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Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3)
Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA.
Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA.
Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2020 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 111, no 1, p. 110-121Article in journal (Refereed) Published
Abstract [en]

Background: Transporter-mediated drug-nutrient interactions have the potential to cause serious adverse events. However, unlike drug-drug interactions, these drug-nutrient interactions receive little attention during drug development. The clinical importance of drug-nutrient interactions was highlighted when a phase III clinical trial was terminated due to severe adverse events resulting from potent inhibition of thiamine transporter 2 (ThTR-2: SLC19A3).

Objective: In this study, we tested the hypothesis that therapeutic drugs inhibit the intestinal thiamine transporter ThTR-2, which may lead to thiamine deficiency.

Methods: For this exploration, we took a multifaceted approach. starting with a high-throughput in vitro primary screen to identify inhibitors, building in silico models to characterize inhibitors, and leveraging real-world data from electronic health records to begin to understand the clinical relevance of these inhibitors.

Results: Our high-throughput screen of 1360 compounds, including many clinically used drugs, identified 146 potential inhibitors at 200 mu M. Inhibition kinetics were determined for 28 drugs with half-maximal inhibitory concentration (IC50) values ranging from 1.03 mu M to >1 mM. Several oral drugs, including metformin, were predicted to have intestinal concentrations that may result in ThTR-2-mediated drug-nutrient interactions. Complementary analysis using electronic health records suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs found to significantly inhibit ThTR2. particularly in vulnerable populations (e.g., individuals with alcoholism).

Conclusions: Our comprehensive analysis of prescription drugs suggests that several marketed drugs inhibit ThTR-2, which may contribute to thiamine deficiency, especially in at-risk populations.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS , 2020. Vol. 111, no 1, p. 110-121
Keywords [en]
drug-nutrient interactions, vitamin B1, transporters, vitamin deficiency, clinical data, high-throughput screen, electronic health records, machine learning
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-403259DOI: 10.1093/ajcn/nqz255ISI: 000505964300016PubMedID: 31764942OAI: oai:DiVA.org:uu-403259DiVA, id: diva2:1388633
Available from: 2020-01-27 Created: 2020-01-27 Last updated: 2020-01-27Bibliographically approved

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