Abstract
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, 0.8 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.