In vivo drug interactions of itopride and trimethylamine mediated by flavin-containing monooxygenase 3 in humanized-liver mice.
Drug Metab Pharmacokinet
; 37: 100369, 2021 Apr.
Article
em En
| MEDLINE
| ID: mdl-33513464
ABSTRACT
Flavin-containing monooxygenase (FMO) catalyzes the oxygenation of a wide variety of medicines and dietary-derived compounds. However, little information is available regarding drug interactions mediated by FMO3 in vivo. Consequently, we investigated interactions between FMO substrates in humanized-liver mice. Trimethylamine-d9 and itopride were, respectively, intravenously and orally administered to humanized-liver mice (n = 5-7). The pharmacokinetic profiles of itopride (the victim drug) in the presence of trimethylamine (the perpetrator drug) were determined for 24 h after co-administration using liquid chromatography/tandem mass spectrometry. Itopride (10 mg/kg) was extensively oxygenated in humanized-liver mice to its N-oxide. The plasma concentrations of itopride N-oxide after co-administration of itopride and trimethylamine (10 and 100 mg/kg) were significantly suppressed in a dose-dependent manner, but only during the early phase, i.e., up to 2 h after co-administration. With the higher dose of trimethylamine, the areas under the concentration-time curves of itopride and its N-oxide significantly increased (1.6-fold) and decreased (to 60%), respectively; modeling suggested that these modified pharmacokinetics resulted from suppression of the in vivo hepatic intrinsic clearance (to 67%). These results suggest that food-derived trimethylamine may result in interactions with FMO drug substrates immediately after administration; however, the potential for this to occur in vivo may be limited.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxigenases
/
Benzamidas
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Compostos de Benzil
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Fígado
/
Metilaminas
Limite:
Animals
Idioma:
En
Revista:
Drug Metab Pharmacokinet
Assunto da revista:
FARMACOLOGIA
/
METABOLISMO
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão