Origins of interindividual variations in theophylline metabolism in man

Abstract

The occurrence of wide interindividual variation in the rate of theophylline metabolism in man is well documented. We have attempted to identify and quantify factors responsible for this, in the hope of contributing to safer and better therapy. Studies of the kinetics of theophylline metabolism in volunteers showed that its conversion to 3-methylxanthine was saturable, the other elimination routes following ist order kinetics. When methylxanthines were removed from the diet for 7 days, the rate of theophylline metabolism rose by 29 %, but when methylxanthine intake was increased above normal levels, there was no change in the rate of theophylline metabolism. The pool of methylxanthines in the normal Western diet is thus sufficient to inhibit theophylline metabolism maximally. Theophylline is commonly administered combined with ethylenediamine, as aminophylline. When given as aminophylline, theophylline was metabolized more rapidly and extensively and excreted in the urine faster. This is not due to changes in plasma protein binding or membrane passage caused by ethylenediamine. A panel of 60 healthy young volunteers was given theophylline orally after an 18 h period without methylxanthines and plasma kinetics of theophylline assessed. Each subject answered questions about their diets, social drug use etc. and these were correlated with theophylline kinetics by multiple regression. By design of the questions and selection of the panel all known influences on theophylline metabolism were considered. The mean CLp was 0.74 ml/min/kg with a range of 0.3–1.4. Multiple regression showed that all of the subject variables accounted for 23 % of the total variation, leaving 77 % due to unknown sources. The most important factor was methylxanthine intake, accounting for 10 % which was in this case an inducing effect of methylxanthines. These results show the importance of methylxanthine intake as a determinant of theophylline kinetics and metabolism. In most cases, the inhibitory effect will outweigh the inducing effect. Other origins, most likely genetic, must be sought for the variability in theophylline metabolism in the general population.