Theophylline metabolites

Pnrines, substituted (direct injection, LLE, SPE) Racemethorphan, racemorphan (optical isomers) Theophylline metabolites (SPE)... 

Schwertner et al. introduced a salting-out procedure, in combination with single extraction using chloroform-isopropanol (95 5). 100 pi plasma samples could be effectively extracted with 2 ml chloroform-isopropanol. Theophylline was derivatized with pentafluoroben-zyl chloride, and 3-isobutyl-l-methylxanthine was used as an internal standard. This standard is similar to theophylline in extractability, derivatization rates, stability and chromatographic properties. Accurate measurements of plasma concentrations ( + 0.22 ug/ml) could be obtained with little or no interference from theophylline metabolites and other coextract-able material. A packed column with 3 OV-17 on Gas Chrom Q and temperature programming from 150°C to 250°C was used in combination with an electron capture detector. 

Konishi, H. Yamqji, A. Measurement of theophylline metabolites produced by reaction with hepatic microsome by high performance liquid chromatography following solid phase extraction. Bio-med.Chromatogr., 1994, 8, 189-192 [extracted theophylline microsomal incubations SPE acetaminophen is IS mouse]... 

Hepatic metabolism is predominantly mediated via the cytochrome P-450 (CYP) isoenzymes CYP2E1 and CYP3A4 (8-hydroxylation to 1,3-dimethyluric acid, 40 to 50%), and CYP1A2 (A-demethylation to 3-methylxanthine, 10 to 15%, and 1-methylxanthine). 1-Methylxanthine is further oxidized, by xanthine oxidase, to 1-methyluric acid (15 to 20%). " Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacological activity, but only... 

Theophylline HPLC Acetazolamide cephalosporins endogenous xanthines and accumulated theophylline metabolites in renal failure (minor effect). 

However, in two other studies allopurinol 300 mg daily for 7 days did not have any effect on the pharmacokinetics of theophylline, following a single 5-m kg intravenous dose of aminophylline. Similarly, steady-state theophylline levels were not affected by allopurinol 100 mg three times daily in 4 subjects. However, there was an alteration in the proportion of different urinary theophylline metabolites methyluric acid decreased and methylxanthine increased. ... 

Naline E, Sanceaume M, Pays M, Advenier C.. / hcation of theophylline metabolite assays to the exploration of liver microsome oxidative function in man. Fundam Clin Pharmacol (1988)2,341-51. 

The elimination half-life of theophylline (given as intravenous aminophyl-line) was no different in premature infants who had been exposed to betamethasone in utero than in those who had not, although the exposed neonates had a wider range of theophylline metabolites indieating greater hepatie metabolism. ... 

Oral coadministration of 5 ml/kg of a cayenne suspension (10% cayenne) and 20 mg/kg theophylline to rabbits significantly increased the plasma levels of theophylline (Bouraoui et al. 1988), whereas oral administration of cayenne (5 ml/kg of a 10% cayenne suspension) and intravenous administration of theophylline (12 mg/kg) did not affect the plasma levels of theophylline (Bouraoui et al. 1995). Dosing with cayenne and theophylline for 7 days in rabbits significantly reduced urinary excretion of the theophylline metabolite 1-methyluric acid (Bouraoui et al. 1995). 

In the clinical area, the largest share of analytical methods development and publication has centered on the determination of theophylline in various body fluids, since theophylline is used as a bronchodilator in asthma. Monitoring serum theophylline levels is much more helpful than monitoring dosage levels.44 Interest in the assay of other methylxanthines and their metabolites has been on the increase, as evidenced by the citations in the literature with a focus on the analysis of various xanthines and methylxanthines. 

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. 

M. Boutroy, P. Vert, R. Royer, P. Monin, and M. Royer-Morrot, Caffeine, a metabolite of theophylline during treatment of apnea in the premature infant, J. Pediatr., 94, 996 (1979). 

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. 

Alkaloids are compounds that contain nitrogen in a heterocyclic ring and are commonly found in about 15-20% of all vascular plants. Alkaloids are subclassified on the basis of the chemical type of their nitrogen-containing ring. They are formed as secondary metabolites from amino acids and usually present a bitter taste accompanied by toxicity that should help to repel insects and herbivores. Alkaloids are found in seeds, leaves, and roots of plants such as coffee beans, guarana seeds, cocoa beans, mate tea leaves, peppermint leaves, coca leaves, and many other plant sources. The most common alkaloids are caffeine, theophylline, nicotine, codeine, and indole... 

Caffeine pharmacokinetics are nonlinear. For example, when comparing a 500 mg dose to a 250 mg dose, the clearance is reduced and elimination half-life is prolonged with the higher dose (Kaplan et al. 1997). Thus, larger doses prolong the action of the drug. Active metabolites of caffeine are paraxanthine, and to a lesser degree, theobromine, and theophylline. Urinary metabolites are I-methylxanthine, l-methyluric acid, and an acetylated uracil derivative. 

Drugs that might be affected by lopinavir/ritonavir include ergot derivatives, oral contraceptives, antiarrhythmics, HMG-CoA reductase inhibitors, HIV protease inhibitors, atovaquone, calcium channel blockers, ketoconazole, itraconazole, pimozide, cisapride, clarithromycin, disulfiram, metronidazole, immunosuppressants, midazolam, triazolam, narcotic analgesics, rifabutin and rifabutin metabolite, sildenafil, warfarin, bupropion, clozapine, desipramine, piroxicam, quinidine, theophylline, and zolpidem. 

Closely related methylxanthines include theophylline (1,3-dimethylxanthine), theobromine (3,7 dimethylxanthine) and paraxanthine (1,7-dimethylxanthine). Theobromine is found primarily in chocolate. These derivatives of caffeine are important because they are pharmacologically active and also are the common metabolites of caffeine. 

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. 

Hemoperfusion is like hemodialysis except that blood is circulated extracorporeally through a column with adsorbent material like resin or charcoal, which binds molecules electrostatically. The molecules likely to be removed are characterized as poorly dialyzable, lipid-soluble, protein bound. Among the indications for hemoperfusion in the management of poisoning include the presence of a poison in a patient with impairment of excretory system (i.e. damaged kidneys), intoxication of a drug known to produce delayed toxicity or metabolized to a more toxic metabolite (i.e. paraquat or methotrexate), deterioration of the clinical state of the poisoned patient despite conservative therapy (i.e. convulsions or cardiac arrhythmias following theophylline intoxication), or development of coma as a complication. 

Theophylline, a dimethylxanthine, causes broncho-dilation, possibly by inhibiting the enzyme phosphodiesterase in smooth muscle of the bronchioli. An other proposed mechanism of action is that of adenosine receptor antagonism. It has positive chronotropic and inotropic, CNS stimulant and weak diuretic properties. In obstructive lung disease sustained release tablets are to be preferred. Theophy-line has a narrow therapeutic index. Therapeutic plasma concentrations are between 7-15 mg/1. Theophylline undergoes N-demethylation via CYPl A2 in the liver and is eliminated in the urine as metabolites... 

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. 

Phenobarbital Enhances phasic GABAa receptor responses reduces excitatory synaptic responses Nearly complete absorption not significantly bound to plasma proteins peak concentrations in Vi to 4 h no active metabolites tjy2 varies from 75 to 125 h Generalized tonic-clonic seizures, partial seizures, myoclonic seizures, generalized seizures, neonatal seizures, status epilepticus Toxicity Sedation, cognitive issues, ataxia, hyperactivity Interactions Valproate, carbamazepine, felbamate, phenytoin, cyclosporine, felodipine, lamotrigine, nifedipine, nimodipine, steroids, theophylline, verapamil, others... 

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. 

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... 

The separation of cimetidine and its metabolites is usually carried out by extraction of the biological medium with 1-octanol fran an aqueous alkaline pH solution followed by mixing, addition of an internal standard and centrifugation. The extraction with octanol is repeated and the combined extracts are re-extracted with dilute hydrochloric acid. The aqueous acid solution is then separated, ethanol is added and mixed. This is then followed by saturating the mixture with a large amount of potassium or sodium carbonate to "salt out" the ethanol layer which contains the cimetidine and its metabolite, the sulfoxide. Several different internal standards have been used Metiamide, 1-methyl-3-[2-[[(5-methyl-imidazole-4-yl) -methyl] thio]ethyl]-2-thiourea,19 31 39 (N-cyano-N1-methy1-N"-(3-(4-imidazolyl)-propyl)guanidine32, and 13-hydroxy-theophylline. 0 After extraction the samples are either evaporated to dryness and reconstituted with a known amount of ethanol, injected directly or dissolved in the mobile phase for the HPLC analysis. 

Metabolites and substrates (urea, triglycerides, bili-rubine, lactate), enzymes (the measurands are the enzyme activities), hormones (aldosterone, estradiol, es-triol, testosterone, thyroxin), drugs (theophylline, digoxin, digitoxin), total proteinAs far as possible, isotope dilution mass spectrometry is used for the primary measurements in both institutes (e.g. [4]). 

---