Mechanisms underlying food–drug interactions: Inhibition of intestinal metabolism and transport

Abstract

Food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant-derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients. Substantial variability in bioactive ingredient composition and activity of a given dietary substance poses a challenge in conducting robust food-drug interaction studies. This confounding factor can be addressed by identifying and characterizing specific components, which could be used as marker compounds to improve clinical trial design and quantitatively predict food effects. Interpretation and integration of data from in vitro, in vivo, and in silico studies require collaborative expertise from multiple disciplines, from botany to clinical pharmacology (i.e., plant to patient). Development of more systematic methods and guidelines is needed to address the general lack of information on examining drug-dietary substance interactions prospectively.

Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation

“…This deficiency is due in part to the complex composition of dietary substances, precluding application of established paradigms used to assess drug-drug interaction risk. A working framework to elucidate potential mechanisms underlying dietary substance-drug interactions has been proposed (https://nccam.nih.gov/sites/nccam.nih.gov/files/ HerbDrugInteractionsWorkshopSummary.pdf; Won et al, 2012;Brantley et al, 2013Brantley et al, , 2014a. This framework centers on the evaluation of isolated constituents to ascertain the relative contribution of each constituent to the mixture, as well as to identify marker constituents that can be used to predict the likelihood and magnitude of these interactions.…”

“…Potent inhibition of enteric UGTs by these constituents/extracts at clinically achievable intestinal concentrations warrants their further evaluation as potential perpetrators of clinically relevant dietary substance-drug interactions via dynamic pharmacokinetic modeling and simulation techniques (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm292362.pdf; Won et al, 2012;Brantley et al, 2014b).…”

“…Consequently, such xenobiotics must traverse the intestinal epithelial barrier before entering the hepatic venous, and eventually systemic, circulation. This barrier is composed primarily of enterocytes that, like hepatocytes, express a plethora of biotransformation enzymes that can influence significantly the extent of presystemic (first-pass) xenobiotic metabolism (Won et al, 2012). Accordingly, inhibition of intestinal enzymes can lead to an increase in hepatic and systemic exposure to the "victim" xenobiotic with the subsequent potential for unwanted effects.…”

“…Despite growing recognition of the potential for dietary substancedrug interactions, systematic approaches to identify and characterize the risk of these interactions remain elusive (Won et al, 2012;Brantley et al, 2014a). Considerations unique to evaluation of UGT inhibition, including luminal orientation of UGT proteins requiring detergents or pore-forming agents to reduce latency, limited availability of authentic glucuronide standards, and a lack of isoform-selective probe substrates and inhibitors, have further hampered efforts to correlate in vitro inhibitory potency with in vivo interaction risk.…”

Rational application of fructose-1,6-diphosphate: From the perspective of pharmacokinetics

“…Caff einated and alcoholic beverages may also aff ect the metabolism of certain drugs (12). In this study, volunteers were fasted for at least 12 hours.…”