Inhibition of warfarin hydroxylation by major tanshinones of Danshen (Salvia miltiorrhiza) in the rat in vitro and in vivo

Danshen (Salvia miltiorrhiza) is commonly used in the treatment of cardiovascular and cerebrovascular diseases. In this study, the effects of a Danshen ethyl acetate extract containing the major tanshinones, an aqueous extract containing salvianolic acid B and danshensu, and individual tanshinones (tanshinone I, tanshinone IIA and cryptotanshinone) on warfarin hydroxylation was investigated. In rat liver microsomes study, the ethyl acetate extract of Danshen, tanshinone I, tanshinone IIA and cryptotanshinone decreased the formation of 4'-, 6- and 7-hydroxy-warfarin, mediated by CYP1A1, CYP2C6 and CYP2C11 activities, respectively. The aqueous extract of Danshen had no effect on warfarin hydroxylation. Both acute and 3-day Danshen treatment significantly decreased Cmax and prolonged Tmax of warfarin in the rats. The formation of 4'- and 7-hydroxywarfarin in vivo was decreased significantly after 3-day danshen treatment. In steady state study in vivo, the steady state plasma warfarin concentration was increased by 23% when Danshen was co-administered. The results suggest that tanshinones inhibited CYP1A1, CYP2C6 and CYP2C11-mediated warfarin metabolism both in vitro and in vivo in the rats. The timing of Danshen intake relative to warfarin contributed to different pharmacokinetics of the free warfarin concentration. (C) 2009 Elsevier GmbH. All rights reserved.