Potential for drug interactions mediated by polymorphic flavin-containing monooxygenase 3 in human livers.

Drug metabolism and pharmacokinetics (2015-03-12)
Makiko Shimizu, Arisa Shiraishi, Ayumi Sato, Satomi Nagashima, Hiroshi Yamazaki
RESUMEN

Human flavin-containing monooxygenase 3 (FMO3) in the liver catalyzes a variety of oxygenations of nitrogen- and sulfur-containing medicines and xenobiotic substances. Because of growing interest in drug interactions mediated by polymorphic FMO3, benzydamine N-oxygenation by human FMO3 was investigated as a model reaction. Among the 41 compounds tested, trimethylamine, methimazole, itopride, and tozasertib (50 μM) suppressed benzydamine N-oxygenation at a substrate concentration of 50 μM by approximately 50% after co-incubation. Suppression of N-oxygenation of benzydamine, trimethylamine, itopride, and tozasertib and S-oxygenation of methimazole and sulindac sulfide after co-incubation with the other five of these six substrates was compared using FMO3 proteins recombinantly expressed in bacterial membranes. Apparent competitive inhibition by methimazole (0-50 μM) of sulindac sulfide S-oxygenation was observed with FMO3 proteins. Sulindac sulfide S-oxygenation activity of Arg205Cys variant FMO3 protein was likely to be suppressed more by methimazole than wild-type or Val257Met variant FMO3 protein was. These results suggest that genetic polymorphism in the human FMO3 gene may lead to changes of drug interactions for N- or S-oxygenations of xenobiotics and endogenous substances and that a probe battery system of benzydamine N-oxygenation and sulindac sulfide S-oxygenation activities is recommended to clarify the drug interactions mediated by FMO3.

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Supelco
Hydrogen chloride – 2-propanol solution, ~1.25 M HCl (T), for GC derivatization, LiChropur
Supelco
Hydrogen chloride – methanol solution, ~1.25 m HCl (T), for GC derivatization, LiChropur
Sigma-Aldrich
Trimethylamine, anhydrous, ≥99%
Sigma-Aldrich
Trimethylamine solution, 43.0-49.0% in H2O (T)
Sigma-Aldrich
Trimethylamine solution, 31-35 wt. % in ethanol, 4.2 M, contains toluene as stabilizer
Sigma-Aldrich
Trimethylamine solution, 25 wt. % in H2O
Supelco
Methimazole, analytical standard
Sigma-Aldrich
2-Mercapto-1-methylimidazole, ≥99%
Sigma-Aldrich
Sulindac, ≥98.0%
Supelco
Methimazole, VETRANAL®, analytical standard
Thiamazole, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Sulindac sulfide, ≥98% (HPLC), solid
USP
Methimazole, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Trimethylamine solution, 25 wt. % in propylene glycol
Sigma-Aldrich
Sulindac, meets USP testing specifications
Sulindac, European Pharmacopoeia (EP) Reference Standard