INTERNATIONAL CONGRESS OF
PharmacoGenetics
A Systems Pharmacology Approach to Food-Drug Interactions: Integrating Metabolism, Transport, and Genetics for Clinical Application
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Maryam Radmanfard,1,* Asal Naghipour_Kordlar,2
1. Department of Basic Sciences, Ta.C., Islamic Azad University, Tabriz, Iran
2. Faculty of Nursing, Tabriz University of Medical Sciences, Tabriz, Iran
- Introduction: Food-drug interactions (FDIs) are a critical area of pharmacotherapy with significant implications for drug safety and efficacy. Traditionally, the focus has been primarily on the inhibition of cytochrome P450 (CYP) enzymes by polyphenolic compounds. However, this view is no longer sufficient to describe the full complexity of the phenomenon. This review, adopting a systems pharmacology approach, provides a modern, integrated framework that encompasses not only Phase I and II metabolic pathways but also the vital role of drug transporters and the deterministic influence of pharmacogenetics {Bosch, 2025 #57}. 1.1. Defining the Scope: Beyond Polyphenols To properly understand FDIs, it is essential to expand the scope of investigation from "polyphenols" to the more accurate and inclusive term "bioactive dietary compounds". This is not merely a semantic correction but a scientific necessity. For example, the furanocoumarins in grapefruit, responsible for some of the most well-known and potent drug interactions, are not polyphenols or flavonoids. They are secondary metabolites biosynthesized from a coumarin precursor (umbelliferone) through prenylation and furan ring formation reactions. Limiting the scope to polyphenols leads to the exclusion of this important class and scientific misclassification. Therefore, this article examines a broad spectrum of bioactive compounds, regardless of their chemical classification, that have the potential to alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs {Zanni, 2025 #59}.
- Methods: Methodological Transparency: A PRISMA-Inspired Approach The claim of a "systematic review" requires adherence to rigorous reporting standards. Although this article is not a quantitative meta-analysis, it is inspired by the principles of the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines to ensure transparency and accuracy. The literature search strategy involved major databases such as PubMed and Google Scholar using keywords like "food-drug interaction," "CYP3A4," "P-glycoprotein," "pharmacogenetics," and names of specific compounds and drugs. The study selection process focused on identifying key articles, including definitive clinical trials, mechanistic in vitro studies, and PBPK modeling papers. This structured approach ensures that the evidence presented is representative of the current state of knowledge. Furthermore, as emphasized in guidelines for writing high-quality reviews, key findings throughout this article are presented with essential study details (e.g., design, dose, population) to provide the necessary context for proper interpretation. This level of detail enhances the credibility of the analysis and allows the reader to assess the strength of the evidence {Kyriacou, 2025 #48}.
- Results: The literature reveals that food-drug interactions are governed by a complex interplay of metabolic and transport pathways, with outcomes heavily influenced by an individual's genetic makeup. The following sections synthesize the key findings from preclinical and clinical research. 2.1. Mechanistic Findings from the Literature A modern understanding of FDIs requires moving beyond an outdated, CYP-centric model to consider an integrated system that includes Phase I metabolism, membrane transport, and Phase II metabolism {Sahoo, 2025 #55}. 2.1.1. Cytochrome P450-Mediated Interactions CYP enzymes, particularly CYP3A4, remain central players in many FDIs. Grapefruit furanocoumarins act as "mechanism-based inhibitors" or "suicide inhibitors" of CYP3A4. They are metabolized by the enzyme into a reactive intermediate that covalently binds to and irreversibly inactivates it. This explains why the inhibitory effect can last up to 72 hours and why simple temporal separation of juice and drug administration is ineffective. Crucially, evidence indicates that at typical consumption levels, the primary site of this interaction is the intestine, not the liver. This selective inhibition of enterocyte CYP3A4 dramatically reduces presystemic (first-pass) metabolism of oral drugs, leading to significant increases in oral bioavailability (AUC) and peak plasma concentration (Cmax). However, the effect is dose-dependent; high, repeated consumption of grapefruit juice can lead to systemic concentrations sufficient to inhibit hepatic CYP3A4 as well, which is confirmed by an increased elimination half-life of probe drugs {Spanakis, 2025 #56}. 2.1.2. Transporter-Mediated Interactions Many interactions previously attributed solely to CYP inhibition are mediated by membrane drug transporters {Bosch, 2025 #57}. • Efflux Transporters (P-gp and BCRP): P-glycoprotein (P-gp/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) are key efflux transporters that limit drug absorption by pumping substrates back into the intestinal lumen. Inhibition of these transporters by dietary compounds can be clinically significant. A prominent example is the interaction between curcumin and sulfasalazine. Curcumin, a potent BCRP inhibitor, increases the systemic exposure of sulfasalazine (a BCRP substrate) by 3.2-fold. This was mechanistically confirmed in animal models where the interaction was absent in BCRP-knockout mice. Other dietary compounds like berberine and ellagic acid are also identified BCRP inhibitors. • Uptake Transporters (OATPs): In contrast, uptake transporters like Organic Anion-Transporting Polypeptides (OATPs) facilitate drug absorption. Inhibition of these transporters leads to a decrease in drug bioavailability. The classic example is the interaction between fruit juices (apple, orange, grapefruit) and fexofenadine. These juices contain compounds that inhibit OATP transporters (notably OATP1A2 and OATP2B1), thereby reducing fexofenadine absorption and systemic exposure. This interaction is transient and can be avoided by separating juice and drug administration by at least 4 hours. 2.1.3. The Role of Phase II Metabolism Ignoring Phase II metabolism (conjugation) is a major flaw in many FDI analyses. For many polyphenolic compounds, conjugation via UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) is the dominant metabolic pathway. The green tea catechin epigallocatechin gallate (EGCG) is an informative example. Despite potent in vitro inhibitory activity, its clinical effects are often minimal due to very low systemic bioavailability. However, after oral intake, EGCG reaches high concentrations in the intestinal lumen, where it can effectively inhibit intestinal UGT enzymes (notably UGT1A1) and efflux transporters before it is itself extensively metabolized. This highlights that the site of interaction (e.g., the gut lumen) is a critical variable {Kyriacou, 2025 #48}. 2.2. The Impact of Pharmacogenetics Genetic variation in drug-metabolizing enzymes and transporters is a key factor in interindividual variability and susceptibility to FDIs. • CYP2C19: This enzyme metabolizes drugs like the antiplatelet prodrug clopidogrel and proton pump inhibitors (PPIs). Reduced-function alleles are common, particularly in Asian populations. For individuals with a Poor Metabolizer (PM) status, the reduced ability to activate clopidogrel leads to an increased risk of major adverse cardiovascular events. • CYP3A5: This polymorphic enzyme is critical for metabolizing the immunosuppressant tacrolimus. Individuals who are "expressers" (carrying at least one functional allele) metabolize tacrolimus rapidly and require 1.5 to 2 times higher doses to achieve therapeutic concentrations compared to "non-expressers". • CYP2C9: This enzyme is vital for metabolizing narrow therapeutic index drugs like warfarin. Reduced-function polymorphisms can significantly increase the risk of bleeding. This genetic baseline leads to the phenomenon of phenoconversion, where extrinsic factors like dietary compounds override an individual's genotype-predicted phenotype. For example, a patient with a Normal Metabolizer (NM) genotype for CYP2D6 becomes a phenotypic PM in the presence of a potent inhibitor like quinidine. This prevents the activation of the prodrug codeine to morphine, resulting in a complete loss of its analgesic effect {Bosch, 2025 #57}. 2.3. Quantitative Risk Assessment and Predictive Modeling To translate pharmacokinetic (PK) changes into meaningful risk assessments, quantitative thresholds are necessary. Regulatory agencies like the U.S. FDA classify interaction severity based on the change in drug exposure (AUC) : • Strong Inhibition: An increase in substrate AUC of ≥ 5-fold. • Moderate Inhibition: An increase in substrate AUC of ≥ 2- to < 5-fold. • Weak Inhibition: An increase in substrate AUC of ≥ 1.25- to < 2-fold. The clinical significance of these changes depends heavily on the drug's therapeutic index. Physiologically based pharmacokinetic (PBPK) modeling is a powerful tool for predicting FDIs by integrating drug-specific parameters (e.g., solubility, permeability) and interaction parameters (e.g., Ki, kinact) with physiological data (e.g., blood flow, enzyme abundance) to simulate a drug's fate in the body. A validated PBPK model can predict the magnitude of an interaction and help dissect the relative contributions of intestinal versus hepatic inhibition {Methaneethorn, 2025 #60}. 3. Discussion: Clinical Application and Risk Mitigation Strategies The ultimate goal of studying FDIs is to translate mechanistic knowledge into practical guidance for clinicians to maximize patient safety. This section converts the synthesized results into specific, actionable decision-making tools. 3.1. High-Risk Interaction Watchlist The primary focus should be on drugs with a narrow therapeutic index (NTI) whose disposition is highly dependent on a single, inhibitable metabolic or transport pathway. Key examples include {Chaachouay, 2025 #54}: • Warfarin (CYP2C9 substrate): Interactions with inhibitors like grapefruit juice can increase the INR and risk of severe bleeding. • Tacrolimus (CYP3A4/5 substrate): Grapefruit juice can cause toxic drug levels, leading to nephrotoxicity. Complete avoidance is necessary. • Simvastatin (CYP3A4 substrate): Grapefruit juice can cause a >10-fold increase in AUC, elevating the risk of myopathy and rhabdomyolysis. Complete avoidance is recommended. • Phenytoin (CYP2C9 substrate): Inhibition of CYP2C9 can lead to toxic levels and neurological symptoms. • Sulfasalazine (BCRP substrate): High-dose curcumin supplements can increase systemic exposure.
- Conclusion: This review has presented a paradigm shift in understanding food-drug interactions, moving from a simplistic, CYP-centric model to a comprehensive systems pharmacology framework. The key takeaways are the integrated ADME model, the importance of presystemic interactions, the personalization required through genetics, and the power of quantitative and predictive modeling. Despite significant progress, knowledge gaps remain. Future research should focus on: • Targeted Clinical Studies: There is an urgent need for more clinical trials specifically investigating transporter- and Phase II enzyme-mediated FDIs. • PBPK Model Development: Building and validating PBPK models for a broader range of bioactive dietary compounds will improve risk prediction. • Supplement Standardization: The high variability in active ingredient content in dietary supplements makes predicting their effects difficult. Stricter standardization and more accurate labeling are essential for safer assessment. Ultimately, the safe and effective management of food-drug interactions requires a multidisciplinary approach where pharmacists, physicians, dietitians, and scientists collaborate to translate mechanistic knowledge into personalized, evidence-based care for patients {Wang, 2025 #58}.
- Keywords: Food-Drug Interactions; Cytochrome P450; Drug Transporters; Pharmacogenetics; Systems Pharmacology.
