Interaction of ranitidine with liver microsomes

Abstract

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. Cytochrome P-450 reduced with dithionite in the presence of ranitidine produced substrate difference spectra with a peak at 447 nm. Ks [spectral dissociation constant] values for the interaction of ranitidine with cytochrome P-450 (not reduced), calculated from double reciprocal plots, were 1.4-2.8 mM. 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 [inhibition constant intercept]and Kis [inhibition constant slope] values were: for inhibition of 7-ethoxycoumarin dealkylation, 0.8-9 and 0.16-0.67 mM, respectively; for inhibition of p-nitroanisole dealkylation, 5.8-13.7 and 1-4.5 mM, respectively. The I50 [median inhibitory concentration] value for 7-ethoxycoumarin dealkylation was 1.8 mM and for p-nitronisole dealkylation .apprx. 7.2 mM (microsomes from phenobarbital-pretreated rats). The EPR spectra of cytochrome P-450 from phenobarbital-pretreated rats, in the presence of ranitidine, reveal 2 types of interaction depending on the ranitidine concentration. At lower concentrations of ranitidine, a ligand exchange reaction with an O atom is indicated, and at higher concentrations are with nitrogenous or thioether ligand of ranitidine.