Background and Purpose: Sonrotoclax (BGB-11417), a second-generation B-cell lymphoma-2 (BCL-2) inhibitor currently in clinical development, requires comprehensive verification of its biotransformation and disposition profiles in safety species. Experimental Approach: [14C]BGB-11417 was employed to assess its pharmacokinetics, excretion, tissue distribution and metabolite profiles in mice and dogs. Radioactivity in plasma and excreta were analyzed to determine pharmacokinetics and mass balance. The metabolite profiles were generated by the chromatographic separation coupled with radioactivity detector/ mass spectrometry. Quantitative whole-body autoradiography (QWBA) was performed to assess tissue distribution in both pigmented or albino mice. Anaerobic or aerobic fecal incubation was conducted to evaluate the biotransformation contribution of gut microbiome. Key Results: Tmax of [14C]BGB-11417 radioactivity was observed at 4 hours, with a T1/2 ranging 6.5-7.2 hours in both species. The highest exposure in organs involved in metabolism and excretion, with 90% of administered radioactivity recovered in mouse excreta within 48h. Slower excretion with individual variability was observed in dogs. A distinct nitro-reduction pathway was detected exclusively in dogs. These metabolites were also detected in anaerobic incubations of [14C]BGB-11417 with human feces. Aerobic incubation of the nitro-reduction metabolite with dog feces directly yielded lipid-conjugated products, confirming that conjugation occurs spontaneously post-reduction rather than on the parent drug. Conclusions and Implications: The concordance between dog fecal metabolites and human fecal incubations underscored cross-species gut microbiome similarities. These findings offer a mechanistic insight into the fate of sonrotoclax in organisms and guide the interpretation of metabolic clearance in human.