Study of Herbal-Drug Interactions (HDIs) Using in Silico Methods – Mission (Im)Possible

Studying herb-drug interactions (HDIs) is extremely important for the clinical practice, as many patients with chronic diseases taking a number of conventional medicines, also take phytomedicines, decoyed by advertising, without realizing that these herbal products in some cases can be harmful instead of beneficial. Herbal extracts contain a very large range of substances (more than 200 sometimes) that can affect both the pharmacokinetic and the pharmacodynamic characteristics of the conventional therapy. However, can these interactions be evaluated by in vitro and in silico methods in order to be highly informative without major clinical trial costs? What are the difficulties that must be taken into account in order to overcome the trade-offs that are being made? This mini-review aims to address briefly these issues and and the difficulty of building the models and the simulations with herbal drugs. More patients suffering from chronic diseases are taking herbal medicines, claiming them to be effective agents with little or negligible undesirable effects. Many of them, however, could lead to important clinical herb-drug interactions (HDIs) [1-3]. Herbal extracts contain many biologically active substances, with specific pharmacological characteristics, which in some cases may act in different directions. The most common form of interaction is the inhibition of the activity of the cytochrome enzymes and, therefore, this mechanism will be largely considered [4]. Evaluation of possible drug interactions is most commonly evaluated in vitro, using isolated liver microsomes or recombinant forms of cytochrome enzymes [5,6]. The mechanism of the inhibition can be – reversible competitive, and irreversible, mechanism-based. The values of inhibitory concentration 50 (IC50) are calculated, which subsequently, after clarifying the mechanism of action, recalculate the inhibition constants (Ki – for reversible, KI and kinact – for irreversible inhibition). So far, the processes are not complicated to perform. According to the guidelines for studying drug interactions, basic static models are used to evaluate the potential of the new drug to cause drug-drug interactions (DDIs). However, in addition to the inhibitory constant, it is necessary to know the plasma concentration of the drug, in the case of plant extracts and fractions, because of the many substances in them, which is a problem. Alternatively, each plant extract exhibiting inhibitory potential on CYP3A4 can be tentatively calculated for the potential for herb-drug interactions with substrates of enterocytic CYP3A4 isoenzymes, using the basic static equations, where plasma concentrations are exchanged with concentrations in GIT, namely: