EFFECTS OF VARIOUS CENTRALLY ACTIVE DRUGS ON HEPATIC MICROSOMAL ENZYMES: A COMPARATIVE STUDY

¹ Department of Pharmacology, The Milton S. Hershey Medical Center, The Pennsylvania State University

The extent to which six centrally active drugs stimulated hepatic microsomal enzymes of mature male rats was compared. Of the three parameters examined, diphenylhydantoin enhanced only ethylmorphine N-demethylase activity and cytochrome P-450 content, whereas the other five drugs stimulated aniline hydroxylase activity as well. By measuring changes in these microsomal systems after 3, 7, and 14 days of drug administration, the stimulatory capacities of the six drugs were determined and compared. The stimulatory capacity of each drug was related to its dose and varied considerably in the temporal pattern exhibited. Near maximal stimulation of all three parameters occurred very early with phenobarbital (after three daily injections), whereas chlorpromazine, diazepam, meprobamate, and diphenylhydantoin produced maximal stimulatory responses only after 7-14 daily injections. Daily administration of high doses of diphenylhydantoin or ethanol decreased the activity or content of at least one of the three microsomal systems under investigation. On a molar basis, phenobarbital was the most potent stimulatory agent after three daily injections; at this time the other five drugs were generally similar to one another. In the doses employed in this study, only phenobarbital produced more than 2-fold stimulation of all three microsomal parameters. After 7 days of administration, diphenylhydantoin elevated ethylmorphine N-demethylase activity 240% above control values.