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 (‐2.6, 0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; ‐12.7 +/‐ 3.7 ml 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 1‐demethylation (‐12.8 +/‐ 5.5% (‐21.5, ‐4.0)), while group B subjects showed a significantly greater inhibition of 1‐ 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.