Induction of liver cytochrome P450s by Danshen-Gegen formula is the leading cause for its pharmacokinetic interactions with warfarin

Abstract

Ethnopharmacological relevance: Although the increased usage of herbal medicine leading to herb-drug interactions is well reported, the mechanism of such interactions between herbal medicines with conventionally prescribed drugs such as warfarin is not yet fully understood. Our previous rat in vivo study demonstrated that co-administration of Danshen-Gegen Formula (DGF), a Radix Salvia miltiorrhiza (Danshen) and Radix Puerariae lobatae (Gegen) containing Chinese medicine formula recently developed for the treatment of cardiovascular disease, with warfarin could cause significant herb-drug interactions. The current study aims to explore the pharmacokinetics-based mechanism of the DGF-warfarin interactions during absorption, distribution and metabolism processes.

Materials and methods: Caco-2 cell monolayer model and rat in situ intestinal perfusion model were used to study the DGF-warfarin interactions during the intestinal absorption processes. Male Sprague-Dawley rats were orally administered warfarin in presence and absence of DGF for consecutive 5 days. The microsomal activity and expression of the liver CYP isozymes were determined and compared among different treatment groups. Blood from the rats administered DGF was employed to evaluate effects of DGF on the plasma protein binding of warfarin.

Results: Absorption studies demonstrated that DGF could potentially increase the intestinal absorption of warfarin (32% and 75% increase of warfarin Papp in Caco-2 and intestinal perfusion models, respectively) via altering the regional pH environment in GI tract. DGF administration could lead to significant increase in liver microsomal activity and mRNA expression of CYP1A1 and CYP2B1, indicating the potential induction on the liver metabolism of warfarin by DGF. Moreover, it has been proven by ex vivo study that the single-dose administration of DGF could decrease the protein binding of warfarin in plasma by at least 11.6%.

Conclusion: Collectively, current study demonstrated that DGF could significantly induce the liver phase I metabolism of warfarin, and to a less extent, potentially increase the intestinal absorption and decrease the plasma protein binding of warfarin. The inductive effects of DGF on the liver phase I metabolism of warfarin may be dominantly responsible for the DGF-warfarin pharmacokinetics interactions.

Keywords: Danshen–Gegen formula; Liver cytochrome P450s induction; Radix Puerariae lobatae; Radix Salvia miltiorrhiza; Warfarin.