Lability of Traditional Chinese Medicine by Intestinal Bacterial Metabolism Results in P450 Cycle-mediated Drug-Drug Interaction

Increasing attention is being paid on how to assess the potential risk for TCM -prescription drug interactions. As many TCMs are capable of biotransformation by intestinal bacteria in the gastrointestinal tract, attention to biotransformation of TCM in the gastrointestinal tract may lead to discovery of novel active components and active mechanisms. In the present study, we proposed that the biotransformation of TCM in human gastrointestinal tract should be integrated into the early evaluation of drug metabolic properties. Ginsenosides were selected as model chemicals since ginseng products are orally administered. There is still no consensus about the in vivo influence of ginseng on cytochrome P450 isoforms (P450s). The majority of naturally occurring ginsenosides (NOGs) is not capable of reaching liver because the absorption of NOGs from the intestines is very poor. However, the intestinal bacteria metabolites, Rh1 and F1, and Compound K (C-K), protopanaxadiol (Ppd), and protopanaxatriol (Ppt) from NOGs may reach the systemic circulation going through liver after oral administration of ginseng extract. We found that in the in vitro experiments, the NOGs exhibited no inhibition or weak inhibition against human P450s activities. Their degradative products in human gastrointestinal tract demonstrate a wide range of direct inhibition of P450-mediated metabolism. The inhibition is reversible and not mechanism-based one. Integrating the in vivo results of their plasma concentrations, we proposed that NOGs might result in ginsenoside-drug interactions via their intestinal bacteria metabolites (C-K, Ppd and Ppt) by influencing CYPs activities. The indirect drug interactions via biotransformation of intestinal bacteria might be a new pathway that needs to be paid additional attention to.