Abstract
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, Cmax 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 Cmax (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.
Key words:
Silybum marianum (L.) Gaertn. - Asteraceae - silymarin - silibinin - milk thistle extract - nifedipine
- CYP3A4 - drug-drug interaction
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Prof. Dr. Uwe Fuhr
Department of Pharmacology
Clinical Pharmacology
University of Cologne
Gleueler Straße 24
50931 Cologne
Germany
Telefon: +49-221-478-5230
Fax: +49-221-478-7011
eMail: uwe.fuhr@uk-koeln.de
