A number of botanically-derived beverages have been shown to inhibit several intestinal CYPs and transporters in vitro, but many of the interactions have not translated to the clinic. These in vitro-in vivo discordances may be due to a lack of sufficient and/or quality data to determine a true positive interaction ( ). Although this review is focused on beverage-drug interactions and associated mechanisms, the proceeding concepts and recommendations for how to advance research strategies and standards in this field can be applied, in general, to any botanically-derived product-drug interactions.

5.1. Methods to improve research practices

Clinical dietary substance-drug interaction studies can be confounded easily by the documented variability of specific constituents (known and unknown) in individual foods. Some in vitro-in vivo discrepancies can be addressed simply by improved documentation of the botanical source material’s origin(s); others may require more rigorous experimental investigation (e.g., discerning additive, synergistic, or inhibitory effects of constituents). Many clinical studies in the literature are incomplete, flawed, or superficial. Strict peer review of relevant manuscripts is essential to promoting best practices. A checklist of recommended questions to consider when evaluating submitted research articles or already published literature is listed in . Robust, systematic methods for evaluating potential dietary substance-drug interactions are critical, as one of the ultimate goals is to establish a framework for the quantitative prediction of food-drug interactions.

Table 3 For a commercially available product, were the following provided – brand name, manufacturer, lot number, ingredients on label, preparation and storage directions, manufacturing process, origin(s) of growth and production? Were any relevant/suspected bioactive constituent(s) measured by a validated analytical method? Was the sample size justified by a power calculation? If assay sensitivity was not an issue, were the sampling times appropriate (i.e., full PK profile captured)? For single or multiple dosing of the drug or dietary substance, was the given dose a typically consumed/recommended/prescribed dose (i.e., reflective of ‘real world’ situations)? Were dietary restrictions imposed on the subjects during the study period? Was a diet history taken prior to and/or during the study period? Was pharmacogenetics considered as a source of variability? Open in a separate window

5.1.2. Appropriate design of in vitro and in vivo food-drug interaction studies The regulation (or lack thereof) of dietary substances in the United States is different from drugs. Although dietary substances are regulated as food (Abdel-Rahman et al., 2011), bioactive compounds in these substances can act like drugs (i.e., cure, mitigate, treat, or prevent disease). Since it is unlikely that legislation will change to require more intense drug-dietary substance interaction studies, individuals in the field can take a cue from the pharmaceutical industry and adopt some or all recommendations made in the FDA’s guidance on drug-drug interaction studies (http://www.fda.gov/cder/guidance) to create a more consistent evaluation approach. Methods and decision trees in the guidance on botanical drug products (Chen et al., 2008) pale in comparison. As stated previously, the experimental design aimed to quantify activity of a dietary substance should be determined by the drug(s)/probe substrate(s) and relevant phytochemical constituent(s) of interest. Data generated from well-designed in vitro studies (e.g., K m , V max , K i , IC 50 determinations), combined with clinical PK information, may serve as a screening mechanism to rule out the need for additional in vivo studies, or provide a mechanistic basis for proper design of clinical studies using a modeling and simulation approach (see Section 5.1.4).