Abstract

Six barbiturates were compared with respect to the extent that they stimulated hepatic microsomal enzymes of mature male rats after 1, 3, 7, and 14 days of daily ip drug administration. Phenobarbital, pentobarbital, secobarbital, thiopental, and barbital stimulated ethylmorphine N-demethylase and aniline hydroxylase activities and increased microsomal cytochrome P-450 content. Considerable temporal differences occurred among these barbiturates in maximal stimulatory responses. Stimulatory responses approached or exceeded 200% of control values after 3, 7, and 14 days of daily phenobarbital (100 mg/kg) administration. Responses exceeding 200% of control values were elicited by barbital (150 mg/kg) during the 14-day observation period. Considerably less stimulation occurred with pentobarbital, secobarbital, and thiopental, and none with hexobarbital. Compared on a molar basis, phenobarbital was the most potent stimulatory agent for each microsomal parameter after three daily ip injections. Correlation coefficients between partition coefficients for these six barbiturates and their stimulatory potencies were less than 0.45 and were considered not to be biologically significant. Oral administration of phenobarbital (100 mg/kg), secobarbital (75 mg/kg), or hexobarbital (150 mg/kg) for 3 consecutive days did not significantly alter the stimulatory response of an identical ip dose of each barbiturate. An association appears to exist between plasma half-lives of phenobarbital (10.1 hr), pentobarbital (2.3 hr), and hexobarbital (36.2 min) and their stimulatory potencies. Hepatic radioactivity 24 hr after administration of these three barbiturates was directly related to their stimulatory potencies.