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

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 microso...

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Bibliographic Details
Published in:Xenobiotica 2005-05, Vol.35 (5), p.499-517
Main Authors: Tachibana, S., Tanaka, M., Fujimaki, Y., Suzuki, W., Ookuma, T., Ohori, Y., Hayashi, K.-I., Iwata, H., Okazaki, O., Sudo, K.-I.
Format: Article
Language:English
Subjects:
Animals
Biotransformation
Calmodulin - antagonists & inhibitors
Calmodulin antagonist
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - metabolism
DY-9760e
Escherichia coli
Escherichia coli - enzymology
Escherichia coli - genetics
glucuronidation
Humans
imidazole
imidazole oxidation
in vitro-in vivo comparison
Indazoles - chemistry
Indazoles - pharmacokinetics
Macaca fascicularis
Magnetic Resonance Spectroscopy
Male
metabolism
Microsomes, Liver - enzymology
NADPH-Ferrihemoprotein Reductase - metabolism
Rats
Rats, Wistar
Recombinant Proteins
ring opening
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Summary: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.
ISSN:0049-8254
1366-5928
DOI:10.1080/00498250500136692