Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450

Jpn J Pharmacol. 2000 Oct;84(2):213-20. 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%). 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 x min(-1) x nmol(-1) FMO, respectively. Desmethyranitinine was not produced by recombinant FMOs. Production of desmethylranitidine by rat and human liver microsomes was inhibited by tranylcypromine, a-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antithyroid Agents / pharmacology
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • 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*
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / metabolism


  • Antithyroid Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Histamine H2 Antagonists
  • Isoenzymes
  • Recombinant Proteins
  • Methimazole
  • Ranitidine
  • Cytochrome P-450 Enzyme System
  • Proadifen
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)