Oxidation of Ranitidine by Isozymes of Flavin-Containing Monooxygenase and Cytochrome P450

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Rat and human liver microsomes oxidized ranitidine to its N−oxide(66−76%)and S−oxide(13−18%)and desmethylranitidine(12−16%).N− and S−oxidations of ranitidine were inhibited by metimazole [flavin−containing monooxygenase(FMO)inhibitor] to 96−97% and 71−85%, respectively, and desmethylation of ranitidine was inhibited by SKF525A [cytochrome P450(CYP)inhibitor] by 71−95%.Recombinant FMO isozymes like FMO1, FMO2, FMO3 and FMO5 produced 39, 79, 2180 and 4 ranitinine N−oxide and 45, 0, 580 and 280 ranitinine S−oxide pmol·min-1·nmol-1 FMO, respectively.Desmethyranitinine was not produced by recombinant FMOs.Production of desmethylranitidine by rat and human liver microsomes was inhibited by tranylcypromine, α−naphthoflavon and quinidine, which are known to inhibit CYP2C19, 1A2 and 2D6, repectively.FMO3, the major form in adult liver, produced both ranitidine N− and S−oxides at a 4 to 1 ratio.FMO1, expressed primarily in human kidney, was 55− and 13−fold less efficient than the hepatic FMO3 in producing ranitidine N− and S−oxides, respectively.FMO2 and FMO5, although expressed slightly in human liver, kidney and lung, were not efficient producers of ranitidine N− and S−oxides.Thus, urinary contents of ranitidine N−oxide can be used as the in vivo probe to determine the hepatic FMO3 activity.
2000-10-01