Dissertation
An Integrative Systems Approach to Predict Herb-Drug Interactions Quantitatively
Doctor of Philosophy (PhD), Washington State University
01/2015
Handle:
https://hdl.handle.net/2376/6195
Abstract
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.
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Details
- Title
- An Integrative Systems Approach to Predict Herb-Drug Interactions Quantitatively
- Creators
- Brandon Tyler Gufford
- Contributors
- Mary F Paine (Advisor)Philip Lazarus (Committee Member)Gary M Pollack (Committee Member)Jeannie M Padowski (Committee Member)John R White (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 244
- Identifiers
- 99900581639701842
- Language
- English
- Resource Type
- Dissertation