Theophylline cytochrome

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Tobacco smoke contains chemicals that induce the cytochrome P-450 isoenzymes 1A1,1A2, and 2E1. Theophylline is metabolized by 1A2 and 2E1, and therefore smoking leads to increased clearance and subsequently decreased plasma levels of the drug.15 Because most patients with COPD are current or past smokers, it is important to assess current tobacco use and adjust the theophylline dose as required based on altered plasma theophylline levels if tobacco use changes. 

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

Oral azoles are associated with significant interactions, particularly due to cytochrome P-450 isoenzymes. Medications that interact with azoles include warfarin, phenytoin, theophylline, rifampin, cyclosporine, and zidovudine. For patients receiving only a few doses, these interactions do not pose a significant risk. These interactions may pose a risk for patients receiving long-term suppressive therapy for recurrent infections. 

The answer is b. (Hardmanr p 906.) Cimetidine reversibly inhibits cytochrome P450. This is important in phase I bio transformation reactions and inhibits the metabolism of such drugs as warfarin, phenytoin, propranolol, metoprolol, quinidine, and theophylline. None of the other enzymes are significantly affected. 

Ha, H.R., Chen, J., Freiburghaus, A.U. and Follath, F. (1995) Metabolism of theophylline by cDNA-expressed human cytochromes P-450. British Journal of Clinical Pharmacology, 39 (3), 321-326. 

Pharmacokinetic interactions Preliminary evidence suggests that Saint-John s-wort induces the cytochrome oxidase enzyme isoform CYP3A4 (Ernst 1999). This raises the potential for pharmacokinetic interactions with drugs metabolized by the same enzyme. A few cases have been reported of reduced warfarin levels (Yue et al. 2000). Similar interactions have also been reported for concurrent use with digoxin, theophylline, and cyclosporin (Nebel et al. 1999 Ruschitzka et al. 2000 Johne et al. 1999). As with any other medication, potential interactions should be considered when taking a combination of drugs. 

Walton et al. (2001a) examined data for compounds eliminated by the cytochrome P450 isoenzymes CYP1A2 in humans. Absorption, bioavailabihty, and route of excretion were generally similar between humans and the test species for each of the substances (caffeine, paraxanthine, theobromine, and theophylline). However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceeded the fourfold default factor for toxicokinetics, whereas the rabbit (2.6) and the dog (1.6) were below this value. 

As it inhibits microsomal cytochrome P450 cimetidine has a high potential for drug interactions not shared by the other H2 receptor antagonists. The oxidative metabolism of agents such as anticoagulants, most antiepileptics, some beta-blockers, warfarin, theophylline and many hypnotics, neuroleptics and antidepressants may be reduced, leading to increased effects. 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

Interferons reduce the activity of hepatic cytochrome P450 enzymes and decrease the clearance of drugs such as theophylline. Their effects may be additive with other drugs that have neurotoxic, hematotoxic or cardiotoxic activity. 

Theophylline Probable induction of cytochrome P450 metabolic pathway Reduced blood levels and bron-chodilator action Monitor theophyline levels and stop SJW Readjust theophyline dose if required... 

Omeprazole can inhibit the metabolism of drugs metabolised mainly by the cytochrome P-450 enzyme subfamily 2C (diazepam, phenytoin), but not of those metabolished by subfamilies lA (caffeine, theophylline), 2D (metoprolol, propranolol), and 3A (ciclosporin, lidocaine (lignocaine), quinidine). Since relatively few drugs are metabolised mainly by 2C compared with 2D and 3A, the potential for omeprazole to interfere with the metabolism of other drugs appears to be limited, but the half lives of diazepam and phenytoin are prolonged as much as by cimetidine. 

Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs, including theophylline, oral anticoagulants, cyclosporine, and methylprednisolone. Erythromycin increases serum concentrations of oral digoxin by increasing its bioavailability. 

The clearances of both theophylline and caffeine are reduced in oral contraceptive users and half-lives are increased, probably because of inhibition of hepatic metabolism by cytochrome P450 (348). Caution in dosage is advisable. 

Yao C, Kunze KL, Kharasch ED, et al. Fluvoxamine-theophylline interaction gap between in vitro and in vivo inhibition constants toward cytochrome P4501A2. Clin Pharmacol Ther 2001 70 415 424. 

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