Study on herb-drug interactions
Creators: name: Yang, Liping
Publisher: name: RMIT University
Year: 2024

description: Herbal medicines, such as St John's wort, garlic, gingko, and ginseng, are commonly used complementary therapies. The human CYP enzymes are a superfamily which consists of at least 57 functional CYP genes. Among them, CYP1A2, 2C9, 2C19, 2D6 and 3A4/5 are the most important enzymes responsible for the Phase I metabolism of therapeutic drugs. When different compounds (e.g., a drug and herbal compound) are co-administered, they may compete at the same active site of CYPs, resulting in potential inhibition. We hypothesize that the atom-atom interactions between the ligands and the residues at the active site of CYPs determine the substrate and inhibitor specificity of individual CYPs. To test our hypothesis, we conducted a series of experiments including in vitro assays to determine inhibitory actions of a variety of natural compounds on human CYPs, pharmacokinetic-based predication of in vivo situation using the in vitro data; and in silico studies to explore the ligand-CYP interactions using docking and pharmacophore modeling methods.<br><br>We first determined the inhibitory effects (IC50) of 56 herbal compounds on activities of five human drug metabolising CYPs (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro using a high throughput approach. The tested herbal components included a variety of structurally distinct compounds such as triterpenoids of danshen (Salvia miltiorrhiza), flavonoids and their glycoside derivatives, saponine, other glucosides, lactones, alkaloids, and acids. A small number of them are found to significantly inhibit human CYP1A2, 2C9, 2C19, 2D6 and 3A4 with differential potency, including tanshinone I, tanshinone IIA, cryptotanshinone, baicalein, quercetin, silybin, osthole and ч-schisandrin.<br><br>Based on the in vitro data obtained, we predicted metabolic herb-drug interactions of these compounds in vivo with the application of appropriate pharmacokinetic principles. Some predicting results were consistent with published clinical reports. For example, the prediction of S. miltiorrhiza increasing the AUC value of warfarin is consistent with the results from clinical case reports. However, a marked disparity has been observed when some predictions are compared with results from clinical studies. For example, the prediction of S. mariani (containing silybin) increasing the AUC of indinavir (a CYP3A4 substrate) is not in agreement with the result of a clinical report where the plasma concentration of indinavir was not altered by co-administered silymarin in healthy volunteers.<br><br>Finally, we studied the interactions of a series of ligands including substrates and inhibitors with CYP1A2 using docking and pharmacophore modeling approaches. We have identified 6 residues at the active site of CYP1A2 which are essential for ligand recognition. Furthermore, the relative potency of potential inhibitors could be predicted through analysis of hydrophobic interactions between the ligand and the 6 essential residues at the active site of CYP1A2. Moreover, we developed a pharmacophore model on the basis of the common features of known CYP1A2 inhibitors. In combination with the docking results, the established pharmacophore model could be applied for screening novel CYP1A2 inhibitors. <br>