THEOPHYLLINE METABOLISM DURING POSTNATAL DEVELOPMENT

Abstract

Few data exist regarding theophylline (T) biotransformation in early postnatal life. In this study T metabolism was characterized in the rat with emphasis on its changes during postnatal development. Liver slices were prepared from Charles River rats and incubated in Krebs-bicarbonate buffer with (8-14C) T under 95% O2-5% CO2 in a metabolic shaker at 37°C. T metabolites were analysed by tlc and hplc. T and 6 main metabolites were recognized in adult liver: 1 methyluric acid; 1 methylxanthine; 1,3 dimethyluric acid; caffeine, a uracil derivative and an unknown polar compound. Preincubation with caffeine and theobromine inhibited T metabolism. SKF 525-A and allopurinol inhibited overall T metabolism; in particular allopurinol inhibited formation of 1 methylxanthine. The specific activity of the enzyme system was 3.9 ± SE 0.4 nm (gm liver)−1. hr−1 in the 4-day-old and increased to a peak of 25.3±1.7 in the 28-day-old rat; Km was similar (67.5 vs. 132.1 μM) but Vmax was two-fold greater in the 28-day-old (23.9 vs. 52.1 nmol [gm liver]−1. hr−1). T and the same metabolites were identified in young and adult rats but the developmental pattern was not uniform. Peak age related activity and involvement of mixed function oxidase system are common features to caffeine (Bioch. Pharmacol. 30: 3145, 1981) and T biotransformation, Xanthine oxidase was involved in T metabolism. As opposed to previous suggestions formation of caffeine from T was not dependent on lack of activity of other pathways.