Herb-Drug Interactions: Milk thistle

2011

Silybum mahanum (L.) Gaertn. (Asteraceae)

Synonym(s) and related species

Lady’s thistle, Marian thistle, Mediterranean milk thistle, St Mary’s thistle.

Carduus marianus, Mariana lactea Hill.

Pharmacopoeias

Milk Thistle (US Ph 32); Milk Thistle Capsules (US Ph 32); Milk Thistle Fruit (British Ph 2009, European Ph 2008); Milk Thistle Tablets (US Ph 32); Powdered Milk Thistle (US Ph 32); Powdered Milk Thistle Extract (US Ph 32); Refined and Standardised Milk Thistle Dry Extract (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4).

Constituents

The mature fruit (seed) of milk thistle contains silymarin, which is a mixture of the flavonolignans silibinin (silybin), silicristin (silychristin), silidianin (silydianin), isosilibinin and others. It may be standardised to contain not less than 1.5% (European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4), or not less than 2% (The United States Ph 32) of silymarin, expressed as silibinin (dried drug). Standardised extracts, containing high levels of silymarin, are often used. Milk thistle fruit also contains various other flavonoids, such as quercetin, and various sterols.

Note that milk thistle leaves do not contain silymarin, and contain the flavonoids, apigenin and luteolin, and the triterpene, beta-sitosterol.

Use and indications

Milk thistle is reported to have hepatoprotective properties and is mainly used for liver diseases and jaundice. Traditionally milk thistle was used by nursing mothers for stimulating milk production, as a bitter tonic, demulcent, as an antidepressant and for dyspeptic complaints. Both the fruit and leaves are used as a herbal medicine, but currently the fruit is the main target of investigation because it contains the pharmacologically active silymarin component. Standardised extracts of silymarin are also commonly used. A water-soluble salt of the individual flavonohgnan silibinin is used intravenously for preventing hepatotoxicity after poisoning with the death cap mushroom Amanita phalloides.

Pharmacokinetics

Several studies have investigated the effect of milk thistle extracts on cytochrome P450 isoenzymes and drug transporters. In some in vitro studies- milk thistle or its flavonohgnan constituents inhibited CYP3A4. Although some clinical pharmacokinetic studies suggest that milk thistle may raise the levels of some CYP3A4 substrates, several other studies have found no effect on CYP3A4 substrates, see midazolam, and protease inhibitors. These conflicting findings may be due, in part, to the dose of milk thistle used. Indeed, some in vitro studies found that the effect of milk thistle on CYP3A4 was sometimes minor or seen only at higher concentrations.-

Other in vitro studies have found that milk thistle or its flavonohgnan constituents were minor or moderate inhibitors of CYP2C9, CYP2C19 and CYP2C8, but the clinical relevance of this seems likely to be limited. It has been suggested that, while in vitro levels of silymarin may cause moderate inhibition of several cytochrome P450 isoenzymes, in vivo levels do not reach inhibitory concentrations and so milk thistle would not be expected to exhibit inhibition at pharmacologically effective concentrations.

Other in vivo and in vitro studies, have found that milk thistle is unlikely to affect the metabolism of drugs that are substrates of CYP1A2A9 (see caffeine), CYP2E1 (see chlorzoxazone) or CYP2D6.

In vitro studies have suggested that silymarin may affect P-glycoprotein substrate binding. However, there is no evidence from human pharmacokinetic studies that milk thistle has a clinically important effect on the levels of drugs that are P-glycoprotein substrates, see digoxin.

Silymarin has also been found to inhibit several UDP-glucuronosyltransferases in vitro. These enzymes are involved in phase II glucuronidation, a process that affects the metabolism of several drugs (such as irinotecan, paracetamol and zidovudine), and reduced activity could theoretically lead to raised drug levels, although the clinical implications of this are, as yet, unclear.

Silibinin dihemisuccinate has also been found to inhibit several of the organic anion-transporting polypeptide (OATP) family in vitro, which could theoretically lead to reduced cellular uptake, and therefore raised levels, of drugs that are OATP substrates. For information on the pharmacokinetics of individual flavonoids present in milk thistle, see under flavonoids.

Interactions overview

In vitro studies have suggested that milk thistle may interact with a number of drugs by inhibiting their metabolism by various cytochrome P450 isoenzymes or affecting their transport by P-glycoprotein. However, in vivo studies suggest that any such inhibition is unlikely to be clinically relevant. Milk thistle may raise the levels of a hepatotoxic metabolite of pyrazinamide. For information on the interactions of individual flavonoids present in milk thistle, see under flavonoids.

Milk thistle + Benzodiazepines

Milk thistle does not appear to affect the pharmacokinetics of midazolam.

Evidence, mechanism, importance and management

In a study 19 healthy subjects were given milk thistle 300 mg three times daily for 14 days (standardised to silymarin 80%) with a single 8-mg oral dose of midazolam on the last day. There was no change in the pharmacokinetics of midazolam, and milk thistle had no effect on the duration of midazolam-induced sleep. Similarly, in another study in 12 healthy subjects, milk thistle 175 mg (standardised to silymarins 80%) given twice daily for 28 days had no significant effects on the metabolism of a single 8-mg dose of midazolam.

These studies show that the pharmacokinetics of midazolam are not affected by the concurrent use of milk thistle. As midazolam is used as a probe substrate for the cytochrome P450 isoenzyme CYP3A4 this study also suggests that milk thistle is unlikely to affect the metabolism of other drugs that are substrates of this isoenzyme. This suggestion is supported by the finding that the metabolism of other known CYP3A4 substrates is not affected by milk thistle.

See also Milk thistle + Protease inhibitors.

Milk thistle + Caffeine

Milk thistle does not appear to affect the pharmacokinetics of caffeine.

Evidence, mechanism, importance and management

In a study in 12 healthy subjects, milk thistle 175 mg (standardised to silymarins 80%) given twice daily for 28 days had no significant effects on the metabolism of a single 100-mg dose of caffeine.

This study suggests that the pharmacokinetics of caffeine are not affected by the concurrent use of milk thistle. As caffeine is used as a probe substrate for the cytochrome P450 isoenzyme CYP1A2 this study also suggests that milk thistle is unlikely to affect the metabolism of other drugs that are substrates of this isoenzyme.

Milk thistle + Chlorzoxazone

Milk thistle does not appear to affect the pharmacokinetics of chlorzoxazone.

Evidence, mechanism, importance and management

In a study in 12 healthy subjects, milk thistle 175 mg (standardised to silymarins 80%) given twice daily for 28 days had no significant effects on the metabolism of a single 250-mg dose of chlorzoxazone.

This study suggests that the pharmacokinetics of chlorzoxazone are not affected by the concurrent use of milk thistle. As chlorzoxazone is used as a probe substrate for the cytochrome P450 isoenzyme CYP2E1 this study also suggests that milk thistle is unlikely to affect the metabolism of other drugs that are substrates of this isoenzyme.

Milk thistle + Digoxin

Milk thistle does not appear to affect the pharmacokinetics of digoxin.

Clinical evidence

In a study, 16 healthy subjects were given a single 400-microgram dose of digoxin before and on the last day of a 14-day course of a milk thistle extract (standardised to 80% silymarin) 300 mg three times daily. No statistically significant changes in the pharmacokinetics of digoxin were found, although there was a trend towards a minor 10% reduction in the AUC of digoxin.

Experimental evidence

See Mechanism, below.

Mechanism

In vitro, P-glycoprotein ATPase activity, which is the energy source for the active transport of drugs across cell membranes by P-glycoprotein, was inhibited by silymarin, suggesting a direct interaction with P-glycoprotein substrate binding. Digoxin is a P-glycoprotein substrate, and it had been suggested that milk thistle would therefore affect digoxin pharmacokinetics.

Importance and management

Direct evidence appears to be limited to one clinical study, which showed that milk thistle does not cause clinically relevant changes in digoxin pharmacokinetics. It would therefore appear that the dose of digoxin would not need to be adjusted in patients also given milk thistle. As digoxin is used as a probe substrate for P-glycoprotein this study also suggests that milk thistle is unlikely to affect the metabolism of other drugs that are substrates of this transporter protein.

Milk thistle + Food

No interactions found.

Milk thistle + Herbal medicines

No interactions found.

Milk thistle + Irinotecan

Milk thistle does not appear to affect the pharmacokinetics of irinotecan.

Evidence, mechanism, importance and management

A pharmacokinetic study was undertaken in 6 patients who were being treated with intravenous irinotecan 125mg/m once weekly for 4 weeks, followed by a 2-week rest period. Four days before the second dose of irinotecan, a 14-day course of 200 mg milk thistle seed extract (containing silymarin 80%) three times daily was started. The pharmacokinetics of irinotecan and its metabolites did not differ from week 1 (no milk thistle), week 2 (4 days of milk thistle) to week3 (12days of milk thistle). No dosage alterations would therefore be expected to be needed if milk thistle (standardised to silymarin 80%) is given with irinotecan.

Milk thistle + Metronidazole

Silymarin (the active constituent of milk thistle) modestly reduces metronidazole levels.

Evidence, mechanism, importance and management

Silymarin (Silybon) 140 mg daily was given to 12 healthy subjects for 9 days, with metronidazole 400 mg three times daily on days 7 to 10. Silymarin reduced the AUC of metronidazole and hydroxy-metronidazole (a major active metabolite) by 28% and the maximum serum levels by 29% and 20%, respectively.

The authors suggest that silymarin causes these pharmacokinetic changes by inducing P-glycoprotein and the cytochrome P450 isoenzyme CYP3A4, which are involved in the transport and metabolism of metronidazole. But evidence from other interactions suggests that a clinically relevant effect on P-glycoprotein and CYP3A4 is unlikely. See Milk thistle + Benzodiazepines, and Milk thistle + Protease inhibitors, below. The general importance of this interaction is unclear, but a 28% reduction in the AUC of metronidazole would not be expected to be of much clinical significance.

Milk thistle + Nifedipine

Milk thistle does not appear to alter the haemodynamic effects of nifedipine.

Clinical evidence

In a study in 16 healthy subjects, silymarin 280 mg was given 10 hours, and 90 minutes, before a 10-mg dose of nifedipine. Silymarin increased the AUC of nifedipine by about 10% and reduced its maximum serum levels by about 30%, but these effects varied greatly between subjects. Silymarin did not alter the haemodynamic effects of nifedipine. One capsule of the product used in this study (Legalon) contains 173 to 186 mg dry extract from milk thistle fruits, equivalent to silymarin 140 mg calculated as silibinin.

Experimental evidence

Two in vitro studies found that silymarin flavonolignans moderately inhibited the oxidation of nifedipine and denitronifedipine, a closely related nifedipine derivative, as marker substrates for CYP3A4 activity.

Mechanism

The maximum serum levels of nifedipine were reduced slightly but the AUC was not, suggesting a delay in nifedipine absorption. This could be due to irregular gastric emptying in the presence of silymarin, or an interaction with drug transporters such as OATP. While the experimental evidence suggests an inhibitory effect on CYP3A4, this has not been found to be clinically significant (see under benzodiazepines).

Importance and management

Evidence appears to be limited to these three studies. The clinical study found that milk thistle may modestly delay the absorption of nifedipine with an apparent high intra-individual variability. However, as there was no considerable change in the pharmacokinetics or pharmacodynamic effects of nifedipine (blood pressure and heart rate), this is probably not clinically relevant. It would appear that the modest effects found in vitro do not translate in to a clinically relevant effect.

Milk thistle + Protease inhibitors

Although some studies have found that milk thistle slightly lowers indinavir levels, it appears that this is a time-dependent effect rather than a drug interaction, since it also occurred in a control group in one study. The balance of evidence suggests that no important pharmacokinetic interaction occurs.

In vitro studies suggest that silibinin does not affect the pharmacokinetics of ritonavir.

Clinical evidence

Milk thistle 175mg three times daily (Thisilyn; Nature’s Way, standardised for 80% silymarin content) for 3 weeks caused a 9% reduction in the AUC of indinavir and a 25% reduction in its trough plasma level after four doses of indinavir 800 mg every 8 hours, but only the value for the trough level reached statistical significance.The authors suggested that the effect on the trough level could represent a time-dependent effect of indinavir pharmacokinetics, as the plasma levels without milk thistle were found to be similarly lowered after a washout phase. In another similar study, in 10 healthy subjects, milk thistle standardised for silymarin 160 mg (General Nutrition Corp.) three times daily for 13 days and then with indinavir 800 mg every 8 hours for 4 doses did not cause any statistically significant changes in the indinavir pharmacokinetics (6% reduction in AUC and 32% reduction in minimum level). In yet another similar study, in 8 healthy subjects, milk thistle capsules (standardised for silymarins 456 mg; Kare and Hope Ltd.), three times daily for 28 days, had no effect on the pharmacokinetics of indinavir 800 mg every 8 hours for four doses when compared with 6 subjects in a control group not receiving milk thistle extract. Both the control and indinavir group had a lower indinavir AUC after the second and third time of administration compared with the first, and this decline was greater in the control group. A meta-analysis of these 3 studies showed no effect of milk thistle on indinavir levels.

Experimental evidence

In a series of experiments on human cell lines and rat hepatocytes, silibinin, the major active constituent of the silymarin flavonolignan mixture found in milk thistle, was found not to affect the pharmacokinetics of ritonavir.

Mechanism

Based on animal data, milk thistle might be expected to increase indinavir levels by inhibiting its metabolism, or transport by P-glycoprotein. However, silibinin was found not to have a significant effect on P-glycoprotein or cytochrome P450 isoenzyme CYP3A4 activity when given with ritonavir. The clinical studies found only a minor reduction in indinavir levels, which was attributed to a time-dependent effect.

Importance and management

The currently available data suggest that milk thistle extract does not have an effect on the pharmacokinetics of indinavir (and possibly ritonavir), although this is not totally conclusive. The reduction in indinavir levels appears to be just a time-dependent effect rather than an effect of the milk thistle, but further study is needed with longer exposure to indinavir than just four doses. Evidence appears to be too slim to prohibit concurrent use, but until more is known it may be prudent to give milk thistle cautiously to patients taking indinavir.

Milk thistle + Pyrazinamide

The interaction between milk thistle and pyrazinamide is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in rats, pyrazinamide and its active metabolite, pyrazinoic acid, were given after either long-term or short-term exposure to silibinin, the major active constituent of the silymarin flavonolignan mixture found in milk thistle. The first group of rats received intravenous silibinin 100 mg/kg for 3 days before an intravenous dose of pyrazinamide 50mg/kg or pyrazinoic acid 30 mg/kg concurrently on the fourth day. The second group received intravenous silibinin 30 mg/kg 10 minutes before an intravenous dose of pyrazinamide 50 mg/kg or pyrazinoic acid 30 mg/kg.

Silibinin had no effect on the pharmacokinetics of pyrazinamide, but increased the AUC of pyrazinoic acid by 3.5-fold in the long-term exposure group and 4-fold in the short-term exposure group. The maximum serum levels of pyrazinoic acid were increased by about 60% and 70% respectively.

Mechanism

It is thought that silibinin may inhibit xanthine oxidase, which is involved in pyrazinamide and pyrazinoic acid hydroxylation. Silibinin may also decrease the hepatobiliary excretion of pyrazinoic acid.

Importance and management

Evidence appears to be limited to experimental data. While no pharmacokinetic changes were seen when milk thistle was given with pyrazinamide, milk thistle appears to increase the levels of the active metabolite, pyrazinoic acid. So far, this has only been shown in rats so determining the clinical relevance of this interaction is difficult. Nevertheless, because of the dose-related hepatotoxic adverse effects associated with pyrazinamide, it would be prudent to bear this possible interaction in mind in case of an unexpected response to treatment.

Milk thistle + Ranitidine

Silymarin, a major constituent of milk thistle, does not appear to affect the pharmackinetics of single-dose ranitidine.

Evidence, mechanism, importance and management

In a study in 12 healthy subjects, silymarin capsules (Sivylar) 140 mg three times daily for 7 days did not significantly affect the pharmacokinetics of a single 150-mg dose of ranitidine. No particular precautions would appear to be necessary if patients take milk thistle and ranitidine together.

Milk thistle + Rosuvastatin

Silymarin, a major constituent of milk thistle, does not appear to affect the pharmackinetics of single-dose rosuvastatin.

Clinical evidence

In a randomised study, 8 healthy subjects were given silymarin (Legalon) 140 mg three times daily for 5 days. On day 4 they were given a single 10-mg oral dose of rosuvastatin. Silymarin did not significantly affect the pharmacokinetics of rosuvastatin.

Experimental evidence

An in vitro study found that silymarin inhibited the uptake of rosuvastatin mediated by the drug transporter proteins OATP1B1 and BCRP.

Mechanism

In vitro study suggests that silymarin may inhibit drug transporter proteins, but this was not shown by any changes in the pharmacokinetics of rosuvastatin in a small clinical study.

Importance and management

No particular precautions would appear to be necessary if patients decide to take milk thistle and rosuvastatin together.