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

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 ranges as those observed in monkeys. These data taken together support the advancement to clinical development of Compound A.

Keywords:

• Aldehyde oxidase (AO enzymes)
• oxidative metabolism
• methylquinoline; in vitro to in vivo correlation (IVIVC)
• pharmacokinetic (PK)

Acknowledgements

The authors acknowledge Dr. Robert Hudkins’ group, for synthesizing the 2-oxo and 4-OH metabolite standards for structure identification; Dr. Lisa Aimone’s group, for conducting IV PK studies in rats; Mr. Alex Kogan, for performing part of the bioanalyses of rat plasma; Drs. Ray Bakhtiar and James Chovan for critical reading of the manuscript.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This research work was supported by Teva Pharmaceuticals, Inc.