Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy

Abstract

bAccording 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 ϳ9 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 [IC 50 ] ‫؍‬ 92.6 ؎ 10.9 and 253.8 ؎ 90.8 M, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC 50 ‫؍‬ 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).

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

“…For the OCTs and OATs, we simply calculated the drug-drug interaction index using the equation C max /IC 50 , where C max indicates the maximum concentration and C max,u indicates the maximum unbound concentration of the inhibitor present in the systemic circulation (27,33,(39)(40)(41).…”

“Target-Site” Drug Metabolism and Transport

“…Using an estimated EMB concentration of 67 mM in the portal system after oral dosing, DDI index analysis indicated a rank order of DDI potencies on hOCT1 as enterocyte (0.6) = hepatocyte (0.6) . proximal tubule cell (0.2), all above the 0.1 threshold value (Pan et al, 2013). These values are indicative of high potential for EMBmediated DDIs on hOCT1 affecting disposition and clearance.…”

“…Treatment of multidrug-resistant tuberculosis (TB; estimated to be 3.7% of new cases and 20% of previously treated cases) includes EMB to reduce the emergence of isoniazid-or rifampinresistant mycobacteria (http://apps.who.int/iris/bitstream/10665/75938/ 1/9789241564502_eng.pdf). In vitro characterization demonstrated that EMB inhibits hOCT1-, hOCT2-, and hOCT3-mediated transport (Pan et al, 2013). Using an estimated EMB concentration of 67 mM in the portal system after oral dosing, DDI index analysis indicated a rank order of DDI potencies on hOCT1 as enterocyte (0.6) = hepatocyte (0.6) .…”

“…For example, a patient population expressing a mutant form of hOCT1 with reduced transport function exhibited significantly altered metformin pharmacokinetics and experienced poorer glucose-lowering effects, i.e., loss of efficacy (Shu et al, 2008). The DDI index of 0.6 for hOCT1 in enterocytes and hepatocytes predicts as much as a 38% loss of hOCT1 transport activity in these cell types during routine EMB therapy (Pan et al, 2013). Together, these observations indicate a strong potential for EMB-metformin interactions on hOCT1 that result in altered drug efficacy in TB-diabetes patients.…”

“…Such analysis was used to assess the DDI potential of the antituberculosis drug ethambutol dihydrochloride (EMB) on hOCTs (Pan et al, 2013). The World Health Organization recommends EMB, along with pyrazinamide, isoniazid, and rifampin, as a front-line antituberculosis drug.…”