Effect of Phenobarbital Administration on thein VitroHydroxylation of Cortisol and on Over-all Substrate and Product Metabolism in the Guinea Pig and Rat

Abstract

Treatment of 4:month-old female strain 13 guinea pigs with phenobarbital (75 mg/kg daily ip) for 18 days stimulated the hepatic microsomal metabolism of cortisol, 2[alpha] and 6[beta]- hydroxycortisol 2.3-, 2.1- and 1.5-fold, respectively. The mean net formation of 2[alpha] and 6[beta]-hydroxycortisol Increased 1.4- and 1.7-fold, respectively. The mean initial rates of 2[alpha] and 6[beta]-hydroxylation by hepatic microsomes (calculated on the assumption of first-order kinetics from the over-all rates of metabolism of substrate and product) were 3.6- and 3.8-fold higher in the drug-treated guinea pigs, suggesting induction of enzymatic activity as a possible mechanism. No significant effect of phenobarbital on the hydroxylation of cortisol or the over-all metabolism of substrate or product by guinea pig adrenal homogenates was found. Treatment of 3-month-old female Sprague-Dawley rats with phenobarbital (75 mg/kg daily ip) for 6 days enhanced the hepatic microsomal 6[beta]-hydroxylatlon of cortisol 3.6-fold, but did not cause a significant change in the over-all metabolism of substrate or product. No significant 2[alpha]-hydroxylation of cortisol was found with rat-liver microsomes.