Assessment of drug-drug interaction for silymarin

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 nifiedipine. Silymarin did not induce cytochromes P450 2C9 and 3A4 at concentrations of 0.1; 1; and 100 mu M, measured as silibinin. The inhibitory effect was tested on the nine major cytochromes P450 1A2, 2A6, 2136, 2C8, 2C9, 2C19, 2136, 2E1, and 3A4 at concentrations of I and 100 mu M silymarin. At 1 mu M concentration no or negligible inhibition of cytochromes P450 1A2, 2A6, 2136, 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 12 mu M, 2C19 with 2 mu M, and 2136 with 12 mu M. Only at the high concentration of 100 mu M silymarin, inhibition at >50% of the cytochromes P450 2136, 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. 2 mu M measured as silibinin, it is evident that there is no drug-drug interaction problem with silymarin. (C) 2007 Published by Elsevier Ltd.