ASSESSING MECHANISMS OF GOLDENSEAL-DRUG INTERACTIONS USING A TRANSLATIONAL RESEARCH APPROACH: AN ITERATIVE PROCESS INTEGRATING IN VITRO KINETICS, PBPK MODELING, AND CLINICAL EVALUATIONS

James T. Nguyen

doi:10.7273/000006577

The use of botanical and other natural products to self-treat chronic medical complications remains ever-increasing, largely due to the general misconception that these products are natural, therefore safe and effective. One such natural product is goldenseal (Hydrastis canadensis L.), a botanical native to the northeastern United States and Canada. Goldenseal was traditionally used by American Indians as a dye for clothing, but nowadays is commonly consumed for its purported anti-hyperlipidemic, anti-microbial, and anti-hyperglycemic properties. Analogous to many other marketed natural products, definitive evidence to substantiate the safe and effective use of goldenseal remains lacking. Regarding safety, goldenseal has been shown to precipitate pharmacokinetic interactions with prescription drugs in human participants. Specifically, goldenseal inhibits the prominent drug metabolizing enzyme cytochrome P450 (CYP) 3A, which has been estimated to catalyze the metabolic elimination of >50% of marketed drugs. However, the granular mechanisms underlying this pharmacokinetic interaction, as well as whether goldenseal can precipitate interactions mediated by common drug transporters, remain to be evaluated. The primary objective of this dissertation was to elucidate mechanisms underlying clinically relevant, pharmacokinetic goldenseal-drug interactions. Chapter 1 provides an overview of the pharmacology, toxicology, and pharmacokinetics of goldenseal and the scientific knowledge gaps regarding the potential for goldenseal to precipitate drug interactions. This introduction highlights a proposed integrative, iterative approach to rigorously assess natural product-drug interactions. In Chapter 2, coadministration of goldenseal was demonstrated to reduce the systemic plasma exposure of metformin by 25% in human participants. The mechanism behind this interaction was presumably inhibition of intestinal absorption processes, including inhibition of apically located uptake transporters, due to the lack of change in metformin terminal half-life and renal clearance. This mechanism was investigated using cell lines overexpressing select transporters, corroborating the clinical findings that goldenseal could inhibit transporters involved in the intestinal absorption of metformin. In Chapter 3, inhibition of CYP3A by goldenseal was re-visited to delve further into the mechanisms involved in the clinical pharmacokinetic interaction with midazolam. Mechanistic evaluations concluded that the second most abundant goldenseal alkaloid, (–)-β-hydrastine, was responsible for the time-dependent inhibition of intestinal CYP3A, suggesting a prolonged inhibitory effect in humans that is akin to the well-established effects of grapefruit juice on intestinal CYP3A. Chapter 4 evaluates the goldenseal-metformin interaction in patients with type 2 diabetes taking therapeutic doses of metformin, whose intestinal absorption partly relies on uptake transporters. Results demonstrated that the systemic exposure to metformin decreased with increasing metformin dose. These observations indicated that a saturable active transport process is responsible for both the nonlinear intestinal absorption of metformin and the nonlinear pharmacokinetic goldenseal-metformin interaction. The culmination of this research is an advanced understanding of the risk for goldenseal to precipitate pharmacokinetic drug interactions. The scientific knowledge gained from this comprehensive work will help guide patients and healthcare providers to better assess situations where supplementation with goldenseal may negatively impact pharmacotherapy. The framework established in this dissertation expands upon the standard, linear in vitro to in vivo extrapolation approach typically used to assess natural product-drug interactions. This work has broad implications regarding how natural products could be studied using an integrated, iterative approach to further understand and delineate granular mechanisms underlying a clinical pharmacokinetic natural product-drug interaction.

ASSESSING MECHANISMS OF GOLDENSEAL-DRUG INTERACTIONS USING A TRANSLATIONAL RESEARCH APPROACH: AN ITERATIVE PROCESS INTEGRATING IN VITRO KINETICS, PBPK MODELING, AND CLINICAL EVALUATIONS

Files and links (1)

Abstract

Metrics

Details