Oxidative Metabolic Pathway of Lenvatinib Mediated by Aldehyde Oxidase

@article{Inoue2014OxidativeMP,
  title={Oxidative Metabolic Pathway of Lenvatinib Mediated by Aldehyde Oxidase},
  author={Kazuko Inoue and Hitoshi Mizuo and Shinki Kawaguchi and Katsuyuki Fukuda and Kazutomi Kusano and Tsutomu Yoshimura},
  journal={Drug Metabolism and Disposition},
  year={2014},
  volume={42},
  pages={1326 - 1333}
}
Lenvatinib is a multityrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors, and is being developed as an anticancer drug. P450s are involved in one of the elimination pathways of lenvatinib, and mono-oxidized metabolites, such as N-oxide (M3) and desmethylated metabolite (M2), form in rats, dogs, monkeys, and humans. Meanwhile, two other oxidative metabolites are produced only in monkey and human liver S9 fractions, and their structures have been identified using… 
Aldehyde oxidase at the crossroad of metabolism and preclinical screening
TLDR
Different in silico, in vitro and in vivo methods for the prediction of AOX metabolizing ability are described and the existing drawbacks and challenges associated with these approaches are focused on.
The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib.
TLDR
The present study indicates that further research focused on drug-drug interactions, in particular on CYP3A4 and CYP1A1 modulators, is needed, to pave new avenues towards TKIs-mediated personalized therapy.
Aldehyde oxidase and its role as a drug metabolizing enzyme.
TLDR
A comprehensive monograph of AO as a drug metabolizing enzyme with emphasis on marketed drugs as well as other xenobiotics, as substrates and inhibitors with the focus on developmental candidates reported in the past five years with regards to pharmacokinetics and toxicity.
Inhibition of Human Aldehyde Oxidase Activity by Diet-Derived Constituents: Structural Influence, Enzyme-Ligand Interactions, and Clinical Relevance
TLDR
Quantitative structure-activity relationship modeling identified three structural descriptors that correlated with inhibition potency (r2 = 0.85), providing a framework for developing in silico models to predict the AO inhibitory activity of a xenobiotic based solely on chemical structure.
Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison
TLDR
The objective of the current study was to further elucidate the metabolic pathways of lenvatinib in humans and to compare these results to the metabolism in rats and monkeys and to identify metabolites seem to be unique to the investigated species.
Evaluation of species differences in the metabolism of the selective NaV1.7 inhibitor DS-1971a, a mixed substrate of cytochrome P450 and aldehyde oxidase
TLDR
In vitro incubation studies could provide information reflecting the in vivo plasma metabolite profiles in mice and monkeys, and the results obtained from the incubation with the human liver S9 fraction and NADPH suggested that a major circulating metabolite in humans is M1, a regioisomer of M2.
Cytochrome P450 and Non–Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics
TLDR
This series of articles provides additional support for the role of non-P450–mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.
Non-cytochrome P450 enzymes involved in the oxidative metabolism of xenobiotics: Focus on the regulation of gene expression and enzyme activity.
TLDR
Overall, this review focuses on the potential xenobiotic factors that contribute to variations in gene expression levels and the activities of non-CYP450 enzymes.
An overview of aldehyde oxidase: an enzyme of emerging importance in novel drug discovery
TLDR
The recent success in resolving the hAOX crystal structure can too be another valuable data source for the study of AOX-catalyzed metabolism of new drug candidates, using computer-aided drug discovery methods.
Metabolism by aldehyde oxidase: drug design and complementary approaches to challenges in drug discovery.
TLDR
The authors' recommendation is an early consideration of AO-mediated metabolism supported by computational and in vitro experimental methods, but not an automatic avoidance of Ao structural flags, many of which are versatile and valuable building blocks.
...
1
2
3
...

References

SHOWING 1-10 OF 19 REFERENCES
Unique Metabolic Pathway of [14C]Lenvatinib after Oral Administration to Male Cynomolgus Monkey
TLDR
A unique metabolic pathway for lenvatinib in monkey and the proposed formation mechanism have been elucidated on the basis of accurate mass and NMR measurements.
Strategies for a comprehensive understanding of metabolism by aldehyde oxidase
TLDR
As the role of AO in metabolism of new drug molecules continues to emerge, it is critical that DMPK scientists have the most updated methodologies to enable formulation of a thorough experimental plan to understand the potential implications of this metabolic pathway.
Potent inhibition of human liver aldehyde oxidase by raloxifene.
  • R. Obach
  • Chemistry, Medicine
    Drug metabolism and disposition: the biological fate of chemicals
  • 2004
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
Species-Specific Metabolism of SGX523 by Aldehyde Oxidase and the Toxicological Implications
TLDR
It is proposed that M11 is likely involved in the observed obstructive nephropathy reported in clinical studies, and illustrates the need to conduct thorough metabolic evaluations early in drug development to select the most relevant nonclinical species for toxicological evaluation.
Drug-metabolizing ability of molybdenum hydroxylases.
TLDR
Drug-drug interactions associated with aldehyde oxidase and xanthine oxidoreductase are of potential clinical significance and the variation of the activity is described in this review.
Aldehyde oxidase activity and inhibition in hepatocytes and cytosolic fractions from mouse, rat, monkey and human.
TLDR
Cryopreserved hepatocytes and cytosolic fractions from animals and humans provide qualitatively similar data within the species, indicating that results from animal studies cannot be safely extrapolated to humans.
Quantitative study of the structural requirements of phthalazine/quinazoline derivatives for interaction with human liver aldehyde oxidase.
Aldehyde oxidase is a molybdenum-containing enzyme distributed throughout the animal kingdom. Although this enzyme is capable of metabolizing a wide range of aldehydes and N-heterocyclic compounds,
Inhibition of zaleplon metabolism by cimetidine in the human liver: in vitro studies with subcellular fractions and precision-cut liver slices
  • A. Renwick, S. Ball, +5 authors B. Lake
  • Chemistry, Medicine
    Xenobiotica; the fate of foreign compounds in biological systems
  • 2002
TLDR
Cimetidine appears to be a more potent inhibitor of aldehyde oxidase than of CYP3A forms and hence in vivo is likely to have a more marked effect on ZAL metabolism to M2 than on DZAL formation.
Aldehyde oxidase-dependent marked species difference in hepatic metabolism of the sedative-hypnotic, zaleplon, between monkeys and rats.
TLDR
N-Desethyl-Zaleplon was formed in the presence of NADPH by microsomes from the liver of rats and monkeys, and its formation was strongly suggested using various cytochrome P-450 inhibitors to be mediated by a number of cytochrom P- 450 isoforms, such as 3A, 2C, and 2D subfamilies.
Case report of extensive metabolism by aldehyde oxidase in humans: Pharmacokinetics and metabolite profile of FK3453 in rats, dogs, and humans
TLDR
Results suggest M4 formation is catalyzed by AO, and therefore, its poor exposure in humans was attributed to extensive AO metabolism.
...
1
2
...