Date of Award

1970

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

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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