THE EFFECT OF CIPROFLOXACIN ON THEOPHYLLINE PHARMACOKINETICS IN HEALTHY-SUBJECTS

1 The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects, 2 Subjects were given a single oral dose of theophylline (3.4 mg kg(-1)), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily. 3 Ciprofloxacin reduced the oral clearance of theophylline by 19% (-7.73 +/- 6.42 ml kg(-1) h(-1) (95% confidence limits -12.66, -2.79)). Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; -1.6 +/- 0.7 ml kg(-1) h(-1) (-26, -0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; -12.7 +/- 3.7 mi kg(-1) h(-1) (-17.2, -8.1)). 4 Comparing groups A and B, the decrease in oral clearance of theophylline in group B could not be ascribed to differences in the AUC of ciprofloxacin. Group A subjects showed only slight inhibition of l-demethylation (-12.8 +/- 5.5% (-21.5, -4.0)), while group B subjects showed a significantly greater inhibition of l-demethylation (-49.9 +/- 9.8% (-62.1, -37.7)), 3-demethylation (-44.8 +/- 8.6% (-55.4, -34.1)) and 8-hydroxylation (-27.0 +/- 3.7% (-31.6, -22.4)), 5 The results suggest that inter-individual variability in the inhibition of theophylline metabolism by ciprofloxacin can be attributed to inter-individual differences in the level of CYP1A2 expression and/or in the degree of inhibition of hepatic CYP1A2 and CYP3A4. 6 The interaction between ciprofloxacin and theophylline can be clinically significant. However, uniform decrease in the theophylline dose is not warranted because there is a negligible change in theophylline clearance when ciprofloxacin is coadministered in a substantial proportion of patients.