Jpn. J. Pharmacol. 84 (2), 213-220 (2000)

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

Woon-Gye Chung¹, Chang-Shin Park¹, Hyung-Keun Roh², Woon-Kee Lee³ and Young-Nam Cha^1,*

¹Department of Pharmacology and Medicinal Toxicology Research Center, and ²Department of Internal Medicine,
College of Medicine, Inha University, Inchon 402-751, Korea
³Department of General Surgery, Gil Medical Center, Gachon Medical School, Inchon 405-760, Korea
*Corresponding author.ﾊﾊFAX:+82-32-885-8303
E-mail: youngnam@dragon.inha.ac.kr

Abstract: 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ﾊ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ﾊ睫min^-1ﾊ睫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.

Keywords: Ranitidine N-oxide, Ranitidine S-oxide, Desmethylranitidine, Flavin-containing monooxygenase probe, Cytochrome P450