Figure 3 from Drug–Drug Interaction Liabilities with BTK Inhibitor TL-895

Interaction of TL-895 with CYP3A4 and CYP3A4-mediated metabolism. Metabolism of TL-895 by CYP3A4 microsomes (A) and the influence of CYP3A deficiency [CYP(−/−)] on the circulating concentration of oral (3 mg/kg) TL-895 in mice (B; N = 5 per group). Influence of TL-895 (10 μmol/L) and the positive control inhibitor ketoconazole (10 μmol/L) on the disappearance of the CYP3A4 substrate triazolam (left Y-axis) and the formation of its metabolite OH-triazolam (right Y-axis) in the presence of CYP3A4 microsomes (C). In vivo ratio of OH-triazolam to parent triazolam recovery in C57BL/6 male mice with vehicle or TL-895 10 mg/kg oral administration (D; N = 6 per group). Microsome data represent mean values (symbols) and SD (error bars, if larger than the symbol) of experiments performed in triplicate. In vivo data represent mean values (symbols) and SE (error bars). A two-way ANOVA was used to compare the main effects of time and treatment group on the percentages of TL-895, triazolam, and OH-triazolam recovery. ****, P < 0.0001. WT, wild type.