The Absorption, Distribution, Excretion, and In Vitro Hepatic Microsomal Metabolism of the Novel CDK Compound XMD12...

Background: Cyclin-dependent kinase 4/6 (CDK4/6) represents one of the clinically validated and therapeutically effective anticancer targets. Methods: This study established a rapid and sensitive HPLC-MS/MS method for quantitative determination of XMD12, a novel CDK4/6 inhibitor developed in our laboratory, in various rat biological matrices including plasma, tissue homogenates, urine and feces. The experimental design comprised three distinct phases: pharmacokinetic evaluation in 10 Sprague-Dawley SD rats (5 receiving 2.0 mg/kg intravenous injection via tail vein and 5 administered 10.0 mg/kg by gastric gavage); tissue distribution assessment in 25 SD rats following a single 20 mg/kg gastric gavage; and an excretion study in 5 SD rats following a single 20 mg/kg gastric gavage. Biological samples were systematically collected post-dosing and analyzed using a validated LC-MS/MS method. Results: Key pharmacokinetic characteristics revealed (1) delayed absorption with significantly limited systemic exposure following gastric gavage; (2) preferential hepatic accumulation post-intestinal absorption followed by rapid clearance through metabolic/biliary pathways with multi-organ collaborative elimination; and (3) time-dependent cumulative excretion predominantly via feces, suggesting final clearance through biliary-mediated intestinal elimination of metabolites. Conclusions: These findings demonstrate XMD12's dynamic disposition pattern characterized by "restricted absorption-hepatic metabolic priority-multi-tissue collaborative clearance" in vivo. This comprehensive investigation provides crucial pharmacokinetic parameters and excretion profiles for the anticancer lead compound XMD12, offering valuable insights for pharmacodynamic and toxicological evaluations while establishing a foundation for structural optimization and derivative screening of lead compounds.