A 60-year-old asthmatic stabilized on oral theophylline is prescribed ciprofloxacin for acute bacterial prostatitis. Three days later she develops nausea, tremor, tachycardia and a seizure. The most likely mechanism is:

• A Additive CNS GABA antagonism between the two drugs
• B Displacement of theophylline from plasma proteins
• C Competition for renal tubular secretion raising theophylline clearance time
• D Inhibition of theophylline metabolism by ciprofloxacin through CYP1A2 inhibition ✓

Explanation

Theophylline is cleared primarily by hepatic metabolism via CYP1A2. Ciprofloxacin is a potent CYP1A2 inhibitor, so coadministration raises theophylline levels into the toxic range, producing nausea, tremor, tachyarrhythmias and seizures. Other strong CYP1A2 inhibitors include fluvoxamine and cimetidine. Renal secretion and protein displacement are irrelevant for theophylline, which has low protein binding and undergoes extensive hepatic metabolism. Tizanidine is another classic CYP1A2 substrate contraindicated with ciprofloxacin.

Reference: Katzung Basic and Clinical Pharmacology, 16th ed.

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