Oxidation of theophylline

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). 

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 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. 

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. 

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... 

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. 

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. 

Cigarette smoke contains minute amounts of polycyclic aromatic hydrocarbons, such as benzol nr pyrene. which are potent inducers of microsomal cytochrome P-4S0 enzymes. This induction increases the oxidation of some drugs in nnokets. For example, theophylline is metabolized more rapidly in smokers than in nonsmokers. This difference is reflected in the marked difference in the plasma half-life of theophylline between smokers (r /2 4.1 hours) and non-smokers u A 7.2 hours). Other drugs, such as phenacetin. pentazocine. and propoxyphene, also reportedly undergo more rapid metabolism in smokers than in nonsmokers. " ... 

Three basic types of N-methylation reactions have been recognized (reactions 2-4, Fig. 13.15). A number of primary amines (e.g., amphetamine) and secondary amines (e.g., tetrahydroisoquinolines) have been shown to be in vitro substrates of amine iV-methyltrans-ferase, whereas some phenylethanolamines and analogs are methylated by phenyletha-nolamine N-methyltransferase (reaction 2). However, such reactions are seldom of significance in vivo, presumably because of effective oxidative N-demethylation. A comparable situation involves the N-41 group in an imidazole ring (reaction 3), exemplified by histamine (49). A therapeutically relevant example is that of theophylline (16) whose iV(9)-meth-ylation is masked by N-demethylation in adult but not newborn humans. 

The hepatic metabolism of certain drugs has also been fonnd to be different in neonates versus children and adults. The N-methylation of theophylline to caffeine occurs in preterm and full-term infants, whereas in adults theophylline is primarily N-demethylated and C-oxidated to monomethylxanthines and methyluric acid, respectively. 

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