Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450.
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.
Chung
W G
WG
Department of Pharmacology and Medicinal Toxicology Research Center, Inha University, Inchon, Korea.
Park
C S
CS
Roh
H K
HK
Lee
W K
WK
Cha
Y N
YN
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D011899:Ranitidine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism
D013956:Antithyroid Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006635:Histamine H2 Antagonists; D007527:Isoenzymes; D011994:Recombinant Proteins; D008713:Methimazole; D011899:Ranitidine; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)