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

• Published in: Japanese Journal of Pharmacology 2000, Vol.84(2), pp.213-220
• Main Authors: Chung, Woon-Gye, Park, Chang-Shin, Roh, Hyung-Keun, Lee, Woon-Kee, Cha, Young-Nam
• Format: Article
• Language: English
• Subjects: Animals; Antithyroid Agents - pharmacology; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Desmethylranitidine; Drug Interactions; Enzyme Inhibitors - pharmacology; Flavin-containing monooxygenase probe; Histamine H2 Antagonists - metabolism; Humans; In Vitro Techniques; Isoenzymes - genetics; Isoenzymes - metabolism; Male; Methimazole - pharmacology; Microsomes, Liver - metabolism; Oxygenases - genetics; Oxygenases - metabolism; Proadifen - pharmacology; Ranitidine - metabolism; Ranitidine 5-oxide; Ranitidine N-oxide; Ranitidine S-oxide; Rats; Rats, Sprague-Dawley; Recombinant Proteins - metabolism
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1254/jjp.84.213

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.