Journal article
Inhibition of human liver aldehyde oxidase: implications for potential drug-drug interactions
Drug metabolism and disposition, Vol.39(12), pp.2381-2386
12/2011
Handle:
https://hdl.handle.net/2376/105819
PMID: 21940905
Abstract
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: K(m) = 8.0 ± 0.4 μM and V(max) = 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 K(ii) and K(is) 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 (K(ii)/K(is) 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 K(i) value relative to the inhibitor concentration in human plasma, having a calculated [I]/K(i) value of 0.4 and 0.8, respectively.
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Details
- Title
- Inhibition of human liver aldehyde oxidase: implications for potential drug-drug interactions
- Creators
- John T Barr - Department of Chemistry, Washington State University, Pullman, WA 99164, USAJeffrey P Jones
- Publication Details
- Drug metabolism and disposition, Vol.39(12), pp.2381-2386
- Academic Unit
- Chemistry, Department of
- Publisher
- United States
- Grant note
- R01 GM084546 / NIGMS NIH HHS R01 GM100874 / NIGMS NIH HHS GM84546 / NIGMS NIH HHS
- Identifiers
- 99900546552701842
- Language
- English
- Resource Type
- Journal article