RT Journal Article
SR Electronic
T1 Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2381
OP 2386
DO 10.1124/dmd.111.041806
VO 39
IS 12
A1 John T. Barr
A1 Jeffrey P. Jones
YR 2011
UL http://dmd.aspetjournals.org/content/39/12/2381.abstract
AB During the course of our research efforts to understand the kinetics of human aldehyde oxidase as a xenobiotic-clearing enzyme, we investigated the effect of eight 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−1 · mg protein−1. Inhibitory potency of the inhibitors tested ranged from 0.1 to 5 μM. Of the eight different inhibitor compounds tested, seven were observed to inhibit through a mixed mode and one 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 the inhibitor concentration in human plasma, having a calculated [I]/Ki value of 0.4 and 0.8, respectively.