Abstract
Vonifimod is a novel sphingosine-1-phosphate receptor (S1PR) modulator with selectivity for S1PR1 and S1PR4 that is under development for the treatment of autoimmune disease. No reports on vonifimod metabolism exist except for the formation of active vonifimod-phosphate in rats. The in vitro metabolic pathways and drug interaction potentials of vonifimod were characterized by identifying the metabolites of vonifimod in human hepatocytes via liquid chromatography-high-resolution mass spectrometry and determining the inhibitory effects of vonifimod on major cytochrome P450 (CYP) and UDPGA-glucuronosyltransferase (UGT) enzyme activities in human liver microsomes. The incubation of vonifimod with human hepatocytes resulted in the formation of nine metabolites, including hydroxy-vonifimod (M1 and M2), inactive carboxylic acids (M3 - M6), active vonifimod-phosphate (M7), and M3 glucuronides (M3-G1 and M3-G2). ω-Hydroxylation of vonifimod to M2 at the methyl terminus of the decyl chain was catalyzed mainly by CYP4F2 enzymes, which were further oxidized to four carboxylic acid metabolites (M3 - M6). UGT1A7, UGT1A8, UGT1A9, and UGT1A10 catalyzed the formation of M3-G2 from M3. Vonifimod revealed the negligible and weak inhibition of major CYP and UGT enzyme activities at 50 µM in human liver microsomes, suggesting that vonifimod has low potential for drug-drug interactions. These findings suggest hepatic metabolism to be the primary elimination pathway for vonifimod.