The effect of trimethoprim on thiamine absorption: A transporter-mediated drug-nutrient interaction

Authors: VORA, BIANCA - University Of California, Davis; WEN, ANITA - University Of California, Davis; YEE, SOOK WAH - University Of California San Francisco (UCSF); TRINH, KIM - Tufts University; AZIMI, MINA - University Of California San Francisco (UCSF); GREEN, ELIZABETH - University Of California San Francisco (UCSF); SIROTA, MARINA - University Of California San Francisco (UCSF); GREENBERG, ANDREW - Tufts University; Newman, John; GIACOMINI, KATHLEEN - University Of California San Francisco (UCSF)

Submitted to: Clinical Pharmacology and Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/7/2023
Publication Date: 5/25/2023
Citation: Vora, B., Wen, A., Yee, S., Trinh, K., Azimi, M., Green, E.A., Sirota, M., Greenberg, A.S., Newman, J.W., Giacomini, K.M. 2023. The effect of trimethoprim on thiamine absorption: A transporter-mediated drug-nutrient interaction. Clinical Pharmacology and Therapeutics. 114(2):381-392. https://doi.org/10.1002/cpt.2932.
DOI: https://doi.org/10.1002/cpt.2932

Interpretive Summary: Thiamine is a water-soluble vitamin found in foods which has a critical role in growth, function, and metabolism. There is limited knowledge how drugs affect blood levels of thiamine. In human studies we provided subjects with the commonly used antibiotic trimethoprim with or without thiamine to probe how this drug would effect thiamine levels after a meal. Trimethoprim increased blood levels of thiamine. Using cultured cells, mice, and review of other studies in humans, we deduced that trimethoprim blocked the actions of a factor called the organic cation transporter 1 (OCT1), which is located on the surface of liver cells where it absorbs thiamine and many drugs into liver cells. Thus blocking the actions of OCT1 reduced liver uptake of thiamine leading to the observed increase in blood thiamine. We further found that trimethoprim prescriptions were associated with increased blood levels of cholesterol and other fats, a side effect of reduced OCT1 activity. In summary, this study reveals that the antibiotic, trimethoprim, and potentially other drugs may influence thiamine levels resulting in alterations in circulating levels of cholesterol and blood fats associated with cardiovascular disease risk.

Technical Abstract: Trimethoprim, an oral antimicrobial agent, is predicted to be a potent, inhibitor of several thiamine transporters, including the primary thiamine intestinal absorptive transporter, ThTR-2, and the hepatic organic cation transporter OCT1. Employing studies in cells and mice, a prospective clinical trial, and real-world data, we aimed to determine the effect of trimethoprim on thiamine absorption. In a randomized, crossover design healthy volunteers (n =7) on a thiamine deficient diet were given a single oral dose of thiamine and thiamine plus trimethoprim, followed by intensive blood sampling. The thiamine maximum concentration achieved (Cmax) and area under the curve (AUC) increased with trimethoprim co-administration (paired t-test p-value: 0.046 and 0.031, respectively), consistent with inhibition of trimethoprim on the hepatic uptake of thiamine via OCT1 (IC50 =4.2 µM). Similar results were seen in mice. Moreover, in the human study, trimethoprim reduced plasma OCT1 biomarkers isobutyryl- and propionylcarnitine, supporting OCT1 inhibition. We further interrogated this mechanism using of real-world data derived from electronic health records. Notably, reduced function OCT1 polymorphisms are associated with higher clinical lipids, and we observed that trimethoprim prescription was associated with higher triglyceride, LDL cholesterol, and total cholesterol levels in HIV patients, consistent with OCT1 inhibition (p-values: 2.2 x 10-16, 5.75 x 10-7, 5.82 x 10-7, respectively). These findings suggest that trimethoprim increases plasma levels of thiamine and various circulating metabolites through inhibition of OCT1 and that OCT1 is a target for drug-nutrient interactions in addition to its known role in drug-drug interactions.