Abstract
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 [14C]metformin uptake and to test if TB drugs are transporter substrates. Metformin uptake was determined by quantifying [14C]metformin radioactivity, and TB drug uptake was analyzed using liquid chromatography-tandem mass spectrometry. DDI indices were calculated (plasma maximum concentrations [Cmax]/50% inhibitory concentrations [IC50]), 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 IC50s 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 (IC50, 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.