Changes in theophylline metabolism during postnatal development in rat liver slices

Abstract

The metabolism of theophylline was studied in liver slices of young and adult rats. Theophylline and six metabolite fractions were recognized in adult liver by thin-layer radiochromatography and high performance liquid chromatography: 1-methyluric acid; 1-methylxanthine; 1,3-dimethyluric acid and/or 3-methylxanthine; caffeine; a uracil derivative and two unknown polar compounds. Pre-incubation with caffeine or theobromine inhibited theophylline metabolism. Allopurinol decreased the formation of three metabolite fractions but markedly increased the production of 1-methylxanthine. SKF 525-A inhibited the overall metabolism of theophylline. The specific activity of the enzyme system was 3.2 ± 0.4 nmoles · (g liver) −1· hr −1 in the 4- to 5-day-old rat and increased to a peak of 25.7 ± 1.7 in the 28-day-old; values for K m and V max in the 7- and 28-day-olds were 132.1 and 67.5 μM, and 23.9 and 52.1 nmoles · (g liver) −1 hr −1 respectively. Theophylline and the same six metabolites were identified in young and adult rats, but the development pattern was not uniform. Peak age-related activity and involvement of mixed-function oxidase system are features which are common to theophylline and caffeine metabolism. Xanthine oxidase played a role in theophylline metabolism. Formation of caffeine from theophylline was not dependent on a lack of activity of other pathways.