Application of theophylline metabolite assays to the exploration of liver microsome oxidative function in man

The effects on theophylline oxidative metabolism of 3 inhibitors of liver microsome activity--cimetidine, troleandomycin and ketoconazole--were investigated in 6 healthy volunteers. The 3 compounds increased plasma theophylline half-life by 73.6 +/- 15.6% (P less than 0.01), 107.8 +/- 9.7% (P less than 0.001) and 21.7 +/- 6.8% (P less than 0.02), respectively, and reduced plasma theophylline clearance by 38.3 +/- 4.8% (P less than 0.001), 51.4 +/- 2.4% (P less than 0.001), and 8.9 +/- 7.8% (NS), respectively. Troleandomycin inhibited to the same extent the 2 theophylline metabolism pathways: N-demethylation resulting in the formation of 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX), and 8-hydroxylation resulting in the formation of 1,3-dimethyluric acid (1,3-DMU). The production clearances of these metabolites were almost equally depressed by 60.2 +/- 3.9%, 60.2 +/- 2.1%, and 51.7 +/- 4.5%, respectively. Cimetidine predominantly inhibited the N-demethylation pathway; the production clearances of 1-MU and 3-MX were depressed by 58.5 +/- 4.0% and 57.5 +/- 4.1% (P less than 0.001), respectively, whereas the production clearance of 1,3-DMU was depressed by 38.3 +/- 6.1% (P less than 0.001). Ketoconazole had no significant effect on the produciton clearances of theophylline metabolites. Measurement of theophylline metabolite formation clearances might be a useful test to explore liver microsome oxidative function.