Clinical Relevance of Drug Interactions Influenced by Foods, Supplements, and Smoking: A Mechanistic Review

Abstract

Drug interactions mediated by foods, supplements, and smoking are classified into pharmacokinetic interactions (PKDIs) and pharmacodynamic interactions (PDDIs). The interaction between warfarin and natto exemplifies a PDDI as vitamin K synthesized by fermenting bacteria in natto attenuates anticoagulant efficacy, with delayed onset and prolonged duration of effect. Grapefruit juice-drug interactions are well characterized and are primarily mediated by irreversible, mechanism based inhibition of intestinal CYP3A4 by certain constituents of grapefruit juice. This interaction results in several fold increases in the AUC and Cmax of CYP3A4 substrates such as felodipine. Furthermore, grapefruit juice inhibits intestinal organic anion transporting polypeptides (OATP) 1A2 mediated uptake, thereby decreasing exposure to drugs such as fexofenadine. Similarly, other fruit juices, including orange and apple juice, reduce drug absorption through inhibition of intestinal OATPs by their constituent compounds. Green tea significantly reduces exposure to its substrate drugs via competitive inhibition of intestinal OATP1A2 by its constituent epigallocatechin gallate (EGCG). St John's wort induces CYP3A4 and P glycoprotein (P-gp) via activation of the pregnane X receptor by its principal active constituent, substantially reducing plasma concentrations of drugs that are substrates of CYP3A4 and P gp. Garlic supplements exhibit antiplatelet properties and can cause PDDIs by suppressing platelet aggregation through modulation of key pathways involved in platelet activation, and they are also known to produce PKDIs with HIV 1 protease inhibitors. Cigarette smoking contributes to clinically meaningful interactions, as smokers often exhibit reduced plasma concentrations of drugs that are CYP1A2 substrates, leading to attenuated therapeutic effects and toxicity. In oncology, smokers receiving taxanes, gemcitabine, or irinotecan often demonstrate reduced hematologic toxicity, which can reflect diminished antitumor efficacy. Collectively, these examples highlight the diverse mechanisms, temporal characteristics, and clinical implications of food , supplement , and smoking mediated drug interactions.