Identification and human exposure prediction of two aldehyde oxidase-mediated metabolites of a methylquinoline-containing drug candidate
| Autor: | Philmore Robertson, Erya Yu, Donghui Cui, Kyle Dobson, Edward T. Hellriegel, Austin C. Li |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Health Toxicology and Mutagenesis Metabolite Drug Evaluation Preclinical Toxicology 030226 pharmacology & pharmacy Biochemistry Rats Sprague-Dawley Mice 03 medical and health sciences chemistry.chemical_compound Dogs 0302 clinical medicine Tandem Mass Spectrometry In vivo Animals Humans Moiety Aldehyde oxidase Pharmacology chemistry.chemical_classification Drug candidate Haplorhini General Medicine Carbon In vitro Rats Aldehyde Oxidase Kinetics HEK293 Cells Enzyme chemistry Human exposure Drug Design 030220 oncology & carcinogenesis Quinolines Oxidation-Reduction Chromatography Liquid |
| Zdroj: | Xenobiotica. 49:302-312 |
| ISSN: | 1366-5928 0049-8254 |
| DOI: | 10.1080/00498254.2018.1444815 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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