Lack of parallelism between microsomal enzyme induction and phenobarbital-induced hypercholeresis in the rat

The relationship between microsomal enzyme induction and the increase in bile flow associated with phenobarbital administration was studied in rats in three experimental situations: examination of the time-course effect of a single dose of phenobarbital (8 mg/100 g body weight) on bile flow and hepatic cytochrome P-450 concentration; study of the influence of SKF 525-A (8 mg/100 g body weight) and cobaltous chloride (6 mg/100 g body weight/day for 3 days) on the phenobarbital-induced hypercholeresis. It was observed that: (a) the maximal increase in bile flow occurred 18 h after the single injection of phenobarbital, while the maximal increase in cytochrome P-450 occurred at 48 h; (b) in rats pretreated with phenobarbital for 3 days, SKF 525-A did not suppress the hypercholeresis due to phenobarbital, and (c) in rats treated with phenobarbital and cobaltous chloride, cytochrome P-450 concentration in the liver was not increased, while bile flow was increased to approximately the same extent as in animals treated with phenobarbital alone. These results further support the hypothesis that microsomal cytochrome P-450-dependent enzyme induction and increase in bile flow are two separate effects of phenobarbital.