Analysis of the inhibition of pethidine N-demethylation by monoamine oxidase inhibitors and some other drugs with special reference to drug interactions in man.

1. N-Demethylation of pethidine was studied in microsomal suspensions from unstarved male rat liver and the N-demethylase identified as belonging to the class of hepatic microsomal mixed function oxidases.2. A study of the structure/action relationships of compounds inhibiting pethidine N-demethylase revealed that hydrazine derivatives including phenylhydrazine, methylphenylhydrazine and mebanazine were all potent competitive inhibitors.3. Pethidine N-demethylase was only slightly inhibited by histamine and amphetamine but not by adrenaline and ephedrine nor by several miscellaneous compounds including piperidine, N-ethylpiperidine, N-methylpiperidine, N-methylammonium, hydrallazine or pethidinic acid.4. Several psychotropic drugs were all found to be potent competitive inhibitors of pethidine N-demethylase. These included monoaminoxidase inhibitors (the most active being nialamide and phenoxypropazine [K(i)=0.01 mM]; the least active iproniazid [K(i)=1.05 mM]); the tranquillizers promazine, propiomazine and chlorpromazine and tricyclic antidepressants (opipramol [K(i)=0.01 mM], imipramine [K(i)=0.03 mM], desipramine [K(i)=0.03 mM] and amitryptyline [K(i)=0.03 mM]). Hydrocortisone [K(i)=0.3 mM], prednisolone [2.8 mM] and nalorphine [0.07 mM] were also inhibitors, whilst SKF 525A was the most active of all [K(i)=0.002 mM].5. These results are discussed in relation to the clinically observed drug interactions which may occur between monoamineoxidase inhibitors and pethidine. It is concluded that since many different groups of drugs, including monoamineoxidase inhibitors, tranquillizers, tricyclic antidepressants, steroids, nalorphine, SKF 525A and barbiturates compete for cytochrome P(450) reductase, it is possible that this mechanism may account, at least in part, for the observed interactions of these various drugs in man.