| Myriad diet-derived substances, including foods, nutritional supplements, and exotic beverages are increasingly sought for their purported health benefits. These natural, seemingly safe, products can perpetrate pharmacokinetic/pharmacodynamic (PK/PD) interactions with conventional medications, placing the consumer at risk for potential adverse effects. Despite the ubiquitous nature of these products, there is a gap in the understanding of their drug interaction liability. This knowledge gap is due in part to the complex and variable chemical composition, prompting the need to characterize key constituents that contribute to perturbations in 'victim' drug PK/PD. Development of a framework to estimate the effect of the mixture using a single, or few, key constituents is principal to risk assessment.;Grapefruit juice (GFJ) is a well-studied beverage shown to inhibit pre-systemic (first-pass) drug metabolism in the gut, increasing systemic drug exposure and potential undesirable effects. GFJ acts by irreversible inhibition of cytochrome P450 3A (CYP3A) activity in the intestinal wall by a class of constituents termed furanocoumarins. 6'7'-Dihydroxybergamottin (DHB) is a well-studied and typically abundant furanocoumarin in GFJ, with inhibitory concentrations (1-5 muM) well below or within concentrations measured in GFJ (<60 muM or <5 mg / 240 mL serving ). The relative abundance and potent activity of DHB in GFJ makes it a promising candidate to serve as a marker constituent representative of the CYP3A-mediated effect of GFJ.;Anecdotal reports touting GFJ as a PK 'booster' raise concern that it may be used to increase systemic exposure to certain drugs. Loperamide is an over-the-counter opioid agonist that acts locally in the gut to slow motility. Incomplete absorption, extensive CYP3A-mediated first-pass metabolism, and active efflux by P-glycoprotein (P-gp) at the blood brain barrier prevent central nervous system opiate-like effects. The candidate marker constituent DHB and the exemplar victim drug loperamide were used to test the central hypothesis that an integrative approach involving in vitro assays, static and dynamic modeling, and proof-of-concept clinical testing can provide robust risk assessment of potential dietary substance-drug interactions. Results from this dissertation project demonstrated that the effects of GFJ on loperamide PK and PD could be predicted using PBPK/PD modeling and simulation. Furthermore, this work provides a refined framework to assess dietary substance-drug interaction risk in a time- and cost- efficient manner. |
