LAUSR

A number of erythropoiesis stimulants are entering the final stage of clinical trials due to recent scientific progress in hypoxia-regulated erythropoiesis. Considering how erythropoiesis-stimulating compounds enhance the capacity of the organism to transport oxygen, they pose a great risk of being misused as performance enhancers. In this paper, we report the metabolic fate of three popular Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors (HIF-PHI) compounds, namely BAY 87-2243, MK-8617, and PT-2385 in equine liver microsomes using Q-Exactive high-resolution mass spectrometry. This study found twenty-two metabolites for BAY 87-2243 (19 phase I and 3 phase II), three metabolites for MK-8617 (all phase I), and five metabolites for PT-2385 (2 phase I and 3 phase II). The major findings of the present study are (1) all three potential HIF-PHI drug candidates, namely BAY 87-2243, MK-8617, and PT-2385 are susceptible to oxidation, producing their corresponding hydroxylated metabolites; (2) the ring dissociated metabolites were detected for BAY 87-2243 and PT-2385; (3) in the case of BAY 87-2243 and PT-2385, glucuronic acid conjugated metabolites were detected; (4) none of the drugs produced sulfonic acid conjugated metabolites.