Identification and human exposure prediction of two aldehyde oxidase-mediated metabolites of a methylquinoline-containing drug candidate

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Austin C LiPhilmore Robertson

Abstract

1. Aldehyde oxidase (AO enzymes)-mediated oxidation predominantly occurs at a carbon atom adjacent to the nitrogen on aromatic azaheterocycles. In the current report, we identified that AO enzymes oxidation took place at both the C-2 and C-4 positions of the methylquinoline moiety of Compound A based on data from mass spectrometric analysis, AO enzymes "litmus" test, and comparison with authentic standards. 2. To assess the potential for inadequate coverage for these two AO enzyme-mediated metabolites in nonclinical safety studies, given concerns due to differences in AO enzymes expression between preclinical species and humans, the human circulating levels of the two AO enzyme-mediated metabolites were predicted prospectively using in vitro and in vivo models. Both formation clearance and elimination clearance of the two metabolites were predicted based on in vitro to in vivo correlation and comparison with in vivo data from rats. 3. The result showed that the 4-OH metabolite of Compound A would account for less than 3% of the total drug-related exposure in human plasma, while the exposure to the 2-oxo metabolite would be relatively high (∼70%). 4. The predicted human exposure levels for the two metabolites are in similar rang...Continue Reading

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Citations

Jun 1, 2019·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Christine Beedham
Sep 25, 2019·Drug Metabolism Reviews·Narges CheshmazarMaryam Hamzeh-Mivehroud
May 5, 2021·Drug Metabolism Reviews·Nikhilesh V DhuriaJasleen K Sodhi
Nov 21, 2020·ACS Medicinal Chemistry Letters·Julia Shanu-WilsonJason Boer
Aug 7, 2019·Journal of Medicinal Chemistry·Nenad ManevskiFrancesca Toselli

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