RT Journal Article
SR Electronic
T1 Oxidative Deamination of Emixustat by Human Vascular Adhesion Protein-1/Semicarbazide-sensitive Amine Oxidase
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.085811
DO 10.1124/dmd.118.085811
A1 Michael J Reid
A1 Russell Eyre
A1 Terry Podoll
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/02/20/dmd.118.085811.abstract
AB Emixustat potently inhibits the visual cycle isomerase RPE65 to reduce the accumulation of toxic bisretinoid by-products that lead to various retinopathies. Orally administered emixustat is cleared rapidly from the plasma, with little excreted unchanged. The hydroxypropylamine moeity that is critical in emixustat's inhibition of RPE65 is oxidatively deaminated to three major carboxylic acid metabolites that appear rapidly in plasma. These metabolites greatly exceed the plasma concentrations of emixustat and demonstrate formation-rate limited metabolite kinetics. This study investigated in vitro deamination of emixustat in human vascular membrane fractions, plasma and recombinant human vascular adhesion protein-1 (VAP-1); demonstrating single enzyme kinetics for the formation of a stable aldehyde intermediate (ACU-5201) in all in vitro systems. The in vitro systems employed herein established sequential formation of the major metabolites with addition of assay components for aldehyde dehydrogenase (ALDH) and cytochrome P450 (CYP). Reaction phenotyping experiments using selective chemical inhibitors and recombinant enzymes of monoamine oxidase (MAO), VAP-1 and lysyl oxidase (LOX), showed that only VAP-1 deaminated emixustat. In individually-derived human vascular membranes from umbilical cord and aorta, rates of emixustat deamination were highly correlated to VAP-1 marker substrate activity (benzylamine) and VAP-1 levels measured by ELISA. In donor-matched plasma samples, soluble VAP-1 activity and levels were lower than in aorta membranes. A variety of potential co-medications did not strongly inhibit emixustat deamination in vitro.