Increasing <i>in vivo</i> drug exposure levels of compound WX-081 (sudapyridine) when used in combination with clofazimine or clarithromycin

To examine the <i>in vivo</i> distribution of WX-081 alone or in combination with clarithromycin (Clr) or clofazimine (CFZ) in rats infected with <i>Mycobacterium abscessus</i> and evaluate the effects of the interactions of WX-081 with Clr and CFZ on its tissue distribution, the concentrations of WX-081 in plasma, brain, vertebral, and lung tissue of Sprague-Dawley rats at 20 min, 1 h, and 16 h post-treatment with 45 mg/kg WX-081 (Group A), 45 mg/kg WX-081 plus 10 mg/kg Clr (Group B), or 45 mg/kg WX-081 plus 25 mg/kg CFZ (Group C) were determined by liquid chromatography-tandem mass spectrometry. Differences between continuous variables were analyzed using Student's <i>t</i>-test (<i>P</i> ≤ 0.05). At 20 min, rats in groups B and C had higher plasma WX-081 concentration than those in Group A (458.7 ng/mL vs. 140.4 ng/mL, <i>P</i> = 0.012; 351.7 ng/mL vs. 140.4 ng/mL, <i>P</i> = 0.022, respectively). At 1 h, only Group B had a higher plasma level than Group A (2,522.3 ng/mL vs. 1,413.2 ng/mL, respectively, <i>P</i> = 0.018), while the WX-081 concentration in Group B lung tissue exceeded that in Group A lung tissue (8,890.9 ng/g vs. 6,666.8 ng/g, respectively, <i>P</i> = 0.041), and that of Group C lungs was lower than that of Group A lung tissue (3,953.4 ng/g vs. 6,666.8 ng/g, respectively, <i>P</i> = 0.014). The lung tissue consistently had the highest WX-081 concentration at all time points. At 20 min, plasma WX-081 levels in groups B and C surpassed that of Group A. At 1 h, Group B had higher plasma and lung WX-081 concentration, while Group C had a lower lung WX-081 concentration than Group A.IMPORTANCEThe study pioneers the exploration of WX-081's <i>in vivo</i> distribution and drug interactions with Clr or CFZ in a rat <i>Mycobacterium abscessus</i> infection model. It shows that co-administration alters tissue distribution, boosting lung concentrations-key for treating pulmonary infections. These insights guide regimen optimization and underscore WX-081's potential as a safer alternative, enhancing treatment for non-tuberculous mycobacterial diseases.