Interaction of Cimetidine with Liver Microsomes

Abstract

1. Cimetidine interacts with liver microsomes from rats pretreated with different inducers of cytochrome P-450 (not reduced) to produce characteristic absorption spectra. Maxima were at 429, 457 and 585 nm, and minima at 392 and 567 nm.

2. In experiments with microsomes from control rats and rats pretreated with phenobarbital, Clophene ® 60 or Clophene ® 30, and with solubilized, partially purified cytochrome P-450 from phenobarbital-pretreated rabbits, the interactions were biphasic, while those of microsomes from rats pretreated with 3-methylchoianthrene were monophasic.

3. Diethylphenylphosphine competitively displaced cimetidine from the active site of cytochrome P-450.

4. The O-dealkylation of 7-ethoxycoumarin was competitively inhibited by the presence of cimetidine. K₁ values were 0.33 mM and 0.18 mM at 0.75 and 0.25 mM cimetidine, respectively.

5. The structurally similar compound 2 (N″-cyano-N-methyl-N'-{2-[(4-methyl- oxazol-5-yl)methylthio]ethyl}guanidine) shows a higher affinity than cimetidine in the ligand interaction with cytochrome P-450, and a higher inhibition rate in 7-ethoxycoumarin dealkylation (K_i= 0.3 mM at inhibitor concn. of 0.5 mM).

6. The e.p.r. spectra of cytochrome P-450 from phenobarbital-pretreated rats, in the presence of cimetidine and of compound 2, were modified by the occurrence of new signals, at aboutg= 2.51 and g=1.88. Ligand field parameters favour the amine and the imidazole nitrogens as possible ligands.