The Modification of Hepatic Microsomal Drug Metabolism by Phenobarbital and D-Amphetamine

Abstract

Louis-Ferdinand, Robert Thomas, Ph.D. , University of Rhode Island August, 1969. The Modification of Hepatic Microsomal Drug Metabolism by Phenobarbital and Amphetamine. Major Professor: Dr. George C. Fuller. This investigation was carried out to provide a mechanistic explanation for the modification of hepatic microsomal drug metabolism produced by amphetamine· and phenobarbital. The influence of phenobarbital administration on the activity of microsomal ribonuclease during induction of drug-metabolizing enzymes, was determined. Administration of phenobarbital (100 mg/kg) for six days resulted in a significant (P .£0. 05) increase in hepatic microsomal oxidative demethylation. Conversely, hepatic microsomal ribonuclease activity of phenobarbital-treated rats was significantly reduced to less than 5% of control values. When phenobarbital (50 mg/kg) was administered for 5 days ribonuclease activity was inhibited to about one-half of control values. Phenolpthalein {3-glucuronidase activity of hepatic microsomal fractions obtained from phenobarbital treated animals was not significantly (P) O. 05) different from controls. Phenobarbital(lxlo-\1olar) did not inhibit ribonuclease activity following in vitro additions to the assay system. Time-response studies were. conducted following the administration of a single dose of phenobarbital (100 mg/kg). Results of these studies indicated that microsomal p-chloro-N-methylaniline (PCMA) demethylase stimulation and ribonuclease inhibition were temporaily related, except for a 24 hour lag in the PCMA demethylase response. Administration of phenobarbital (50 mg/kg twice-daily) produced significant inhibition of ribonuclease and stimulaticn of drug metabolism in liver microsomes of intact, adrenalectomized or hypophysectomized rats. Administration of 3-methylcholanthrene (40 mg/kg) to male rats resulted in a non-significant inhibition of ribonuclease activity while p-nitroanisole demethylation was stimulated three-fold. In vitro recombination experiments in which 105, 000 x g rat liver supernatants from control and treated animals were combined ·with rnicrosomes