In vivo drug interactions of itopride and trimethylamine mediated by flavin-containing monooxygenase 3 in humanized-liver mice

• Published in: Drug metabolism and pharmacokinetics 2021-04, Vol.37, p.100369, Article 100369
• Main Authors: Shimizu, Makiko, Uehara, Shotaro, Suemizu, Hiroshi, Yamazaki, Hiroshi
• Format: Article
• Language: English
• Subjects: Clearance; FMO3; Hepatic intrinsic clearance; Itopride N-oxide; Trimethylamine N-oxide
• ISSN: 1347-4367; 1880-0920
• DOI: 10.1016/j.dmpk.2020.11.004

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. [Display omitted]