DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

0090-9556/04/3201-89-97$20.00
DMD 32:89-97, 2004

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Obach, R. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Obach, R. S.

POTENT INHIBITION OF HUMAN LIVER ALDEHYDE OXIDASE BY RALOXIFENE

R. Scott Obach

Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut

The selective estrogen receptor modulator, raloxifene, has been demonstrated as a potent uncompetitive inhibitor of human liver aldehyde oxidase-catalyzed oxidation of phthalazine, vanillin, and nicotine-{Delta}1'(5')-iminium ion, with Ki values of 0.87 to 1.4 nM. Inhibition was not time-dependent. Raloxifene has also been shown to be a noncompetitive inhibitor of an aldehyde oxidase-catalyzed reduction reaction of a hydroxamic acid-containing compound, with a Ki of 51 nM. However, raloxifene had only small effects on xanthine oxidase, an enzyme related to aldehyde oxidase. In addition, several other compounds of the same therapeutic class as raloxifene were examined for their potential to inhibit aldehyde oxidase. However, none were as potent as raloxifene, since IC50 values were orders of magnitude higher and ranged from 0.29 to 57 µ M. In an examination of analogs of raloxifene, it was shown that the bisphenol structure with a hydrophobic group on the 3-position of the benzthiophene ring system was the most important element that imparts inhibitory potency. The relevance of these data to the mechanistic understanding of aldehyde oxidase catalysis, as well as to the potential for raloxifene to cause drug interactions with agents for which aldehyde oxidase-mediated metabolism is important, such as zaleplon or famciclovir, is discussed.

Address correspondence to: R. Scott Obach, MS 4088, Groton Laboratories, Pfizer, Inc., Groton, CT 06340. E-mail: obachrs{at}groton.pfizer.com




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
D. Dalvie, T. Cosker, T. Boyden, S. Zhou, C. Schroeder, and M. J. Potchoiba
Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 in Plasma and Urine of Humans
Drug Metab. Dispos., September 1, 2008; 36(9): 1869 - 1883.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Prevention ResearchHome page
C. B. Yoo, J. C. Chuang, H.-M. Byun, G. Egger, A. S. Yang, L. Dubeau, T. Long, P. W. Laird, V. E. Marquez, and P. A. Jones
Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice
Cancer Prevention Research, September 1, 2008; 1(4): 233 - 240.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. A. Erickson, S. Hollfelder, J. Tenge, M. Gohdes, J. J. Burkhardt, and P. A. Krieter
In Vitro Metabolism of the Analgesic Bicifadine in the Mouse, Rat, Monkey, and Human
Drug Metab. Dispos., December 1, 2007; 35(12): 2232 - 2241.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
E. Higashi, M. Nakajima, M. Katoh, S. Tokudome, and T. Yokoi
Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6
Drug Metab. Dispos., April 1, 2007; 35(4): 508 - 514.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Terao, M. Kurosaki, M. M. Barzago, E. Varasano, A. Boldetti, A. Bastone, M. Fratelli, and E. Garattini
Avian and Canine Aldehyde Oxidases: NOVEL INSIGHTS INTO THE BIOLOGY AND EVOLUTION OF MOLYBDO-FLAVOENZYMES
J. Biol. Chem., July 14, 2006; 281(28): 19748 - 19761.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. B. Otteneder, C. G. Knutson, J. S. Daniels, M. Hashim, B. C. Crews, R. P. Remmel, H. Wang, C. Rizzo, and L. J. Marnett
In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M1dG
PNAS, April 25, 2006; 103(17): 6665 - 6669.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. Seo, T. Yan, J. E. Schupp, T. Radivoyevitch, and T. J. Kinsella
Schedule-Dependent Drug Effects of Oral 5-Iodo-2-Pyrimidinone-2'-Deoxyribose as an In vivo Radiosensitizer in U251 Human Glioblastoma Xenografts
Clin. Cancer Res., October 15, 2005; 11(20): 7499 - 7507.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
S. E. Murphy, V. Raulinaitis, and K. M. Brown
NICOTINE 5'-OXIDATION AND METHYL OXIDATION BY P450 2A ENZYMES
Drug Metab. Dispos., August 1, 2005; 33(8): 1166 - 1173.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
J. Hukkanen, P. Jacob III, and N. L. Benowitz
Metabolism and Disposition Kinetics of Nicotine
Pharmacol. Rev., March 1, 2005; 57(1): 79 - 115.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics.