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

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ABSTRACT

Rat and human liver microsomes oxidized ranitidine to its N-oxide (66-76%) and S-oxide (13-18%) and desmethylranitidine (12-16%). A- 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 FMOl, FM02, FM03 and FM05 produced 39, 79, 2180 and 4 ranitinine N-oxide and 45, 0, 580 and 280 ranitinine 5-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. FM03, the major form in adult liver, produced both ranitidine A- and 5-oxides at a 4 to 1 ratio. FMOl, expressed primarily in human kidney, was 55- and 13-fold less efficient than the hepatic FM03 in producing ranitidine A- and 5-oxides, respectively. FM02 and FM05, although expressed slightly in human liver, kidney and lung, were not efficient producers of ranitidine A- and 5-oxides. Thus, urinary contents of ranitidine N-oxide can be used as the in vivo probe to determine the hepatic FM03 activity.

Keywords:

Ranitidine N-oxide
Ranitidine 5-oxide
Desmethylranitidine
Flavin-containing monooxygenase probe
Cytochrome P450

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