The metabolic fate of [<sup>3</sup>H]econazole in man

Midgley, I.; Bladeren, P.J. van; Hawkins, David R.; Chasseaud, L. F.; Darragh, A.; Brodie, R.R.; Walmsley, L.M.

doi:10.3109/00498258109045871

Cited by 21 publications

(9 citation statements)

References 7 publications

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“…During this study, two oxidative metabolites of the imidazole ring of DY-9760e were identified. Similar oxidation of the imidazole ring moiety has been reported for ketoconazole, econazole, nafimidone, and croconazole (Midgley et al 1981;Girkin et al 1983;Nakano et al 1989;Rush et al 1990;Whitehouse et al 1994). Two oxidative metabolites of the imidazole ring of ketoconazole were found in mouse liver after oral administration.…”

Section: Discussionsupporting

confidence: 57%

Metabolism of the calmodulin antagonist DY-9760e in animals and humans

Tachibana¹,

Tanaka²,

Fujimaki³

et al. 2005

Xenobiotica

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The in vitro metabolism of the calmodulin antagonist DY-9760e was investigated using liver microsomes from humans and three other animal species and compared with the in vivo metabolism in rats after intravenous administration of DY-9760e. Seven major metabolites were produced by human liver microsomes by the following metabolic pathways: N-dealkylation, phenyl hydroxylation, O-demethylation and imidazole oxidation. These metabolites were also produced by liver microsomes from monkeys, dogs and rats; additionally, a hydroxylated derivative of the indazole moiety was produced only by rat microsomes. To identify the structures of two imidazole ring metabolites whose authentic compounds could not be obtained, Escherichia coli co-expressing human cytochrome P450 CYP3A4 and NADPH-P450 reductase was used to biosynthesize these metabolites. NMR spectra elucidated the precise structures; oxidation occurred at the imidazole ring, and the subsequent ring-opening resulted in the generation of amide and formylamine groups. Glucuronide conjugates of the hydroxylated and O-demethylated derivatives were major components in rat bile. Therefore, DY-9760e metabolites generated in vitro correspond to the aglycones of the major metabolites observed in rat bile.

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Section: Discussionsupporting

confidence: 57%

Metabolism of the calmodulin antagonist DY-9760e in animals and humans

Tachibana¹,

Tanaka²,

Fujimaki³

et al. 2005

Xenobiotica

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“…Econazole (Fig. 7) undergoes the imidazole oxidations into the 2,4-dioxo-, 2-hydroxy-5-oxo-and 2,5-dioxo derivatives in humans and excreted in the urine as glucuronides after the O-dealkylations 46) .…”

Section: Placements Of Imidazole Fungicidesmentioning

confidence: 99%

Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system

2020

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Human CYP3A4 is involved in metabolisms of diverse hydrophobic chemicals. Using the data of therapeutic azole fungicides known to interact with CYP3A4, applicability of CYP3A4 Template system was first confirmed to reconstitute faithfully the interaction on Template. More than twenty numbers of pesticide azoles were then applied to the Template system. All the azole stereo-isomers applied, except for talarozole, interacted through nitrogen atoms of triazole or imidazole parts and sat stably for inhibitions through fulfilling three-essential interactions. For their CYP3A4-mediated oxidations, clear distinctions were suggested among the enantiomers and diastereomers of azole pesticides on Templates. Thus, the stereoisomers would have their-own regio-and stereo-selective profiles of the metabolisms. A combined metabolic profile of each azole obtained with CYP3A4 Template system, however, resembled with the reported profile of the in vivo metabolism in rats. These results suggest the major roles of CYP3A forms on the metabolisms of most of azole pesticides in both rats and humans. Free triazole is a metabolite of azole fungicides having a methylene-spacer between triazole and the rest of the main structures in experimental animals and humans. During the simulation experiments, a placement for the oxidation of a methylene spacer between the triazole and main carbon-skeleton was found to be available throughout the azole fungicides tested on Template. The occurrence of this reaction to lead to triazole-release is thus discussed in relation to the possible involvement of CYP3A forms.

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“…39 Despite showing promising activity in vitro against each of these diseases, oral and intravenous administration have proven ineffective due to the poor pharmacokinetics of the drug, which has no gastrointestinal absorption, and rapidly undergoes metabolism and protein binding in the blood stream. 36,40 As such, a prodrug system capable of increasing the effective dose of econazole could be beneficial to the treatment of a number of conditions. Ruthenium complexes with 1 or 2 econazole ligands were prepared in a single step in moderate yield from reaction of econazole nitrate with [Ru(phen) 2 Cl 2 ] (phen = 1,10phenanthroline).…”

mentioning

confidence: 99%

“…This is encouraging for the development of a prodrug of econazole as the free drug is rapidly metabolized to inactive products in vivo. 36,40 The photolytic stability of the complexes was monitored by UV-visible absorbance and emission spectroscopy, and mass spectrometry. An aqueous solution of 2 was irradiated with green light (520 nm) for 1 h (53 J cm -2 ) and changes in its spectra monitored over time.…”

mentioning

confidence: 99%