Vonifimod

Vonifimod is converted by pooled human liver microsomes to M1, M2, M3, and M7, but not to the β-oxidation products M4-M6; in human cDNA-expressed CYP systems, M2 is mainly formed by CYP4F2, while CYP2D6 and CYP2E1 are involved in the formation of M1^[1].

Vonifimod (2 μM) undergoes extensive hepatic metabolism in human hepatocytes, with an elimination half-life of 56.1 min, an intrinsic clearance of 88.2 mL/min/kg, and a hepatic extraction ratio of 0.81^[1].
Vonifimod (3 μM) generates 9 metabolites after incubation with human hepatocytes, including hydroxylated Vonifimod (M1, M2), inactive carboxylic acid metabolites (M3‑M6), active Vonifimod‑phosphate (M7), and glucuronic acid conjugates of M3 (M3‑G1, M3‑G2)^[1].
The intrinsic clearance of Vonifimod in human liver microsomes is mainly attributed to Ketoconazole (HY-B0105)-sensitive CYP activity, consistent with CYP3A/CYP4F2, reducing Clint from 161 to 57.0 µL/min/mg protein^[1].
Vonifimod weakly inhibits CYP2B6 in human liver microsomes, with an IC₅₀ of 44.9 µM without preincubation and 49.1 µM with 30 min preincubation; moreover, at 50 µM it shows negligible inhibition of the activities of the major UGT enzymes tested in human liver microsomes^[1].