Influence of theophylline on the renal clearance of erythromycin

The influence of theophylline on the kinetics of erythromycin was studied in 11 healthy subjects who received both drugs intravenously in therapeutic doses. Total clearance, terminal half-life and volume of distribution of erythromycin were not altered by concomitant theophylline treatment. However, renal clearance of erythromycin was enhanced by theophylline treatment (86.0 +/- 81.1 ml/min vs. 32.5 +/- 15.9 ml/min, with vs. without theophylline). Theophylline also altered urinary flow rate (4.7 +/- 1.6 ml/min vs. 1.9 +/- 1.2 ml/min, with vs. without theophylline) whereas fluid intake was identical (125 ml/h) as well as the pH of the urine (pH 6.5). The possible explanation that theophylline is acting via enhancing urinary flow rate, which reduced tubular reabsorption of erythromycin, has been ruled out by the findings of an additional trial done in 6 out of the 11 subjects. In this trial, renal clearance of erythromycin was not influenced by enhanced urinary flow rate (7.2 +/- 1.9 ml/min) which was due to high fluid intake (500 ml/h) whereas the pH of the urine was kept at 6.5 as in the first part of the study. When other mechanisms to explain the observed interaction were discussed taking into account our published results on theophylline kinetics influenced by concomitant erythromycin administration, the most likely explanation for our finding seems to be the interaction between erythromycin and 1-methyluric acid, one of the theophylline metabolites.