6136-37-4Relevant articles and documents
Metabolism of theophylline and its inhibition by fluoroquinolones in rat hepatic microsomes
Davis,Aarons,Houston
, p. 563 - 573 (1995)
1. The effects of β-naphthoflavone, dexamethasone, phenobarbitone and isosafrole on the metabolism of theophylline by rat liver microsomes have been studied. Only β-naphthoflavone, a known P4501A inducer, increased the rate of 1-methylxanthine formation (3-fold), whereas all the inducers studied increased the rate of 1,3-dimethyluric acid production (2.5-3-fold). 2. To study the effects of a range of fluoroquinolones on theophylline metabolism, β-naphthoflavone-induced microsomes mere used, as the ratio for metabolite production rates was similar to that of untreated microsomes (4:1,3-dimethyluric acid: 1-methylxanthine at 2 mM theophylline). High concentrations of fluoroquinolones (0.5-1.5 mM) were required to affect microsomal theophylline metabolism. 1-Methylxanthine was more sensitive to fluoroquinolone inhibition by enoxacin, ciprofloxacin, norfloxacin and pipemidic acid than 1,3-dimethyluric acid; CP67015, had a significant effect on 1,3-dimethyluric acid production only; binfloxacin had no effect on either pathway. 3. Ethoxycoumarin, a rapidly metabolized substrate, was also investigated as a surrogate for theophylline in in vitro experiments. Fluoroquinolone inhibition of ethoxycoumarin O-de-ethylation in β-naphthoflavone-induced microsomes was quantitatively greater but qualitatively similar to theophylline metabolism (IC(50s) 440-870 μM at 2 μM 7-ethoxycoumarin). 4. These data are comparable with previous rat experiments in vivo, indicating that enoxacin, ciprofloxacin and norfloxacin have similar intrinsic activity in the inhibition of theophylline metabolism.
Multiplicity of cytochrome P-450 species involved in theophylline metabolism in mouse hepatic microsomes
Konishi,Morita,Yamaji
, p. 576 - 580 (2007/10/03)
To ascertain the multiplicity of the cytochrome P-450 (P-450) species participating in the individual metabolic conversion of theophylline by 8-hydroxylation, 3-demethylation and 1-demethylation in mice, kinetics were studied under various conditions using untreated and inducer-treated mouse hepatic microsomes. Eadie-Hofstee plots of 1-demethylation in untreated microsomes exhibited a straight line, whereas those of 8-hydroxylation and 3-demethylation were curved lines. The biphasic kinetics indicated the contribution of two P-450 populations to the respective metabolic pathways; one characterized by high affinity and low capacity, the other by low affinity and high capacity. The high affinity population was efficiently induced by β-naphthoflavone (β-NF), and was highly susceptible to inhibition by a specific CYP1A inhibitor. The low affinity population was sensitive to induction by phenobarbital (PB), and was markedly inhibited by preferential inhibitors for PB-inducible P-450 species. The present results indicated that two P-450 populations contributed to the theophylline metabolism in mouse hepatic microsomes, and that the high and low affinity populations corresponded, respectively, to CYP1A, and a PB-inducible P-450 species having a much higher capacity than CYP1A.
General synthesis and properties of 1-monosubstituted xanthines
Muller
, p. 125 - 128 (2007/10/02)
A general convenient synthesis of 1-monosubstituted xanthines (7H-imidazo[4,5-d]pyrimidine-2,6(1H,3H)-diones), starting from 3-substituted 6-aminouracils, is described. After conversion of the 6-aminouracils to the corresponding 5,6-diaminouracils, reaction with formic acid, or with triethyl orthoformate, leads to the novel xanthines in good to excellent yields, while ring closure in alkaline medium, which is commonly used in xanthine synthesis, is not successful.
