Date of Award

1970

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Interdepartmental Program

First Advisor

George C. Fuller

Abstract

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 β-glucuronidase activity of hepatic microsomal fractions obtained from phenobarbital treated animals was not significantly (P> 0.05) different from controls. Phenobarbital (1x10-2 Molar) 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 temporarily 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 stimulation 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.

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