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 nifedipine. Silymarin did not induce cytochromes P450 2C9 and 3A4 at concentrations of 0.1; 1; and 100 microM, 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 100 microM silymarin. At 1 microM 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 Ki of silymarin was determined for cytochromes P450 3A4 with 12 microM, 2C19 with 2 microM, and 2D6 with 12 microM. Only at the high concentration of 100 microM 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. 0.2 microM measured as silibinin, it is evident that there is no drug-drug interaction problem with silymarin.
Doehmer
Johannes
J
GenPharmTox Biotech AG, Fraunhofer Str. 9, D-82152 Planegg/Martinsried, Germany. johannes.doehmer@genpharmtox.de
Tewes
Bernhard
B
Klein
Kai-Uwe
KU
Gritzko
Kristin
K
Muschick
Holger
H
Mengs
Ulrich
U
D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003627:Data Interpretation, Statistical; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009543:Nifedipine / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D012838:Silymarin / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D020011:Protective Agents; D012838:Silymarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine