Assessment of drug-drug interaction for silymarin
Dr Oesterheld’s Comment: Silymarin (aka silibinin, silybin) is an extract of milk thistle, an antioxidant herbal that is being tested in a variety of conditions, diabetes, cancer and liver injury and others was originally shown to have in vitro inhibiton against CYP3A4. Two studies, one vitro and one in vivo studies have shown that its effects on CYP3A4 in vivo are not significant when compared to its effects in vitro.
Toxicol In Vitro. 2007 Dec 8 [Epub ahead of print]Assessment of drug-drug interaction for silymarin.
Doehmer J, Tewes B, Klein KU, Gritzko K, Muschick H, Mengs U.GenPharmTox Biotech AG, Fraunhofer Str. 9, D-82152 Planegg/ Martinsried, Germany.
Silymarin was assessed for drug-drug interaction by permeability studies with Caco-2 cells, for cytochrome P450 induction with human primary hepatocytes and for cytochrome P450 inhibition with human liver microsomes. Studies with Caco-2 cells revealed no interference of silymarin with the permeability of nifedipine. Silymarin did not induce cytochromes P450 2C9 and 3A4 at concentrations of 0.1; 1; and 100muM, measured as silibinin. The inhibitory effect was tested on the nine major cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations of 1 and 100muM silymarin. At 1muM concentration no or negligible inhibition of cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, and 2E1, minor inhibition of 3A4 (<20%), and moderate inhibition of 2C19 and 2D6 (<40%) were observed. Inhibition constant K(i) of silymarin was determined for cytochromes P450 3A4 with 12muM, 2C19 with 2muM, and 2D6 with 12muM. Only at the high concentration of100muM silymarin, inhibition at >50% of the cytochromes P450 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 was observed, and no or moderate inhibition was for the cytochromes P450 1A2, 2A6, and 2E1. However, in view of the clinically relevant plasma concentration of approx. 0.2muM measured as silibinin, it is evident that there is no drug-drug interaction problem with silymarin. PMID: 18249085
Planta Med. 2007 Nov;73(14):1429-35. Epub 2007 Oct 30.
The effect of silymarin on oral nifedipine pharmacokinetics. Fuhr U, Beckmann-Knopp S, Jetter A, Lück H, Mengs U. Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany. firstname.lastname@example.org
Silibinin, the main component of silymarin (a milk thistle extract used for treatment of liver injury), has been shown to inhibit CYP3A4 in human liver microsomes. The present study was conducted to examine whether inhibition of CYP3A4 by silymarin is also present IN VIVO. Immediate release nifedipine (10 mg) was administered as a CYP3A4 test drug either alone or with co- administration of silymarin (280 mg administered 10 hours and 1.5 hours prior to the administration of nifedipine) to 16 healthy male volunteers (mean age 27 years, mean body weight 77 kg). Nifedipine and silibinin concentrations were quantified by HPLC, heart rate and blood pressure were monitored for safety reasons. Pharmacokinetic parameters were calculated by non-compartmental methods, and the potential interaction by silymarin was handled as an equivalence problem. We found that nifedipine AUC was 1.13-fold higher (90 % CI, 0.97- to 1.32-fold) in the silymarin period, C (max) values were 0.70- fold (90 % CI, 0.39- to 1.27-fold) of those of the reference period, with a trend to delayed absorption in the silymarin period. Intraindividual variability especially for C (max) (intrasubject CV 120 %) was unexpectedly high. There was no meaningful effect on hemodynamic parameters. In conclusion, our data suggest that co- administration of silymarin does not considerably change the extent of absorption or metabolism of nifedipine but may decrease the absorption rate. Silymarin thus is not a potent CYP3A4 inhibitor IN VIVO. PMID: 17968815