Bacterial metabolism rescues the inhibition of intestinal drug absorption by food and drug additives

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 27; pp. 16009 - 16018
• Main Authors: Zou, Ling, Spanogiannopoulos, Peter, Pieper, Lindsey M., Chien, Huan-Chieh, Cai, Wenlong, Khuri, Natalia, Pottel, Joshua, Vora, Bianca, Ni, Zhanglin, Tsakalozou, Eleftheria, Zhang, Wenjun, Shoichet, Brian K., Giacomini, Kathleen M., Turnbaugh, Peter J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.07.2020
• Subjects: Absorption; Additives; Animals; Anti-Allergic Agents - metabolism; Anti-Allergic Agents - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP-Binding Cassette Sub-Family B Member 4; Azo Compounds; Azo dyes; Bacteria; Bacteria - isolation & purification; Bacteria - metabolism; Biological Sciences; Community structure; Digestive system; Drug additives; Dyes; Enzymatic activity; Excipients; Excipients - metabolism; Excipients - pharmacokinetics; Female; Fexofenadine; Food; Food additives; Food Additives - metabolism; Food Additives - pharmacokinetics; Food dyes; Gastrointestinal Microbiome - physiology; Gastrointestinal tract; Genetic diversity; Gnotobiotic; Histamine H1 Antagonists, Non-Sedating - metabolism; Histamine H1 Antagonists, Non-Sedating - pharmacokinetics; Humans; Hydrophobicity; Intestinal Absorption - drug effects; Intestinal Absorption - physiology; Intestinal microflora; Intestine; Male; Metabolites; Mice; Mice, Inbred BALB C; Mice, Knockout; Microbiomes; Microorganisms; Molecular weight; Organic Anion Transporters - metabolism; Pharmacokinetics; Pharmacovigilance; Substrates; Terfenadine - analogs & derivatives; azoreductases; food additives; drug absorption; excipients; human gut microbiome
• DOI: 10.1073/pnas.1920483117
• ISSN: 0027-8424; 1091-6490

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R−N=N−R′) dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.