Mechanistic study on the species differences in metabolism and excretion pathways of ivarmacitinib between humans and rats

[¹⁴C]Ivarmacitinib (SHR0302) exhibits significant species differences in metabolic and excretory processes between humans and rats. In humans, urine is the primary excretion route (60.95% of dose), with SHR161279 (mono-oxidation) as the main urinary metabolite (33.61%). In rats, fecal excretion predominates (84.1% of dose), with parent drug (54.5%) and SHR146622 (N-demethylation, 8.50%) as major fecal components. To elucidate the potential mechanisms underlying these species differences, studies were conducted to investigate the metabolism and excretion pathways of ivarmacitinib in humans and rats. Mechanistically, the distinct metabolic profiles are driven by species-specific cytochrome P450 activities. Human liver microsome preferentially produced SHR161279 via CYP2C8, whereas rat liver microsome preferentially produced SHR146622 via CYP3A. Regarding disposition and excretion, in humans, transporter studies showed that SHR161279 was excreted into bile via P-glycoprotein, whereas ivarmacitinib and SHR146622 underwent passive diffusion into blood. Subsequently, ivarmacitinib (accounting for 90.42% in area under the curve-pooled plasma) entered the kidneys probably via passive diffusion. Ivarmacitinib was metabolized in human kidney microsome to form SHR161279. In rats, ivarmacitinib and its metabolites were substrates for P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2, leading to predominant fecal excretion. Enzyme kinetics also indicated that ivarmacitinib was metabolized more slowly in human liver microsome. In contrast, in rats, ivarmacitinib was more metabolized to highly polar metabolites, which were more readily transported into bile via transporters localized on the canalicular membrane of hepatocytes, ultimately leading to species differences in excretion pathways between humans and rats. SIGNIFICANCE STATEMENT: This study elucidates the interspecies difference mechanism in the metabolic and excretory pathways of ivarmacitinib in humans and rats. Urine excretion is predominant in humans, unlike the predominant fecal excretion observed in rats. Meanwhile, SHR161279 is the primary metabolite in human urine, whereas SHR146622 is the primary metabolite in rat feces. These differences are attributed to the expression and activity of cytochrome P450 enzymes and transporters.