Assessment of the in vitro cytochrome P450 (CYP) inhibition potential of Nafithromycin, a next generation lactone ketolide antibiotic.

Assessment of the in vitro cytochrome P450 (CYP) inhibition potential of Nafithromycin, a next generation lactone ketolide antibiotic. Xenobiotica. 2020 Oct 20;:1-33 Authors: Chavan RP, Zope VS, Chavan NN, Patil K, Yeole RD, Bhagwat SB, Patel MV Abstract Nafithromycin is a next generation lactone ketolide antibiotic slated to enter phase III clinical development in India for the treatment of CABP as a shorter 800mg-OD X3 day therapeutic regimen. Nafithromycin exhibits potent activity against MDR Streptococcus pneumoniae including erythromycin and telithromycin-resistant resistant strains. Older macrolides/ketolides are reported to be potent inhibitors of CYP3A4/5. To facilitate comparative assessment of drug-drug interaction potential, CYP inhibitory activities of nafithromycin was evaluated in comparison with clarithromycin, telithromycin, cethromycin and solithromycin. CYP inhibitory activities were assessed against key CYP isoforms (CYP1A2,2B6, 2C8,2C9,2C19,2D6 and CYP3A4/5) using human liver microsomes. Additionally, time-, metabolism-based inhibition (TDI, MBI) and k inact /K I activities were also investigated for CYP3A4/5. Nafithromycin did not inhibit key CYP enzymes and was found to be a weak inhibitor of CYP3A4/5. Comparator antibiotics were found to be potent inhibitors with 2 to 50 fold leftward shifts in CYP3A4/5 IC50 values, while such shift was not noted for nafithromycin. k inact /K I ratio of nafithromycin was 3 to...
Source: Xenobiotica - Category: Research Authors: Tags: Xenobiotica Source Type: research