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 and the probe substrate estrone 3‐sulfate, IC50s 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 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 abs...
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Special Issue Article Source Type: research