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.