A common misconception concerning milk thistle (Silybum marianum) is that, since it is a liver herb, it is likely to increase the metabolism and clearance of many drugs due to enhanced hepatic detoxification. This is certainly fueled by in vitro studies showing this effect (1) and an in vivo study in rats where high doses increased phase I hepatic metabolism. Oral administration of silymarin (100 mg/kg/day) to rats resulted in a significant increase in the activity of the mixed-function oxidation system (cytochrome P450; aminopyrine demethylation, p-nitroanisole demethylation). However, an experimentally-induced reduction in activities of the mixed-function oxidation system and glucose-6-phosphatase could not be prevented by pretreatment with silymarin.
In human volunteers, treatment with silymarin (210 mg/day for 28 days) had no influence on the metabolism of aminopyrine or phenylbutazone. (2) Concentrated milk thistle (silymarin) extract at commonly administered doses did not interfere with indinavir therapy in patients with HIV. (3) In other words, despite the findings of in vitro and in vivo studies, there was no evidence from clinical studies that milk thistle extract increases phase I/II liver metabolism. The reason behind this discrepancy is probably that normal clinical doses are not high enough to achieve the effects shown at the artificially high doses used in experimental models.
But a study has recently been published which, on the face of it, appears to challenge this position. (4) A clinical study was undertaken in 12 healthy volunteers. At first, subjects received metronidazole (Flagyl; a substrate for cytochrome CYP3A4 and CYP2C9) alone at a dose of 400 mg every 8 h for 3 days. On day 4, blood and urine were collected at different time points and metronidazole levels were measured. After a washout period of one week silymarin was given at a daily dose of 140 mg for 9 days. From day 7 both silymarin (140 mg/day) and metronidazole (3 X 400 mg/day) were given till the 9th day. On day 10, blood and urine were collected as above and the levels of metronidazole and its metabolite were measured. Administration of silymarin increased the clearance of metronidazole and its major metabolite, hydroxy-metronidazole (HM) by 29.51% and 31.90% respectively, with a concomitant decrease in half-life and maximum concentration. Urinary excretions of acid-metronidazole, HM and metronidazole were all decreased.
Commentary
The key to understanding this recent study is the decreased levels of metronidazole and its metabolites in serum and urine. This suggests reduced absorption into the bloodstream via the induction of the drug transporting P-glycoprotein (P-gp), particularly at the level of the intestine. P-gp is a molecule that acts as a drug efflux pump at epithelial cells, especially the intestinal wall. In other words, induction of P-gp results in less absorption of any drug which is subject to its effects. So the most likely explanation of the findings is a reduced uptake due to P-gp induction, rather than increased clearance resulting from the induction of hepatic phase I cytochrome P450 enzymes such as CYP 3A4. Nonetheless, it is possible that silymarin could reduce the oral bioavailability of other drugs susceptible to P-gp, which include paclitaxel and digoxin.
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References
1. Mills S, Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. Churchill Livingstone, Edinburgh, 2000, pp 556-557.
2. Leber HW, Knauff S. Arzneim-Forsch 1976; 26(8): 1603-1605
3. Piscitelli SC, Formentini E, Burstein AH et al. Pharmacotherapy 2002; 22(5): 551-556
4. Rajnarayana K, Reddy MS, Vidyasagar J et al. Arzneim-Forsch 2004; 54(2): 109-113
