INHIBITION OF DRUG-METABOLIZING ENZYMES OF LIVER MICROSOMES BY HYDRAZINE DERIVATIVES IN RELATION TO THEIR LIPID SOLUBILITY

Abstract

The activity of drug-metabolizing enzymes of liver microsomes is inhibited by various compounds and the administration of these compounds markedly alters the pharmacological activities of other drugs (1-3). Iproniazid is a well-known inhibitor of monoamine oxidase and it was the first compound of hydrazine derivatives as the inhibitor of drug metabolizing enzymes (4). Moreover, the other monoamine oxidase inhibitors, such as JB 516 (phenylisopropylhydrazine) and W 1544 (phenethylhydrazine) inhibited the metabolism of hexobarbital and meprobamate (5-7). La Roche and Brodie (6) showed that the activity of these compounds as the inhibitor of hexobarbital metabolism is not related to their ability to inhibit monoamine oxidase. On the other hand, it has been established that the compounds of low lipid solubility are not metabolized by liver microsomes (8). It is, therefore, likely that the lipid solubility of hydrazine derivative may be an important factor for the inhibition of drug-metabolizing enzymes. In the present communication, we wish to report that isoniazid and many other hydrazine derivatives inhibit the oxidation of hexobarbital, pentobarbital, meprobamate and carisoprodol and the N-demethylation of aminopyrine both in vitro and in vivo in relation to their lipid solubility. These results are typical example to show that the lipid solubility of compounds is more important factors rather than their chemical configuration for the inhibition of drugmetabolizing enzymes of liver microsomes.