Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol
| Autor: | Jan B. Koenderink, Reinout van Crevel, Albert Bilos, Rob E. Aarnoutse, Lindsey H.M. te Brake, Aaron Ohene Buaben, Jeroen J. M. W. van den Heuvel, Frans G. M. Russel |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Organic Cation Transport Proteins 030106 microbiology Moxifloxacin lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Cmax Antitubercular Agents Pharmacology 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine In vivo medicine Humans Hypoglycemic Agents Pharmacology (medical) Drug Interactions IC50 Ethambutol business.industry Isoniazid Organic Cation Transporter 2 Pyrazinamide Metformin Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] Infectious Diseases HEK293 Cells business medicine.drug Fluoroquinolones Octamer Transcription Factor-1 |
| Zdroj: | Antimicrobial Agents and Chemotherapy, 60, 7105-7114 Antimicrobial Agents and Chemotherapy, 60, 12, pp. 7105-7114 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | It is largely unknown if simultaneous administration of tuberculosis (TB) drugs and metformin leads to drug-drug interactions (DDIs). Disposition of metformin is determined by organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs). Thus, any DDIs would primarily be mediated via these transporters. This study aimed to assess the in vitro inhibitory effects of TB drugs (rifampin, isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin, and linezolid) on metformin transport and whether TB drugs are also substrates themselves of OCTs and MATEs. HEK293 cells overexpressing OCT1, OCT2, OCT3, MATE1, and MATE2K were used to study TB drug-mediated inhibition of [ 14 C]metformin uptake and to test if TB drugs are transporter substrates. Metformin uptake was determined by quantifying [ 14 C]metformin radioactivity, and TB drug uptake was analyzed using liquid chromatography-tandem mass spectrometry. DDI indices were calculated (plasma maximum concentrations [ C max ]/50% inhibitory concentrations [IC 50 ]), and based on the literature, a cutoff of >0.1 was assumed to warrant further in vivo investigation. Moxifloxacin was the only TB drug identified as a potent inhibitor (DDI index of >0.1) of MATE1- and MATE2K-mediated metformin transport, with IC 50 s of 12 μM (95% confidence intervals [CI], 5.1 to 29 μM) and 7.6 μM (95% CI, 0.2 to 242 μM), respectively. Of all TB drugs, only ethambutol appeared to be a substrate of OCT1, OCT2, OCT3, MATE1, and MATE2K. MATE1-mediated ethambutol uptake was inhibited strongly (DDI index of >0.1) by moxifloxacin (IC 50 , 12 μM [95% CI, 3.4 to 43 μM]). Our findings provide a mechanistic basis for DDI predictions concerning ethambutol. According to international guidelines, an in vivo interaction study is warranted for the observed in vitro interaction between ethambutol and moxifloxacin. |
| Databáze: | OpenAIRE |
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