The best-fit equation was assessed from visual inspection of observed vs predicted data, randomness of residuals, Akaike information criteria, and standard errors of parameter estimates. Statistical Analysis Data are presented while means standard deviations of triplicate determinations unless indicated otherwise. (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC50) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and <10 M, respectively, using HIM as the enzyme source and was 2.8, 4.3, and <10 M, respectively, using recombinant CYP3A4 as the enzyme source. These inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice conversation DS21360717 observed in the clinical study. (Ericaceae), maslinic acid, corosolic acid, ursolic acid, cytochrome P450 3A Introduction Dangerous interactions between medications arise frequently from one drug impairing the removal of another, most commonly via inhibition of one or more cytochrome P450 (CYP) enzymes. Consequently, regulatory companies recommend thorough characterization of CYP inhibition properties of new chemical entities, at least during preclinical development [1]. In contrast, CYP inhibition potential of most herbal remedies/dietary supplements is not evaluated prior to marketing, since such products are not regulated in the same manner as drugs, even though they consist of mixtures of diverse chemical entities [2]. Grapefruit juice (systems [2, 4]. A clinical study including a furanocoumarin-free grapefruit juice and the model DS21360717 CYP3A substrate, felodipine, established furanocoumarins, in aggregate, as key mediators of the felodipine-grapefruit juice conversation [5]. These observations may be extended to other drugs that undergo considerable first-pass metabolism by enteric CYP3A, including some calcium channel antagonists (e.g., felodipine, verapamil), HMG CoA reductase inhibitors (e.g., simvastatin, lovastatin), and immunosuppressants (e.g., cyclosporine, tacrolimus). Protocols, regulations, or even general strategies to investigate interactions between drugs and dietary substances are in nascent stages of development [2]. Recognition of this knowledge space prompted our research group to investigate potential drug-diet interactions prospectively. Inhibition of enteric CYP3A-mediated metabolism has been a main focus, as dietary substances enter the body by the oral route and are most likely to alter drug absorption/elimination processes in the intestine [2]. Moreover, dietary substances used as herbal remedies were selected, since patients often mix folkloric and prescription medications, often unbeknownst to their physicians and/or pharmacists [6, 7]. Finally, we have approached drug-diet interactions from your vantage points of both natural products and drug metabolism sciences, melding bioactivity-directed fractionation with CYP phenotyping methods. This merger of disciplines should allow identification of causative ingredients, as well as underlying mechanisms, that contribute to clinically relevant drug-dietary material interactions in a time-efficient manner. To test the aforementioned strategy, a natural products/drug metabolism approach was used to investigate five different cranberry juices as inhibitors of intestinal CYP3A activity [8]. Cranberry juice is used generally, and often prophylactically, for urinary tract infections (UTIs), particularly by women and the aged. This folkloric treatment of UTIs has been ascribed to proanthocyanidins with A-type linkages [9], which have been shown to inhibit adhesion of bacterial fimbriae to uroepithelial cells (examined in Goat polyclonal to IgG (H+L)(HRPO) [10]). In addition, some data have emerged regarding benefits of cranberry products to mitigate some cancers and vascular and dental diseases [11-13], likely stimulating cranberry product consumption. Yet, only a few drug-cranberry juice conversation studies have been reported, of which results were inconclusive. For example, in rats, cranberry juice was as effective as grapefruit juice in enhancing systemic exposure of the DS21360717 CYP3A substrate nifedipine [14]. Alternatively, a clinical study including a different CYP3A substrate (cyclosporine) and cranberry juice indicated no conversation [15]. Similarly, a separate clinical study reported that cranberry juice experienced no effect on the pharmacokinetics DS21360717 of the CYP3A probe substrate midazolam [16]. Although caveats to these studies were discussed previously [8], until a year ago, the literature suggested that cranberry juice has a drug conversation liability for rats, but not humans, thus having no clinical issues. While these inconsistencies may demonstrate a lack of a drug-cranberry juice conversation, an alternative explanation, as explained and exhibited [8], is usually that inherent variability in chemical constituents in study materials could lead to disparate results. Similarly, inconsistency in study materials has been cited as a reason why studies of clinical benefits of cranberry have been inconclusive [17]. Indeed, as reported by our research group [8], a commercial product was recognized that showed a significant conversation.