Ciprofloxacin interaction with theophylline

All quinolones interact with multivalent cations, forming chelation complexes resulting in reduced absorption. Major offenders are antacids vitamins containing calcium and iron can also be problematic. All fluoroquinolones interact with warfarin, didanosine (ddi), and phenytoin, resulting in decreased absorption or metabolism. Ciprofloxacin and other second-generation drugs interact with theophylline by decreasing its clearance, which leads to theophylline toxicity. 

The interaction between the quinolone antibacterials and CYP1A2 has been studied in some depth for enoxacin and pefloxacin. Both compounds have been shown to inhibit CYPlA2-mediated metabolism of caffeine in vitro (49). This in vitro inhibition translated into a twofold decrease in caffeine clearance by pefloxacin and a sixfold decrease in clearance by enoxacin (50). Because pefloxacin undergoes N-demethylation to norfloxacin (51) and norfloxacin is much more potent as an inhibitor than pefloxacin (50), the observed in vivo interaction seen for pefloxacin may, in part, be due to norfloxacin. Many other quinolone antibacterial agents have been investigated for their interaction with theophylline, and ciprofloxacin has also been shown to have notable inhibitory effects (52). 

Fluoroquinolones. Ciprofloxacin and enoxacin (Pene-trex) may markedly increase serum concentrations of medications such as theophylline by inhibiting their hepatic metabolism. Certain other fluoroquinolones, such as levofloxacin (Levaquin), are not likely to inhibit hepatic enzyme systems and interact with these medications. 

These cases of interactions of aminophylline with macro-lide antibiotics illustrate that serious, even fatal, adverse effects can occur when possible interactions are not considered. In both cases, experienced physicians prescribed appropriate antimicrobial drugs, but omitted to consider the possibility of interactions with aminophylline, and failed to reduce the dose of aminophyUme or to measure theophylline concentrations. In the first case the development of tachycardia, hypokalemia, acidosis, vomiting, and convulsions can be explained on the basis of theophylline toxicity caused by ciprofloxacin, while in the second the anxiety, tremor, and cardiac arrests could all have resulted from an interaction of aminophylline and erythromycin. These cases add to an extensive literature that emphasizes the potential for interaction between aminophylline and drugs metabolized by CYP1A2. 

There are numerous cases that describe the interaction between ciprofloxacin and theophylline or aminophylline, which commonly report large increases in serum theophylline levels (32 to 478% or 1.3 to 5.6-fold increases), often associated with toxicity. " From 1987 to 1988, the CSM in the UK had received 8 reports of clinically important adverse interactions between these two drugs, with one fatal case. By 1991, the FDA in the US had received 39 reports of the interaction, with three deaths. ... 

The interactions of enoxacin and ciprofloxacin with theophylline are well documented, well established and of clinical importance. The effect of enoxacin is marked and occurs in most patients, whereas the incidence with ciprofloxacin is uncertain and problems do not develop in all patients. The risk seems greatest in the elderly and those with theophylline levels already towards the top end of the therapeutic range. Toxicity may develop rapidly (within 2 to 3 days) unless the theophylline dosage is reduced. 

Drug interactions The effect of antacids and cations on the absorption of these agents was considered above. Ciprofloxacin, ofloxacin and enoxacin can increase the serum levels of theophylline by inhibiting its metabolism. They also may raise levels of warfarin, caffeine and cyclosporine. Cimetidine interferes with the... 

Norfloxacin and ciprofloxacin decrease the systemic clearance of theophylline to an extent that could be of clinical significance (Prince et al.r 1989). The effect of the interaction can be avoided by adjusting the dosage rate of theophylline in accordance with the decreased clearance so that steady-state plasma theophylline concentrations remain within the therapeutic range (6-16 pig/mL). 

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