Comparison of methods to study enzyme induction in man.

A combination of several in vivo parameters has been applied in male healthy volunteers to test the suitability of these parameters to indicate enzyme induction in man: Urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol, activity of serum gamma-glut amyltranspeptidase, and pharmacokinetics of aminopyrine respond significantly to phenobarbital treatment. Glucaric acid excretion is enhanced about 7-fold. Its response to induction overcomes the large individual and inter-individual variations which exist in the untreated state for glucaric acid excretion and the other parameters applied, as well. Total body clearance of aminopyrine as obtained after an oral test dose increases more than twofold from 251 to 551 ml/min upon phenobarbital treatment. This arises from increases in both the elimination constant and the apparent volume of distribution, as well. Urinary excretion of aminoantipyrine during 24 hr is about doubled, whereas the elimination of acetyl-aminotipyrine is not much affected. 6 beta-hydroxycortisol excretion in urine and activity of serum gamma-glutamyltranspeptidase are significantly augmented to about 150% of control values. Half life times of phenobarbital measured after termination of treatment are in normal range, suggesting no self-induction of phenobarbital metabolism. Because of the complexity of drug metabolizing enzymes only a combination of different parameters reliably indicates alterations in this enzyme system by inducing agents.