Effect of phenobarbitone on hepatic drug-metabolizing enzymes and urinary D-glucaric acid excretion in man.

Abstract

1 The activities of some hepatic drug-metabolizing enzymes representative of the four major pathways for the biotransformation of drugs were estimated in diagnostic wedge biopsy specimens obtained from 22 patients with Hodgkin's disease. Twelve patients (nine males and three females) were not on prolonged pre-operative treatment with any known inducing drugs. In this group, hexobarbitone oxidase activity, cytochrome P450 and microsomal protein contents were in the same range as those reported by other workers. 2 Ten patients (five males and five females) were pre-operatively treated with phenobarbitone (90 mg daily) for at least seven days. This resulted in a significant increase of hexobarbitone oxidase activity, cytochrome P450 and microsomal protein contents when the phenobarbitone untreated and treated groups were compared as a whole and provides direct evidence of induction of hepatic mixed function oxidase system. In respect of p-nitroreductase, 1-leucyl-beta-naphthylamide splitting enzyme and UDP glucuronyl transferase, there was no difference between the treated and untreated groups. 3 When untreated and treated patients were compared, the induction of the hepatic mixed function oxidase system, was associated with a significant increase in urinary D-glucaric acid excretion. In treated patients, however, there was no correlation between any of the indices studied and post-phenobarbitone D-glucaric acid content or the rise in D-glucaric acid excretion. However, the correlation between cytochrome P450 content and post-phenobarbitone D-glucaric acid or the rise in D-glucaric acid excretion was only just below statistical significance (r = 0.696 and 0.690 respectively, 0.10 greater than P greater than 0.05) whereas in the untreated group there was no correlation (r = 0.231, P greater than 0.60). 4 In two patients, whose phenobarbitone was discontinued for at least six days prior to surgery, all indices studied had returned to untreated values, except for microsomal protein content which remained significantly elevated.