confused with Angelica, which is Angelica archangelica L.

Pharmacopoeias

Angelica Sinensis Root for use in THM (British Ph 2009); Processed Angelica Sinensis Root for use in THMP (British Pharmacopoeia 2009).

Constituents

The major constituents include natural coumarins (angelicin, archangelicin, bergapten, osthole, psoralen and xanthotoxin) and volatile oils. Other constituents include caffeic and chlorogenic acids, and ferulic acid. Angelica sinensis also contains a series of phthalides (n-butylidenephthalide, ligustilide, n-butylphthalide).

Use and indications

One of the most common uses of Chinese angelica root is for the treatment of menopausal symptoms and menstrual disorders. It has also been used for rheumatism, ulcers, anaemia, constipation, psoriasis, the management of hypertension and to relieve allergic conditions.

Pharmacokinetics

Evidence is limited to experimental studies, which suggest that the effects of Angelica dahurica and Angelica sinensis may not be equivalent. Most of the evidence relates to Angelica dahurica, which may inhibit the cytochrome P450 isoenzymes CYP2C9 (see tolbutamide), CYP2C19 (see diazepam) and CYP3A4 (see nifedipine). If all these effects are found to be clinically relevant then Chinese angelica (where Angelica dahurica is used) has the potential to raise the levels of a wide range of conventional drugs.

Interactions overview

Angelica dahurica may raise the levels of diazepam and tolbutamide, thereby increasing their effects. More limited evidence suggests that nifedipine may be similarly affected. Case reports suggest that Chinese angelica may increase the bleeding time in response to warfarin, and may possess oestrogenic effects, which could be of benefit, but which may also, theoretically, oppose the effects of oestrogen antagonists, such as tamoxifen.

Chinese angelica + Diazepam

The interaction between Angelica dahurica and diazepam is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in rats, Angelica dahurica had little effect on the pharmacokinetics of intravenous diazepam 10 mg/kg. However, when diazepam 5 mg/kg was given orally, the AUC of diazepam was markedly increased from levels below detection to detectable levels, and the maximum plasma level was increased fourfold. In a mobility study, Angelica dahurica potentiated the muscle relaxant effects of intravenous diazepam.

Mechanism

In rats, diazepam is principally metabolised in the liver by cytochrome P450 isoenzymes including CYP2C19. It is thought that this isoenzyme is inhibited by Angelica dahurica. It was also suggested by the authors that there was a considerable effect of Angelica dahurica on the first-pass metabolism of diazepam.

Importance and management

Although the data are from animal studies, because of the potential for increased levels and effects of diazepam, until more is known it may be prudent to advise caution when giving Angelica dahurica with oral diazepam. Warn patients that they may experience increased sedation.

Note that it may not be appropriate to extrapolate from Angelica dahurica to other species such as Angelica sinensis, since, in one study, Angelica sinensis had much less effect on CYP3A4 than Angelica dahurica, see under nifedipine, below.

Chinese angelica + Food

No interactions found.

Chinese angelica + Herbal medicines

No interactions found.

Chinese angelica + Nifedipine

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

Clinical evidence

No interactions found.

Experimental evidence

In a study, rats were given an extract of Angelica dahurica, and then rat liver microsomes were prepared and incubated with nifedipine. Angelica dahurica was found to inhibit the activity of nifedipine oxidase 1 to 6 hours after administration, by about 30 to 40%.

Mechanism

Nifedipine oxidation is mediated by the cytochrome P450 isoenzyme CYP3A4. This activity of Angelica dahurica was shown to be related to furanocoumarin constituents. Other in vitro studies suggest that an alcoholic extract of Angelica dahurica more potently inhibited CYP3A4 than an aqueous decoction, whereas extracts of Angelica sinensis had no significant effect on CYP3A4.

Importance and management

Evidence is limited to experimental studies, but what is known suggests that any CYP3A4 inhibitory effects of Chinese angelica depend on the species and the type of extract used. The results are difficult to reliably extrapolate to the use of Chinese angelica with nifedipine in humans, but it is possible that alcoholic extracts of Angelica dahurica may decrease nifedipine metabolism, and therefore increase its levels and effects. Be aware of this possibility if both substances are given.

Chinese angelica + Oestrogens or Oestrogen antagonists

Chinese angelica may contain oestrogenic compounds. This may result in additive effects with oestrogens or it may oppose the effects of oestrogens. Similarly, Chinese angelica may have additive effects with oestrogen antagonists or oppose the effects of oestrogen antagonists (e.g. tamoxifen).

Clinical evidence

A letter in the Medical Journal of Australia draws attention to the fact that some women with breast cancer receiving chemotherapy or hormone antagonists who develop menopausal symptoms have found relief from hot flushes by taking a Chinese herb ‘dong quai’ (or ‘danggui’ root), which has been identified as Angelica sinensis. A possible explanation is that this and some other herbs (agnus castus, hops flower, ginseng root and black cohosh) have significant oestrogen-binding activity and physiological oestrogenic actions.

The oestrogenic potential of Chinese angelica is, however, somewhat unclear. A phytoestrogenic preparation containing soy extract 75 mg, black cohosh 25 mg and Angelica polymorpha (a species related to Chinese angelica) 50 mg taken twice daily reduced the average frequency of menstrually-associated migraine attacks in a 15-week period by 54% in a randomised, placebo-controlled study in 42 women. The preparation used in this study was standardised to content of isoflavones from soy, ligustilide from Angelica polymorpha and triterpenes from black cohosh. In contrast, in another randomised, placebo-controlled study, Angelica sinensis root 4.5 g daily did not produce significant oestrogen-like responses in endometrial thickness or vaginal maturation and did not relieve menopausal symptoms in 71 postmenopausal women. The Angelica sinensis preparation in this study was standardised to content of ferulic acid.

Experimental evidence

In various in vitro and animal studies, Chinese angelica extract has been shown to inhibit the binding of estradiol to the oestrogen receptor and increase uterine growth (oestrogenic effects). However, it also decreased uterine c-myc mRNA levels (which is induced by oestrogens).

Mechanism

If Chinese angelica has oestrogenic actions, which are not established, then it might directly stimulate breast cancer growth and oppose the actions of competitive oestrogen receptor antagonists such as tamoxifen. See also Isoflavones + Tamoxifen.

Importance and management

One clinical study and the anecdotal cases mentioned in the letter suggest that Chinese angelica, either alone, or with other phytoestrogens, may possess oestrogenic properties. In contrast, in a well-controlled study, Chinese angelica alone did not produce oestrogen-like responses. The concern is that, if Chinese angelica does have oestrogenic effects, it might stimulate breast cancer growth and antagonise the effects of hormone antagonists used to treat cancer. Until more is known, it may be prudent to avoid using herbs with purported oestrogenic effects in women with oestrogen-sensitive cancers. This is more strictly a disease-herb interaction. See also Isoflavones + Tamoxifen.

Chinese angelica + Tolbutamide

The interaction between Angelica dahurica and tolbutamide is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study, rats were given an extract of Angelica dahurica, and then rat liver microsomes were prepared and incubated with tolbutamide. Angelica dahurica was found to inhibit the activity of tolbutamide hydroxylase 1 to 6 hours after administration, by up to about 60%. In further experiments in rats, the AUC of intravenous tolbutamide 10 mg/kg was increased 2.5-fold by Angelica dahurica 1 g/kg.

Mechanism

Angelica dahurica inhibits the activity of the cytochrome P450 CYP2C subfamily of isoenzymes, which are involved in the metabolism of tolbutamide.

Importance and management

Although there is a lack of clinical evidence, because of the potential for increased levels of tolbutamide, it may be prudent to exercise some caution when using medicines containing Angelica dahurica in patients taking tolbutamide. Patients may wish to consider increasing the frequency of blood-glucose monitoring. It may not be appropriate to extrapolate from Angelica dahurica to other species such as Angelica sinensis, because in one study Angelica sinensis did not possess the same enzyme inhibitory properties as Angelica dahurica, see nifedipine.

Chinese angelica + Warfarin and related drugs

Two case reports describe a very marked increase in the anticoagulant effects of warfarin when Chinese angelica was given.

Clinical evidence

A 46-year-old African-American woman with atrial fibrillation taking warfarin had a greater than twofold increase in her prothrombin time and INR after taking Chinese angelica for 4 weeks. The prothrombin time and INR had returned to normal 4 weeks after stopping Chinese angelica. In another case, a woman who had been taking warfarin for 10 years developed widespread bruising and an INR of 10, a month after starting to take Chinese angelica.

A further report describes spontaneous subarachnoid haemorrhage in a 53-year-old woman not taking anticoagulants, which was attributed to a herbal supplement containing Chinese angelica root 100 mg and a number of other herbs. See Red clover + Anticoagulants.

Experimental evidence

In a study in rabbits, Chinese angelica aqueous extract 2 g/kg twice daily for 3 days significantly decreased the prothrombin time in response to a single 2-mg/kg dose of warfarin without altering the plasma warfarin concentrations. However, when the study was repeated with warfarin at steady state, prothrombin times tended to be increased after the addition of Chinese angelica, although, as with the single-dose study, warfarin plasma levels were not significantly altered. In an in vitro study, Chinese angelica extract alone slightly increased prothrombin time.

Mechanism

The reasons for this interaction are not fully understood but Chinese angelica is known to contain natural coumarin derivatives, which may possibly have anticoagulant properties: these could be additive with those of warfarin. However, note that many coumarins do not have anticoagulant effects, see coumarins. The data suggest that alteration of warfarin levels is not involved, but other studies suggest that the herb may inhibit the cytochrome P450 isoenzyme CYP2C9, which is the main route of warfarin metabolism. See tolbutamide, above.

Importance and management

Clinical evidence for an interaction between Chinese angelica and warfarin appears to be limited to the case reports cited, and an interaction is not fully established. Nevertheless, it would seem prudent to warn patients taking warfarin, and possibly other coumarin anticoagulants, of the potential risks of also taking Chinese angelica. For safety, the use of Chinese angelica should be avoided unless the effects on anticoagulation can be monitored. More study is needed.