Prioritizing Pharmacokinetic Drug Interaction Precipitants in Natural Products: Application to OATP Inhibitors in Grapefruit Juice

Abstract

Background and objectiveHerbal and other natural products typically contain multiple constituents that can precipitate adverse pharmacokinetic interactions with conventional drugs. Streamlined approaches are needed to prioritize candidate natural product precipitants during early investigation of these complex interactions. Grapefruit juice is a well‐characterized natural product that increases systemic exposure to several drugs via inhibition of organic anion‐transporting polypeptide (OATP) uptake in the intestine. Using grapefruit juice as a model natural product, a streamlined approach was developed to prioritize OATP inhibitors as precipitants of pharmacokinetic grapefruit juice‐drug interactions.MethodsOATP2B1‐expressing MDCKII cells and the probe substrate estrone 3‐sulfate were used to assess the inhibitory effects of candidate constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6′,7‐dihydroxybergamottin), and polymethoxyflavone (nobiletin, tangeretin) classes contained in grapefruit juice. IC50s were recovered via nonlinear least‐squares regression analysis. Intestinal absorption simulations based on physiochemical properties were used to estimate the unbound intracellular enterocyte concentration (Ient) of each constituent. Two ratios were determined for each constituent: Ient/IC50 and maximum reported concentration in grapefruit juice to IC50 (IGFJ/IC50). Constituents were ranked in order of drug interaction liability according to pre‐defined cutoff values (Ient/IC50, 0.1; IGFJ/IC50, 10).ResultsNobiletin was the most potent OATP2B1 inhibitor (IC50, 3.7 μM); 6′,7‐dihydroxybergamottin, naringin, naringenin, and tangeretin were moderately potent (IC50, 22–39 μM); and hesperidin and bergamottin were the least potent (IC50 >300 μM). The Ient/IC50 for naringin, naringenin, nobiletin, and tangeretin exceeded 0.1. The IGFJ/IC50 for naringenin and naringin exceeded 10.ConclusionsBoth Ient/IC50 and IGFJ/IC50 correctly prioritized the flavanones, and excluded the furanocoumarins, as precipitants of intestinal OATP‐mediated grapefruit juice‐drug interactions in humans. The more sensitive Ient/IC50 identified two polymethoxyflavones as potential additional inhibitors. A similar approach could be applied to other natural products for initial prioritization of constituents as potential precipitants of pharmacokinetic natural product‐drug interactions.Support or Funding InformationThis work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM077482] and National Center for Advancing Translational Sciences [Grant UL1TR001111]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.