Interaction of ranitidine with liver microsomes.
1. Ranitidine interacts with liver microsomes from rats pretreated with different inducers of cytochrome P-450 to produce substrate difference optical spectra with a peak at 426-429 nm and a trough at 390-400 nm. 2. Cytochrome P-450 reduced with dithionite in the presence of ranitidine produced substrate difference spectra with a peak at 447 nm. 3. Ks values for the interaction of ranitidine with cytochrome P-450 (not reduced), calculated from double reciprocal plots, were in the range 1.4-2.8 mM. 4. The O-dealkylation of 7-ethoxycoumarin and of p-nitroanisole was inhibited by the presence of ranitidine and the inhibition was of a mixed type. Kii and Kis values were: for inhibition of 7-ethoxycoumarin dealkylation, 0.8 to 9 mM, and 0.16 to 0.67 mM, respectively; for inhibition of p-nitroanisole dealkylation, 5.8 to 13.7 mM, and 1 to 4.5 mM, respectively. 5. The I50 values for 7-ethoxycoumarin dealkylation was 1.8 mM and for p-nitroanisole dealkylation about 7.2 mM (microsomes from phenobarbital-pretreated rats). 6. The e.p.r. spectra of cytochrome P-450 from phenobarbital-pretreated rats, in the presence of ranitidine, reveal two types of interaction depending on the ranitidine concentration. At lower concentrations of ranitidine, a ligand exchange reaction with an oxygen atom is indicated, and at higher concentrations are with nitrogenous or thioether ligand of ranitidine.
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005663:Furans / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011899:Ranitidine; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
D005663:Furans; D006635:Histamine H2 Antagonists; D004364:Pharmaceutical Preparations; D011899:Ranitidine; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital