Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice

Abstract

Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health-care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells (Madin-Darby canine kidney type II) and the probe substrate estrone 3-sulfate, IC_50s were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6',7'-dihydroxybergamottin) and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice. Nobiletin was the most potent (IC₅₀ , 3.7 μm); 6',7'-dihydroxybergamottin, naringin, naringenin and tangeretin were moderately potent (IC₅₀ , 20-50 μm); and bergamottin and hesperidin were the least potent (IC₅₀ , >300 μm) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine the ratios of unbound concentration to IC₅₀ for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: OATP2B1; drug interaction; grapefruit juice; simulation; transporter.

Fig. 1

Structures of constituents from representative chemical classes contained in grapefruit juice.

Fig. 2

Concentration-dependent modulation of OATP2B1-mediated estrone-3-sulfate uptake by grapefruit juice constituents representative of three chemical classes (A–G). Percent control activity is relative to vehicle condition. Symbols and error bars denote means and standard errors, respectively, of triplicate incubations. Curves denote nonlinear least-squares regression of observed data.

Fig. 3

Forest plot of the [I]_ent/IC₅₀ and [I]_GFJ/IC₅₀ ratios for grapefruit juice (GFJ) constituents as inhibitors of intestinal OATP2B1. [I]_ent/IC₅₀ (gray), ratio of the unbound concentration in simulated enterocyte compartments to IC₅₀. [I]_GFJ/IC₅₀ (orange), ratio of maximum constituent concentration in GFJ to IC₅₀. The absorption simulation predicted [I]_ents of 560 (naringin), 63.9 (naringenin), 16.8 (hesperidin), 2.28 (DHB), 2.78 (bergamottin), 3.71 (nobiletin), and 8.85 (tangeretin) μM. Gray and orange lines denote ratios at which a clinical interaction study is suggested for each metric: [I]_ent/IC₅₀, 0.1 (gray); [I]_GFJ/IC₅₀, 10 (orange). DHB, 6′,7′-dihydroxybergamottin. Red circles indicate constituents whose ratios exceeded these threshold values.