PT  - JOURNAL ARTICLE
AU  - John Barr
AU  - Jeffrey Jones
TI  - Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-drug Interactions
AID  - 10.1124/dmd.111.041806
DP  - 2011 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.111.041806
4099  - http://dmd.aspetjournals.org/content/early/2011/09/23/dmd.111.041806.short
4100  - http://dmd.aspetjournals.org/content/early/2011/09/23/dmd.111.041806.full
AB  - During the course of our research efforts to understand the kinetics of human AOX as a xenobiotic clearing enzyme, we investigated the effect of 8 different inhibitors on the oxidation of the probe substrate phthalazine. Saturation kinetic parameters for phthalazine oxidation in human liver cytosol were found to be the following: Km = 8.0 ± 0.4 µM and Vmax = 4.3 ± 0.1 nmol/min/mg protein. Inhibitory potency of the inhibitors tested ranged from 0.1 µM to 5 µM. Of the 8 different inhibitor compounds tested, 7 were observed to inhibit through a mixed mode and 1 through a strictly competitive mode. A ratio of the Kii and Kis values was used to assess the relative competitiveness of each inhibitor. For the mixed inhibitors, the mode of inhibition varied from mostly uncompetitive to predominantly competitive (Kii / Kis values ranging from 0.1 to 15). The implications for potential drug-drug interactions and inhibition mechanism are discussed. We found two inhibitors, clozapine and chlorpromazine, that have a moderate predicted risk of drug-drug interactions based on the Ki value relative to inhibitor concentration in human plasma, having a calculated [I]/Ki value of 0.4 and 0.8 respectively.