Protein binding investigation of first-line and second-line antituberculosis drugs

Abstract

Data about antituberculosis drugs binding are incomplete for first-line drugs and lacking for second-line drugs that are used extensively for multi-drug resistant tuberculosis (levofloxacin, linezolid and moxifloxacin). Thus, the main purposes of this study were first to investigate thoroughly the relation between the carrier-proteins level and the drug binding and second to investigate the feasibility of predicting the free drug concentrations by the means of in vitro and in vivo results. In vitro experiments mimicked real-case samples by spiking drugs combinations from the clinical practice. We measured a median in vivo protein binding of 1.5% for ethambutol, 9.7% for isoniazid, 0.7% for pyrazinamide and 88.2% for rifampicin; and a median in vitro protein binding of 26.2% for levofloxacin, 12.8% for linezolid and 46.3% for moxifloxacin. The albumin concentration had a moderate impact on the moxifloxacin binding and a strong impact on the levofloxacin, linezolid and rifampicin binding (below values of 30 g/L). The determination of the free drug concentration seems to have few interests for ethambutol, isoniazid, moxifloxacin and pyrazinamide, a limited interest for linezolid because of its low binding and a major interest for rifampicin in hypoalbuminemia TB patients and for levofloxacin because their total concentration was an inaccurate reflection of the free concentration. The free concentration predicted by mathematical model was suitable for levofloxacin and linezolid, unlike for rifampicin, where the real free concentration should be measured. Further investigations should be carried out to investigate the benefit of the free concentration for levofloxacin, linezolid and rifampicin mainly in the critical period of active tuberculosis associated to hypoalbuminemia.