FZJ-003 is a selective Janus kinase 1 (JAK1) inhibitor with structural modification of filgotinib for rheumatoid arthritis (RA) treatment. In this study, a series of in vivo and in vitro experiments were conducted to investigate the specific contribution of the intestine and liver to the disposition of FZJ-003 compared with filgotinib. Results showed that FZJ-003 exhibited over 2-fold higher systemic exposure and lower clearance than those of filgotinib, after intravenous or intragastric administration at the equivalent mole dose level to conscious rats. In anesthetized rats treated with different dosing routes, FZJ-003 exhibited higher intestinal bioavailability (Fa·Fg, 98.47 vs 34.54%) but lower hepatic bioavailability (Fh, 61.45 vs 92.07%). Permeability test in Caco-2 cells indicated that FZJ-003 was probably transported by passive diffusion (efflux ratio 1.37 < 2, indicating the approximately equivalent Papp values in two directions) with a little higher permeability (Papp,AP-to-BL, 1.42 × 10-6vs 1.01 × 10-6 cm·s-1, FZJ-003 vs filgotinib). Metabolic studies in pre-systemic incubation systems showed that FZJ-003 experienced more NADPH-dependent metabolism, especially in hepatic microsomes fractions. Unlike filgotinib, there was no obvious amide-hydrolyzed metabolite of FZJ-003 detected throughout the pre-systemic metabolic sites. Collectively, these data suggest that the higher systemic exposure of FZJ-003 than filgotinib is mainly attributed to the higher intestinal bioavailability including bypassing the amide hydrolysis and possible efflux by intestinal epithelial cells, which strongly support the structural design purpose in terms of pharmacokinetics.
Keywords: Amide hydrolysis; Hepatic metabolism; Intestinal absorption; Intestinal metabolism; Pre-systemic metabolism.
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