Biotransformation and disposition of C14-labeled sonrotoclax ([14C]BGB-11417) in preclinical safety species and characterization of unique contribution from gut microbiome.
Tingting Cai, Dan Su, Zhiyu Tang, Jianmei Liu, Wei Tang, Yue Wu, Fan Wang
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引用次数: 0
Abstract
Introduction: 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.
Methods: [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 human fecal incubation was conducted to evaluate the biotransformation contribution of gut microbiome.
Results: Tmax of [14C]BGB-11417 radioactivity was observed at 4 h, with a T1/2 ranging 6.5-7.2 h in both species. The highest tissue exposure was noted in metabolic and excretory organs, with 90% of the administered radioactivity eliminated through mouse excreta within 48 h. Prolonged excretion kinetics accompanied by marked inter-individual variability were observed in dog excreta. 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.
Conclusion: 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.
期刊介绍：
Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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