Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy
Document Type
Article
Original Publication Date
2013
Journal/Book/Conference Title
Antimicrobial Agents and Chemotherapy
Volume
57
Issue
10
First Page
5053
Last Page
5059
DOI of Original Publication
10.1128/AAC.01255-13
Date of Submission
October 2015
Abstract
According to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2′-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50 = 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting that in vivo pharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin).
Rights
Copyright © 2013, American Society for Microbiology. All Rights Reserved.
Is Part Of
VCU Pharmaceutics Publications
Comments
Originally published at doi:10.1128/AAC.01255-13
PMCID: PMC3811444