Potent inhibition of human liver aldehyde oxidase by raloxifene.

doi:10.1124/DMD.32.1.89

Paper

Potent inhibition of human liver aldehyde oxidase by raloxifene.

Published 2004 · R. Obach

Drug metabolism and disposition: the biological fate of chemicals

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160

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19

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Abstract

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-Delta1'(5')-iminium ion, with K(i) 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 K(i) 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 IC(50) values were orders of magnitude higher and ranged from 0.29 to 57 micro 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.

In Vitro Study

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Raloxifene is a potent inhibitor of human liver aldehyde oxidase, potentially causing drug interactions with agents requiring aldehyde oxidase-mediated metabolism.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Potent inhibition of human liver aldehyde oxidase by raloxifene.

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References

Human Liver Aldehyde Oxidase: Inhibition by 239 Drugs

239 drugs, including raloxifene, tamoxifen, estradiol, and ethinyl estradiol, show potential inhibition of aldehyde oxidase in human liver cytosol, potentially causing drug interactions.

Inhibition-based metabolic drug-drug interactions: predictions from in vitro data.

In vitro data can predict in vivo metabolic drug-drug interactions, but issues remain in estimation of inhibitor concentration and in vivo inhibition constants.

Metabolism of zaleplon by human liver: evidence for involvement of aldehyde oxidase

Zaleplon metabolism in human liver is primarily catalyzed by aldehyde oxidase, with products dependent on both aldehyde oxidase and CYP3A forms.

Inhibition of zaleplon metabolism by cimetidine in the human liver: in vitro studies with subcellular fractions and precision-cut liver slices

Cimetidine inhibits zaleplon metabolism in the human liver, with a more potent inhibitory effect on aldehyde oxidase than CYP3A forms, potentially impacting M2 formation in vivo.

Optimizing Drug Development: Strategies to Assess Drug Metabolism/Transporter Interaction Potential—Toward a Consensus

This conference aimed to establish a consensus on the conduct of in vitro and in vivo studies of metabolic and transport interactions in drug development, aiming to optimize drug development and reduce drug-drug interactions.

Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential--towards a consensus.

This conference aimed to establish a consensus on the conduct of in vitro and in vivo studies of drug metabolism/transporter interaction potential, aiming to optimize drug development and reduce risk.

Aldehyde oxidase-dependent marked species difference in hepatic metabolism of the sedative-hypnotic, zaleplon, between monkeys and rats.

Aldehyde oxidase activity plays a key role in the hepatic metabolism of zaleplon, a sedative-hypnotic, between rats and monkeys.

Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver.

Deamination plays a crucial role in the biotransformation of citalopram and its demethylated metabolites, particularly in the brain, where cytochrome P450 plays a low role.

In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver.

Famciclovir and 6-deoxypenciclovir are oxidized to 6-oxo-famciclovir and penciclovir by human, guinea pig, rabbit, and rat liver aldehyde oxidase, with xanthine

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