J Clin Pharmacol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Sign In to gain access to subscriptions and/or personal tools.
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Citing Articles
Right arrow Citing Articles via ISI Web of Science (13)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Obach, R. S.
Right arrow Articles by Beedham, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Obach, R. S.
Right arrow Articles by Beedham, C.

DRUG METABOLISM

Human Liver Aldehyde Oxidase: Inhibition by 239 Drugs

R. Scott Obach, PhD, Phuong Huynh, BSc, Mary C. Allen, MSc and Christine Beedham, PhD, MRPharmS

From Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, and the University of Bradford, West Yorkshire, United Kingdom.

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 µM. 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.

Key Words: Drug interactions • aldehyde oxidase • drug metabolism • aldehyde oxidase inhibition

Address for reprints: R. Scott Obach, MS 4088, Pfizer Global Research and Development, Groton, CT 06340.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2004 by the American College of Clinical Pharmacology