Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol

Abstract

c 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 (MATEsT uberculosis (TB) remains a leading cause of morbidity and mortality in developing countries, claiming over a million lives annually (1). Treatment of TB requires long and intensive combination drug therapy, which can be complicated by the presence of concurrent diseases. The noncommunicable disease diabetes mellitus (DM) impacts TB with increasing magnitude (2, 3). At the moment, an estimated 15% of TB cases can be attributed to DM (3).Patients with DM have three times the risk of developing active TB compared to nondiabetics (3, 4), probably because of impaired host defenses. In addition, patients with TB and DM show a worse response to TB treatment than patients with TB alone and thus face a higher risk of TB treatment failure, relapse after cure, and death (5). The impact of DM will only increase further due to the rising prevalence of DM, especially in countries where TB is endemic. On the other hand, DM management is hampered by TB treatment. The TB drug rifampin possibly affects blood glucose itself and induces hyperglycemia by augmenting intestinal absorption of glucose or reducing insulin sensitivity (6, 7).Metformin is the first-choice antihyperglycemic drug to treat diabetes mellitus type 2. It is affordable and may be advantageous when combined with rifampin, as it is not metabolized. Metformin lowers both basal and postprandial plasma glucose (8) by inhibiting the production of hepatic glucose, reducing intestinal glucose absorption, and improving glucose uptake and utilization (9). Interestingly, recent data show that metformin also inhibits the intracellular growth of M. tuberculosis, restricts disease immunopathology, and augments the efficacy of conventional TB drugs. It has even been suggested as a possible adjunctive to standard TB treatment in nondiabetic TB patients (10).Metformin is eliminated unchanged into the urine with a halflife of approximately 5 h (11). Over a range of renal functions, the mean renal clearance in the population is approximately 4 times greater than that of creatinine, indicating that tubular secretion is the most important route of elimination (11). The oral absorption, hepatic uptake, and renal excretion of metformin are largely mediated by membrane transporters of the solute carrier (SLC) family, namely, organic cation transporters 1, 2, and 3 (OCT1, OCT2, and OCT3) and multidrug and toxin extrusion proteins 1 and 2K (MATE1 and MATE2K) ( Fig. 1) (11, 12). Genetic polymorphisms in these transporter genes explain at least some of the variability observed in metformin pharmacokinetics and drug responses (11). Furthermore, from studies of humans and mice, we know that inhibitors of OCTs and MATEs can alter the disposition of concomitantly administered organic cations, increasing

Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro

“…2). The transport characteristics of ethambutol for OCT1 and OCT2 were consistent with a recent report, except for the multidrug and toxic compound extrusion (MATE) transporters (34). However, our study revealed that MATE transporters are unlikely to be involved with ethambutol transport and elimination from the kidney.…”

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

“…Adjunctive therapy with host-modulating agents likely must strike a balance between an antimicrobial effect and excessive host inflammation, which may promote bacterial growth. Therefore, further preclinical pharmacokinetics studies of MetF coadministered with the first-line antitubercular regimen are urgently needed to guide the future study of this promising agent in clinical trials (19,20). In addition, detailed pharmacodynamics studies are required to relate plasma drug exposures in mice to AMPK activation and anti-TB activity in cell culture systems (6,21).…”

Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

“…Also, EMB absorption may be affected by uptake transporters, not simply passive diffusion, given EMB's low permeability into enterocytes (39). Recently, EMB has been reported to be a substrate of organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and P-gp (40,41). OCTs are known as uptake transporters expressed in various epithelial cells, such as intestine, liver, and lungs (30).…”