What pharmacokinetic property is responsible for increased theophylline blood levels in a patient with chronic obstructive pulmonary disease (COPD) after starting fluvoxamine for unipolar depression?

Fluvoxamine Increases Theophylline Blood Levels Through CYP1A2 Inhibition

The increased blood levels of theophylline in the 68-year-old COPD patient after starting fluvoxamine are primarily caused by fluvoxamine's potent inhibition of CYP1A2, which is responsible for theophylline metabolism. 1

Mechanism of Interaction

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has significant effects on drug metabolism through its actions on hepatic cytochrome P450 enzymes. The interaction with theophylline occurs through the following mechanism:

• Fluvoxamine is a very potent inhibitor of CYP1A2, with studies showing inhibitor constant (Ki) values as low as 0.07-0.13 μM for theophylline metabolism 1
• Theophylline is predominantly metabolized by CYP1A2 in the liver 1, 2
• When fluvoxamine inhibits CYP1A2, theophylline clearance is dramatically reduced, leading to increased blood levels and potential toxicity 3

Clinical Significance

This interaction has substantial clinical implications:

• Fluvoxamine can decrease theophylline clearance by up to 65% 3
• Studies show theophylline half-life can increase from 6.6 hours to 22 hours during fluvoxamine co-administration 2
• Theophylline has a narrow therapeutic window (5-15 μg/mL), and levels above this range can cause serious side effects 4

Potential Consequences

Elevated theophylline levels can lead to significant adverse effects:

• Gastrointestinal: nausea, vomiting, diarrhea, gastric irritation 4, 5
• Neurological: headache, tremor, irritability, seizures 4, 5
• Cardiovascular: tachycardia, arrhythmias 4, 5

Clinical Management

When fluvoxamine and theophylline must be co-administered:

• Reduce theophylline dose to approximately one-third of the usual maintenance dose 3
• Monitor theophylline plasma concentrations regularly 3
• Watch for signs of theophylline toxicity (nausea, vomiting, headache, tachycardia, seizures) 4
• Consider alternative antidepressants with less effect on CYP1A2 if appropriate

Comparison with Other Options

While the question asks specifically about the pharmacokinetic mechanism, it's worth noting that:

• CYP2D6 inhibition (option B) is not significantly involved in theophylline metabolism
• CYP3A4 inhibition (option C) plays a minor role in theophylline metabolism compared to CYP1A2
• Fluvoxamine does inhibit CYP3A4 and CYP2D6, but much less potently than it inhibits CYP1A2 6

Common Pitfalls to Avoid

1. Failing to recognize this interaction before initiating fluvoxamine in patients on theophylline
2. Not reducing theophylline dose when starting fluvoxamine
3. Inadequate monitoring of theophylline levels after starting fluvoxamine
4. Overlooking symptoms of theophylline toxicity when they emerge

This case highlights the importance of understanding cytochrome P450-mediated drug interactions, particularly when prescribing medications with narrow therapeutic windows like theophylline.