Differential Effects of GPA 1851 on Hepatic Microsomal Drug Metabolism Dependent on Dosage and Time of Sacrifice

Abstract

Investigations of effects exerted by various compounds on hepatic microsomal mixed function oxidases are frequently designed for and performed under a single set of conditions with respect to dosage and time of sacrifice after drug administration. From these data a generalization may be derived as to whether a particular drug inhibits, induces or produces no change in these enzymes. Limitations of this approach are illustrated by experiments with GPA 1851, an imidazolone derivative with anti-inflammatory properties. Two hours after a single oral dose of 50 mg/kg, rat hepatic microsomal aniline hydroxylase and ethylmorphine N-demethylase activities were markedly reduced, whereas if the rats were sacrificed 24 h after this oral dose, aniline hydroxylase activity and cytochrome P-450 were enhanced. When rats were sacrificed 24 h after the last of 4 daily oral doses of GPA 1851, no significant change occurred in aniline hydroxylase or ethylmorphine N-demethylase activities, but cytochrome P-450 content was elevated.