An integrative systems approach to predict herb-drug interactions quantitatively

Consumers often supplement their drug regimens with alternative therapies, including herbal products. Despite this widespread practice, reliable information to determine the risk or safety of herb-drug interactions is lacking. Assessing herb-drug interaction risk is challenging due to the complex composition of herbal products and relative dearth of knowledge of individual constituents that perpetrate these interactions. An integrated in vitro-in silico-in vivo approach involving human-derived in vitro systems, static and dynamic modeling, and proof-of-concept clinical studies provides a mechanistic framework to address these challenges.;Herbal products consist of multiple constituents that can alter drug disposition by multiple mechanisms. Inhibition of intestinal UDP-glucuronosyl transferases (UGTs) represents one potential mechanism that has not been investigated systematically. High-throughput screening of a small library of herbal product constituents identified multiple inhibitors of intestinal UGT1As. Silibinin, a semi-purified milk thistle extract, was selected as an exemplar herbal product to extend upon these results using the clinically relevant intestinal UGT1A victim drug, raloxifene. Incorporation of inhibition kinetics into a mechanistic static model suggested moderate clinical interaction risk. Physiologically-based pharmacokinetic (PBPK) models were developed to predict the clinical pharmacokinetic consequences of the silibinin-raloxifene interaction and inform design of a proof-of-concept clinical study. Clinical evaluation involving healthy volunteers substantiated model predictions and suggested low interaction risk of silibinin administered with raloxifene.;The objective of this dissertation was to evaluate the application of a quantitative framework to assess the risk of an herb-drug interaction mediated via a mechanism not previously investigated in humans. This objective was accomplished by recovering in vitro kinetic and binding parameters associated with the silibinin-raloxifene interaction, expanding a PBPK silibinin-drug interaction model by incorporating the recovered parameters, and conducting a proof-of-concept clinical study to evaluate model predictions. Although outlined in the specific context of the silibinin-raloxifene interaction, the principles underlying these approaches can be applied to the study of a multitude of herb-drug interactions. Ultimately, these integrative approaches can be used to establish paradigms for the prospective evaluation of herb-drug interaction potential that will provide information to promote safe, evidence-based use of herbal products in combination with conventional medications.