The effect of chronic phenobarbital administration on some hepatic drug-metabolizing enzyme activities in the rat

Abstract

Prolonged administration of phenobarbital produces an increase in hepatic microsomal drug-metabolizing enzyme activity in some animals. Burns and Conney 1 gave phenobarbital to dogs for 2 months and found enhanced metabolism of phenylbutazone for as long as 6 weeks after cessation of therapy. In a similar study, Remmer et al. 2,3 noted that canine microsomal enzyme activity, with hexobarbital and aminopyrine as substrates, remained elevated for 2 to 4 months after stopping a 2–3-month course of phenobarbital treatment. A single overdose of hypnotics in man can enhance 4-aminoantipyrine production from Novalgin for as long as 15 days. 2 The activity of microsomal drug-metabolizing enzymes in rat liver during and after chronic phenobarbital administration has not been studied. Using rats, Orrenius and Ernster 4 have shown that formation of formaldehyde from aminopyrine falls to control levels within 6 days after short-term administration of phenobarbital (every day for 5 days). In view of this, four microsomal drug-metabolizing pathways were measured in livers from rats given phenobarbital for varying periods of time up to 2 months. A plateau in rate of hexobarbital metabolism was reached during the treatment with phenobarbital, and a rapid decline in enzyme activity was observed after stopping this treatment.