Theophylline, oxidation

After influenza immunization there was a reduction in blood theophylline concentrations in patients and healthy volunteers (58). The authors concluded that flu vaccine may influence the pharmacokinetics of several drugs, and a second group found that theophylline oxidation was significantly reduced at 1 day, but not at 7 days, after immunization (57). However, others did not confirm these effects (55,59). The lack of a clinical interaction with theophylline has also been confirmed by a report of the US Immunization Practices Advisory Committee (9). 

Theophylline, 9-aryl-synthesis, 5, 576 Theophylline, 8-arylamino-synthesis, 5, 576 Theophylline, 9-benzyl-rearrangement, 5, 534 Theophylline, 8-chloro-reduction, 5, 541 Theophylline, 6-deoxy-reduction, 5, 541 Theophylline, 8-dimethylamino-synthesis, 5, 580 Theophylline, 8-methyl-synthesis, 5, 591 Theophylline, 8-methylthio-synthesis, 5, 578 Theophylline, 8-nitro-synthesis, 5, 538 Theophylline, 7-phenyl-synthesis, 5, 581 Theophylline, 8-phenyl-7-oxide... 

The key metabolites of caffeine (a trimethylxanthine) found in plasma, are the dimethylxanthines paraxanthine, theophylline, and theobromine the monomethylxanthine 1-methylxanthine the C-8 oxidized monomethylxanthine 1-methyluric acid and the ring oxidized uracil 5-acetyl-amino-6-amino-3-methyluracil. 

In the case of the methylated xanthines, particularly theophylline, theobromine and caffeine, the preponderance of data on the metabolism of these compounds in man suggests that a methylated uric acid is the principal product. However, the data presented earlier proposes at best a 77 per cent accounting of the methylated xanthine administered. The question can be raised as to whether the final products observed upon electrochemical oxidation of these compounds aids these studies. Very recently studies of metabolism of caffeine have revealed that 3,6,8-trimethylallantoin is a metabolite of caffeine 48>. This methylated allantoin is, of course, a major product observed electrochemically. The mechanism developed for the electrochemical oxidation seems to nicely rationalize the observed products and electrochemical behavior. The mechanism of biological oxidation could well be very similar, although insufficient work has yet been performed to come to any definite conclusions. There is however, one major difference between the electrochemical and biological reactions which is concerned with the fact that in the former situation no demethylation occurs whereas in the latter systems considerable demethylation appears to take place. 

Y.H. Zhu, Z.L. Zhang, and D.W. Pang, Electrochemical oxidation of theophylline at multi-wall carbon nanotube modified glassy carbon electrodes. J. Electroanal. Chem. 581, 303-309 (2005). 

Failla M, To Y, Ito M, Adcock IM, Barnes PJ, Ito K. (2007) Oxidative stress-induced PI3-kinase activation reduces HDAC activity and is inhibited by theophylline. Proc Am Thorac Soc 2 A45 (Abstr.)... 

Again, theophylline, which is only excreted in adult urine as oxidative metabolites, is excreted almost entirely as unchanged drug in the urine of premature infants. 

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. 

Crowley JJ, Cusack BJ, Jue SG, et al. Aging and drug interactions II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men. J Phannacol Exp Ther... 

In humans it has been demonstrated that increasing the ratio of protein to carbohydrate in the diet stimulates oxidation of antipyrine and theophylline, while changing the ratio of fat to carbohydrate had no effect. In related studies, humans fed charcoal-broiled beef (food high in polycyclic hydrocarbon content) for several days had significantly enhanced activities of CYPs 1A1 and 1A2, resulting in enhanced metabolism of phenacetin, theophylline, and antipyrine. Studies of this nature indicate that there is significant interindividual variability in these observed responses. 

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Three of the human metabolites of donepezil have not undergone extensive safety tests in animals. These comprise two O-demethylated derivatives and an N-oxidation product. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. The rate of metabolism of donepezil is slow and does not appear to be saturable. These findings are consistent with the results from formal pharmacokinetic studies which showed that donepezil and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin... 

Fervenulin 1-oxide (90) reacts with secondary amines to give low yields of 8-aIkyamino-theophyllines (91), but with ammonia or with primary amines the final product is 1,3-dimethyl-5-imino-6-hydroxyiminouracil (92) (Scheme 30) [94CHE(30)1087],... 

Robson RA, Begg EJ, Atkinson HC, et al. Comparative effects of ciprofloxacin and lomefloxacin on the oxidative metabolism of theophylline. Br J Clin Pharmacol 1990 29 491 193. 

In like manner, the oxygen atom of a purine 7-iV-oxide may be incorporated into an expanded ring, and theophylline 7-iV-oxides (501) give rise to pyrimido[5,4-c][l,2,5]oxadiazines (502) on heating (Equation (107)) <66LA(692)134,66LA(699)145,67FRP90508). 

Metabolism Erythromycin is extensively metabolized and is known to inhibit the oxidation of a number of drugs through its interaction with the cytochrome P-450 system (see p. 14). Clarithromycin is oxidized to the 14-hydroxy derivative, which retains antibiotic activity interference with the metabolism of drugs such as theophylline and carbamazepine has been reported. Azithromycin does not undergo metabolism. 

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