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Pan, Xiaolei, Wang, Li, Gruendemann, Dirk and Sweet, Douglas H. (2013). Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy. Antimicrob. Agents Chemother., 57 (10). S. 5053 - 5060. WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 0066-4804

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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 similar to 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 mu M, 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).

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pan, Xiaolei UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Li UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruendemann, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Sweet, Douglas H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-474999
DOI:	10.1128/AAC.01255-13
Journal or Publication Title:	Antimicrob. Agents Chemother.
Volume:	57
Number:	10
Page Range:	S. 5053 - 5060
Date:	2013
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	0066-4804
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOLECULAR-IDENTIFICATION; GENETIC-VARIATION; P-GLYCOPROTEIN; NEPHROTOXICITY; TUBERCULOSIS; PHARMACOKINETICS; EXPRESSION; CISPLATIN; ROLES; ORGANIC-CATION-TRANSPORTER-1 Multiple languages Microbiology; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47499