Role of drug metabolism in protection against chlorphentermine-induced pulmonary phospholipidosis in adult rat

Abstract

Daily oral administration of either 20 or 60 mg/kg chlorphentermine for 1 week to adult rats produced a dose-related decrease in body and liver weight. In lung, the chlorphentermine-induced accumulation of alveolar foam cells and increase in relative tissue to body weight was also dose dependent. Although both doses of this anorectic drug failed to markedly alter the activity of hepatic and pulmonary microsomal aniline hydroxylase, a significant elevation in aminopyrine N-demethylase was noted in both tissues of rats given 60 mg/kg chlorphentermine. Treatment with phenobarbital (30 mg/kg/day) for 1 week stimulated the activities of pulmonary and hepatic aniline hydroxylase and aminopyrine N-demethylase. Simultaneous administration of phenobarbital and either dose of anorectic prevented the chlorphentermine-induced decrease in body and liver weight as well as increase in relative lung weight. In addition, phenobarbital blocked the development of alveolar foam cells in rats administered 20 mg/kg chlorphentermine and reduced this number in animals receiving the higher dose. Concurrent administration of phenobarbital and chlorphentermine elevated the activities of hepatic aniline hydroxylase and aminopyrine N-demethylase to the same extent as barbiturate alone. Although simultaneous 20 mg/kg anorectic and phenobarbital increased both pulmonary enzymes in a manner similar to barbiturate alone, a synergistic rise was noted in aminopyrine N-demethylase activity of lungs from rats given the higher chlorphentermine dose and phenobarbital. Our results suggest that one of the mechanisms which contributes to the protection afforded by phenobarbital in diminishing chlorphentermine-induced pulmonary phospholipidosis appears to be through stimulation of drug metabolism.