Ocular Distribution and Metabolite Profiling of Vorolanib in Rats and Its In Vitro Metabolism Using Human Recombinant Enzymes.

PURPOSE: Vorolanib is a multitarget tyrosine kinase inhibitor with anti-angiogenic potential for diabetic macular edema (DME) and neovascular age-related macular degeneration (wAMD), but its ocular disposition and metabolism are unclear. This study investigated the cytochrome P450 (CYP) phenotyping, ocular distribution, and metabolite profiles of vorolanib in rats.

METHODS

Male Sprague-Dawley rat (SD rats) received a single intravenous (IV) (2 mg/kg) or oral (50 mg/kg) vorolanib. Drug concentrations in plasma and ocular tissues were measured by liquid chromatography-tandem mass spectrometry. Metabolic contribution of recombinant human CYPs (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) was assessed, and metabolites were identified by LC-high-resolution mass spectrometry.

RESULTS

Recombinant human CYP3A4 was the predominant metabolizing enzyme, accounting for 85.6% of intrinsic clearance (CLint = 3.76 µL/min/pmol), followed by CYP2C8 (10.6%). Vorolanib exhibited high IV clearance but achieved higher concentrations in the cornea, retina, and plasma within 4 h after oral administration. Fourteen metabolites (M1-M14) were identified in plasma, and eight were detected in ocular tissues. M9 (mono-oxygenation/reduction) and M10 (N-demethylation) were major in the cornea and retina after oral dosing. Recombinant human CYP3A4 primarily generated M2, M9, M10, M11, and M12, while CYP2C8 contributed to M2 and M9. Major pathways included mono-oxygenation, N-demethylation, reduction, dehydrogenation, and glucuronidation.

CONCLUSIONS

Vorolanib is extensively metabolized by CYP3A4 and CYP2C8 in humans, and both the parent compound and its metabolites are widely distributed to ocular tissues in rats. The detection of multiple metabolites in these tissues emphasizes the need to consider both the parent drug and its active metabolites when evaluating ophthalmic efficacy and safety.