Theophylline metabolism

Anderson, K. E. et al. (1991). Diet and cimetidine induce comparable changes in theophylline metabolism in normal subjects. Hepatology, 13, 941-6. 

Dose adjustments should generally be made based on trough serum concentration results. A conservative therapeutic range of 8 to 15 mcg/mL is often targeted, especially in elderly patients, to minimize the likelihood of toxicity. Once a dose is established, concentrations should be monitored once or twice a year unless the disease worsens, medications that interfere with theophylline metabolism are added, or toxicity is suspected. 

The quinolones have been found to cause erosion of cartilage in the joints of immature animals [56]. This observation, which has been seen in several studies, has resulted in the contraindication of quinolones for the treatment of children. A study analyzing the risk-benefit situation for the use of pefloxacin in children (clinically, several adverse athralgic effects have been attributed to this agent) has appeared [57]. The underlying mechanism responsible for these effects has yet to be established, and the development of an agent which is safe for paediatric use would be a major advance in quinolone therapy. Some of the quinolones, such as enoxacin, have been shown to interfere with theophylline metabolism [58], and side-effects associated with this agent may be related to this property. 

Geriatric Considerations - Summary Increased risk of side effects in patients with CVD and hepatic dysfunction. Theophylline has a narrow therapeutic index and is associated with numerous drug interactions. Target serum concentrations are 5-20 mg/L, with adverse effects increasing between 15-20 mg/L. Hepatic metabolism and renal excretion declines with age and the half-life of theophylline increases by 3 to 9 hours in older adults. Smoking induces theophylline metabolism therefore, if a pa-tienf sfops smoking, empiric dosage reduction may be indicated and follow serum concenfrafions closely. 

Although it has been largely replaced by inhaled agonists, theophylline continues to be used for the treatment of bronchospasm by some patients with asthma and bronchitis (see Chapter 20). A dose of 20-30 tablets can cause serious or fatal poisoning. Chronic or subacute theophylline poisoning can also occur as a result of accidental overmedication or use of a drug that interferes with theophylline metabolism (eg, cimetidine, ciprofloxacin, erythromycin see Chapter 4). 

Theophylline [NE] Increased theophylline metabolism reduced theophylline effect. 

Theophylline [P] Decreased theophylline metabolism Increased plasma theophylline. 

Theophylline [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit theophylline metabolism gatifloxacin, levofloxacin, lomefloxacin, ofloxacin, and sparfloxacin appear to have little effect. 

In contrast, decreases in theophylline metabolism by selective inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, or by selective and potent inhibitors of CYP3A4, such as the macrolide antibiotics, have resulted in serious theophylline toxicity (22). It is postulated that taken over time, the macrolide antibiotics act as mechanism-based inhibitors of CYP isoforms other than just CYP3A4. Some nonselective inhibitors of P450s, such as cimetidine, some p-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. 

Orlando R, Padrini R, Perazzi M, et al. (2006) Liver dysfunction markedly decreases the inhibition of cytochrome P450 lA2-mediated theophylline metabolism by fluvoxamine. Clin Pharmacol Ther 79 489-499. 

PENTOXIFYLLINE BRONCHODILATORS- THEOPHYLLINE Possibly t theophylline levels Uncertain possibly competitive inhibition of theophylline metabolism (pentoxifylline is also a xanthine derivative) Warn patients of the possibility of adverse effects of theophylline monitor levels if necessaiy... 

INTERFERON ALFA BRONCHODILATORS -THEOPHYLLINE t theophylline levels Inhibition of theophylline metabolism Monitor theophylline levels before, during and after co-administration... 

Kraus DM, Fischer JH, Reitz SJ, Kecskes SA, Yeh TF, McCulloch KM, Tung EC, CwikMJ. Alterations in theophylline metabolism during the first year of life. Clin Pharmacol Ther 1993 54 351-9. 

Grygiel JJ, Birkett DJ, Phill D. Effect of age on patterns of theophylline metabolism. Clin Pharmacol Ther 1980 28 456-62. 

---