Human liver aldehyde oxidase: inhibition by 239 drugs.
The authors tested 239 frequently used drugs and other compounds for their potential to inhibit the drug-metabolizing enzyme, aldehyde oxidase, in human liver cytosol. A sensitive, moderate throughput HPLC-MS assay was developed for 1-phthalazinone, the aldehyde oxidase-catalyzed product of phthalazine oxidation. Inhibition of this activity was examined for the 239 drugs and other compounds of interest at a test concentration of 50 microM. Thirty-six compounds exhibited greater than 80% inhibition and were further examined for measurement of IC50. The most potent inhibitor observed was the selective estrogen receptor modulator, raloxifene (IC50=2.9 nM), and tamoxifen, estradiol, and ethinyl estradiol were also potent inhibitors. Other classes of drugs that demonstrated inhibition of aldehyde oxidase included phenothiazines, tricyclic antidepressants, tricyclic atypical antipsychotic agents, and dihydropyridine calcium channel blockers, along with some other drugs, including loratadine, cyclobenzaprine, amodiaquine, maprotiline, ondansetron, propafenone, domperidone, quinacrine, ketoconazole, verapamil, tacrine, and salmeterol. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which aldehyde oxidase is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme.
Obach
R Scott
RS
Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA.
Huynh
Phuong
P
Allen
Mary C
MC
Beedham
Christine
C
D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004364:Pharmaceutical Preparations; D020845:Selective Estrogen Receptor Modulators; D042931:Aldehyde Oxidase