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PubMed1983

Impairment of aminopyrine clearance in aspirin-damaged canine gastric mucosa.

Using an in vivo canine chambered stomach preparation, the clearance of [14C]aminopyrine across mucosa when intravenously infused and the back-diffusion of this substance from gastric lumen to mucosa when topically applied to gastric epithelium were evaluated in aspirin-damaged gastric epithelium. In mucosa damaged by either 20 mM or 40 mM aspirin, the recovery of [14C]aminopyrine, when topically mixed with acid (pH = 1.1) perfusate solution, was not significantly different from nondamaged control mucosa. In addition, the degree of "trapping" of this substance from back-diffusion was not different in damaged mucosa from that observed in nondamaged epithelium. In contrast, when [14C]aminopyrine was intravenously infused, its clearance was significantly impaired in aspirin-damaged mucosa when compared with control studies, as evidenced by the increased "trapping" of this substance in injured epithelium. These findings indicate that movement of aminopyrine from plasma to gastric lumen is impaired in damaged epithelium, making the aminopyrine clearance technique an unreliable method to accurately measure absolute gastric blood flow in this experimental setting.

Aminopyrine↗
PubMed1976

Abnormal aminopyrine metabolism in patients with hepatic neoplasm. Detection by breath test.

Aminopyrine metabolism was assessed by the aminopyrine breath test (ABT) in 153 patients with malignant disease, of whom 75 had hepatic neoplasm and 78 had none. Radioactive carbon dioxide (14CO2) exhalation was measured two hours after oral administration of a trace dose of carbon-14 labeled aminopyrine. The ABT was correct in 62 of 75 (83%) patients with hepatic neoplasm and in 73 of 78 (94%) patients without. It was correct in 16 of 22 (73%) patients who had hepatic neoplasm without abnormal serum biochemistry. Aminopyrine metabolic clearance rate (AMCR) was 32.4 ml/min in patients with hepatic neoplasm and 103.4 +/- 18.8 ml/min in the patients without. There was a highly significant correlation between ABT and AMCR (r =.76, P less than .01). We conclude that aminopyrine metabolism is depressed in most patients with hepatic neoplasm and that the ABT affords a useful method for detecting malignant tumors of the liver.

Administration, Oral↗
PubMedDate not supplied

Aminopyrine demethylation kinetics. Use of metabolite exhalation rates as an index of enhanced mixed-function oxidase activity in vivo.

The usefulness of determining aminopyrine demethylation kinetics via monitoring of metabolite exhalation rats had been assessed. In rats receiving [N-dimethyl-14C]aminopyrine, a biexponential decline in the 14CO2 exhalation rate is apparent when monitoring is continued over a 5 to 6-hr period. Both the fast phase (representing the first demethylation) and the slower phase (representing the second demethylation) are markedly influenced by phenobarbital and promethazine pretreatment. These changes are consistent with enhanced mixed-function oxidase activity. Examination of the urinary excretion products of aminopyrine obtained in these studies support this claim. The sensitivity of the above index of mixed-function oxidase activity is increased considerably by the use of crossover experimental designs. Considerable interanimal variation is observed in the metabolite production in both exhaled air and urine from rats administered aminopyrine.

Aminopyrine↗
PubMed1985

1H-NMR study of the interaction of aminopyrine with purified rat liver microsomal cytochrome P-450.

Longitudinal relaxation (T1) measurements for all lines (N(CH3)2, N(CH3), C(CH3), phenyl) in the aminopyrine 1H-NMR spectrum were used to study the interaction of aminopyrine with purified microsomal cytochrome P-450 from livers of phenobarbital-treated rats. The paramagnetic contribution to the observed T1(-1) values was determined from its dependence on aminopyrine concentration. The Solomon-Bloembergen equation was used to calculate between Fe3+ and aminopyrine distances in the enzyme-substrate complex. For all protons these distances are about 8 A.

Aminopyrine↗
PubMed1983

Partial inhibition of hepatic microsomal aminopyrine N-demethylase by caffeine in partially purified cytochrome P450.

Cytochrome P-450 substrate interactions were studied with cytochrome P-450 partially purified from livers of untreated, phenobarbital-treated, benzo[a]pyrene-treated and caffeine-treated rats. Partial inhibition of aminopyrine N-demethylase in presence of in vitro caffeine observed with intact microsomes was further investigated in a reconstituted system composed of partially purified cytochrome P-450 and cytochrome c reductase. Caffeine addition (in vitro) to partially purified cytochrome P-450 altered the hexobarbital, aniline and ethylisocyanide induced spectral change, and decreased NADPH oxidation in presence of substrates aminopyrine and acetanilide. NADPH oxidation was found to be increased in presence of aminopyrine and unaltered in presence of acetanilide in reconstituted system having partially purified cytochrome P-450 from caffeine-treated rats. Our studies suggest that caffeine acts as a true modifier of cytochrome P-450 and is possibly responsible for the formation of abortive complexes with aminopyrine.

Aminopyrine N-Demethylase↗
PubMed1975

Aminopyrine--an effective modifier of liver and serum gamma glutamyl transpeptidase.

Serum activities of gamma glutamyl transpeptidase, alanine and aspartate aminotransferases, and alkaline phosphatase were determined in children on long-term treatment with aminopyrine. Gamma glutamyl transpeptidase activity was increased up to 15 times above the upper normal limit in children, who received aminopyrine for two weeks or longer. Livers of rats treated with aminopyrine (600 mg/kg/day for 18 to 25 days) had an exceedingly increased activity of gamma glutamyl transpeptidase and a slightly elevated microsomal cytochrome P-450 content. Apparently isolated enhancement of serum gamma glutamyl transpeptidase during aminopyrine medication represents a drug-induced increase of microsomal liver enzymes without clinical relevance and without evidence of damage of liver cells.

Adolescent↗
PubMed1978

Phenobarbital stimulation of cytochrome P-450 and aminopyrine N-demethylase in hyperplastic liver nodules during LD-ethionine carcinogenesis.

Microsomes isolated from hyperplastic liver nodules and hepatomas, induced by DL-ethionine, exhibited a reduced cytochrome P-450 content and aminopyrine N-demethylase activity when compared to the organelles of control and surrounding non-nodular liver. Phenobarbital administration to rats caused an increase of microsomal protein, cytochrome P-450 and aminopyrine N-demethylase in all tissue tested. In the hepatoma the rise of cytochrome P-450 and aminopyrine N-demethylase/g of tissue was very low and it is compensated by a slight increase of microsomal protein. In hyperplastic nodules as well as in control and surrounding livers, cytochrome P-450 and aminopyrine N-demethylase increased more than microsomal protein. However, the phenobarbital-induced stimulation was significantly lower in hyperplastic nodules than in control and surrounding livers.

Aminopyrine N-Demethylase↗
PubMed1997

Oxidation of aminopyrine by the hydroperoxidase activity of lipoxygenase: a new proposed mechanism of N-demethylation.

The oxidation of aminopyrine, an N-alkyl aromatic amine, by the hydroperoxidase activity of lipoxygenase was studied. Aminopyrine gave rise to a purple color in the presence of H2O2 and lipoxygenase, the color being proportional to the aminopyrine radical cation. The H2O2/aminopyrine radical cation molar ratio was 0.5. The overall reaction was considered as an enzymic-chemical second order mechanism with substrate regeneration. From the equations, the apparent constant of the radical cation's decomposition (k'app) was evaluated under different experimental conditions. It was found to be inversely proportional to the proton concentration but unaffected by the concentration of aminopyrine. These results suggest a new comprehensive mechanism for N-demethylation, which takes into account the described presence of both nitrogen- and carbon-centered radicals and the marked effect of pH on the stability of the radical cation.

Aminopyrine↗
PubMed1989

High activity of cytochrome P-450-linked aminopyrine N-demethylase in mouse brain microsomes, and associated sex-related difference.

The presence of cytochrome P-450 and associated mono-oxygenase activities was examined in brain microsomes from male and female mice. Although the cytochrome P-450 level in male mouse brain was very low as compared with mouse liver, the aminopyrine N-demethylase and morphine N-demethylase specific activities in male mouse brain were much higher than those observed in mouse liver. Ethoxycoumarin O-de-ethylase and aniline hydroxylase activities were, however, not detected in mouse brain. Sex-related differences were observed in both the cytochrome P-450 levels and aminopyrine N-demethylase activity in mouse brain, the levels of both being higher in male mouse brain as compared with female mouse brain. Aminopyrine N-demethylase activity in mouse brain microsomes was dependent on the presence of oxygen and NADPH and could be inhibited by piperonyl butoxide, N-octyl imidazole and carbon monoxide. Antiserum raised to the phenobarbital-inducible form of rat liver cytochrome P-450 [P-450(b+e)] inhibited mouse brain aminopyrine N-demethylase activity by around 80+ mouse brain microsomal protein exhibited cross-reactivity against this antiserum when examined by Ouchterlony double diffusion and immunoblotting. The present results indicate the presence of a phenobarbital-inducible form of cytochrome P-450 (or a form of cytochrome P-450 that is similar immunologically) in mouse brain microsomes, which is associated with a sex-related difference.

Aminopyrine N-Demethylase↗
PubMed1982

Interpretation of CO2 exhalation rate data from demethylation of aminopyrine and its metabolite monomethylaminoantipyrine.

1 Aminopyrine breath tests make use of the commercially available (N-dimethyl-[14C])-aminopyrine. A pharmacokinetic model has been proposed to relate 14CO2 exhalation rates (CER) to the demethylation of ([14C]-methyl)-aminopyrine (AP) and -monomethylaminoantipyrine (MAP). 2 computer simulations based on the model show that the shape of the CER-time profile is largely dependent on the ratio of the MAP to AP elimination rate constants. If this ratio equals 0.5 then the CERs decline in the monoexponential fashion. Ratios less than 0.5 result in concave biexponential curves whereas ratios greater than 0.5 result in convex curves. When demethylation is not complete for both compounds the transfer from biexponential to monoexponential behaviour will only occur at ratios greater than 0.5. 3 The resolution of concave biexponential CER-time profiles to give accurate estimates of AP and MAP elimination rate constants can only be achieved when the length of the experiment is adequate. The commonly employed 2 microCi tracer dose of aminopyrine is insufficient to monitor CER over the necessary time period to detect the proposed biexponential decline.

Aminopyridines↗
PubMed1994

Evaluation of indocyanine green retention and aminopyrine breath tests in patients with malignant biliary obstruction.

Impaired hepatic function is a major contributory factor to the high incidence of postoperative morbidity and mortality in patients with malignant biliary obstruction. Dynamic hepatic function tests such as indocyanine green (ICG) retention and aminopyrine breath tests were evaluated in such patients to define whether they were clinically useful for prediction of postoperative morbidity and mortality. Forty-four patients with malignant biliary obstruction undergoing surgery for relief of obstructive jaundice were recruited into the study. Indocyanine green retention and aminopyrine breath tests were carried out in all patients pre-operatively and repeated in 36 patients postoperatively. The ICG retention was abnormal in all patients before surgery and there was significant improvement 2 weeks after surgery (32.8 +/- 2.5% vs 18.3 +/- 2.8%, P = 0.001). The change in ICG retention levels correlated with the serum bilirubin levels but the pre-operative ICG retention value could not predict postoperative morbidity and mortality. The aminopyrine breath test was abnormal in all but one patient. It correlated with pre-operative prothrombin time of the patients before surgery but it did not improve significantly after surgery and was not predictive of postoperative outcome. It is concluded that both ICG retention and aminopyrine breath tests have limited clinical value in the pre-operative evaluation of patients with malignant biliary obstruction.

Aged↗
PubMed1982

N-Demethylation of aminopyrine by the nasal mucosa in mice and rats.

N-demethylation of aminopyrine was demonstrated in the nasal mucosa of C57 Bl mice and Sprague-Dawley rats by measurements of the 14CO2 formed at incubation of 14C-aminopyrine with tissue-slices. The metabolism of aminopyrine by the nasal mucosa was induced by phenobarbital pretreatment and susceptible to inhibition with metyrapone and SKF 525 A suggesting the presence of cytochrome P-450-dependent enzyme system in the tissue. Immediately after injection of 14C-aminopyrine in rats a uniform distribution of radioactivity in the body was recorded. After thirty minutes, however, a preferential localization of radioactivity was found in the nasal mucosa and in the liver. By pretreatment with metyrapone the uptake of radioactivity in the nasal mucosa and in the liver was blocked suggesting that the observed accumulation of radioactivity is due to metabolites.

Aminopyrine N-Demethylase↗
PubMed1984

Carbonic anhydrase activity and aminopyrine uptake in isolated gastric mucosal cells.

The role of carbonic anhydrase in the regulation and production of gastric acid was examined. Studies were done on isolated rabbit fundic mucosal cells, in which carbonic anhydrase activity and [14C]aminopyrine uptake were measured. The oxyntic cell-enriched cell fractions had the largest carbonic anhydrase content (4.2 +/- 0.1 U/10(6) cells) compared with other mucosal cells. The cellular carbonic anhydrase content of all isolated cell fractions was primarily a soluble enzyme, accounting for 10% of the total mucosal enzyme quantity. The remainder was found in the incubation medium from the mucosal dispersion procedure. The remaining cellular carbonic anhydrase activity in the oxyntic cell fraction was not enhanced by secretagogues. [14C]aminopyrine uptake increased dose dependently in the presence of histamine and dibutyryl cAMP. Acetazolamide (0.2 mM) inhibited the cellular carbonic anhydrase activity (99%) but did not interfere with the cellular uptake of [14C]aminopyrine. The present data from isolated cells suggest that cellular carbonic anhydrase in the oxyntic cell does not appear to be an integral step in the initiation of secretory function of isolated oxyntic cells. The lack of interference by the carbonic anhydrase inhibitor with H+ production does not exclude a role for carbonic anhydrase at high levels of acid secretion as it may occur in vivo, since isolated oxyntic cells probably do not achieve maximal rates of acid secretion and aminopyrine uptake reflects acid gradients and not rate of acid secretion.

Acetazolamide↗
PubMed1981

Characteristic biotransformation of aminopyrine in rat when administered with barbital.

After the administration of aminopyrine with or without barbital to rats, aminopyrine and its main metabolites were detected in plasma and the brain by means of gas chromatography-mass spectrometry. It was clarified that a marked increase of 4-monomethylaminoantipyrine was observed in the case of coadministration of aminopyrine and barbital, while the plasma level of aminopyrine decreased significantly compared with single administration.

Aminopyrine↗
PubMed1989

Chloroperoxidase-catalyzed oxidation of aminopyrine.

Although in the absence of halide ion chloroperoxidase did not catalyze the ethylhydroperoxide (EHP)-supported oxidation of aminopyrine, in the presence of Br- or Cl-, chloroperoxidase did catalyze the oxidation of aminopyrine, generating the aminopyrine cation radical (AP+). The initial rate of AP+ formation was determined by monitoring the absorbance at 565 nm. The pH optimum of the reaction was centered around 5.0. The rate of AP+ formation showed typical Michaelis-Menten saturation kinetics with respect to EHP, aminopyrine and Br-. The rate of formation of bromine in the chloroperoxidase-EHP-Br- system was also determined by measuring the change in absorbance at 267 nm. In the system containing 1 mM EHP and 0.2 M KBr at pH 5.0, the rate was 1.8 nmol of bromine/s/micrograms of chloroperoxidase, which was slower than that of AP+ formation under the same conditions. The present results suggest that the formation of AP+ is initiated by the halogenation of the N,N-dimethylamino group followed by the homolysis of the haloammonium cation, and that the most likely halogenating reagent is an enzyme-bound halogenating intermediate.

Aminopyrine↗
PubMed1977

Hepatic aminopyrine N-demethylase system: further studies of assay procedure.

Rat hepatic aminopyrine N-demethylase activity was measured by detecting the amount of formaldehyde produced from aminopyrine. Some optimal conditions for the N-demethylation were determined using both isolated microsomes and whole homogenates, and the standard assay method is described. Formaldehyde production from the substrate by microsomal enzyme system was linear to the amount of microsomes added during 3 min reaction time, whereas long-time incubation caused a decrease in the apparent activity of aminopyrine N-demethylation. The N-demethylase activity observed in normal rat liver homogenate was quite similar to that in microsomes when the activity was expressed on the basis of cytochrome P-450 as molecular activity. Pretreatment of animals with typical inducers, phenobarbital and 3-methylcholanthrene, resulted in alteration of the aminopyrine N-demethylase system, which was detectable in both microsomes and whole homogenates.

Aminopyrine↗
PubMed1998

Histamine H2-receptor antagonism of T-593, an anti-ulcer agent: studies on aminopyrine accumulation in isolated canine gastric mucosal cells.

Histamine H2-receptor antagonistic properties of the anti-ulcer agent T-593, (+/-)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl] -3-[2[[[5-(methylamino)methyl-2-furyl]methyl]thio] ethyl] -2-(methylsulfonyl)guanidine, were investigated on [14C]aminopyrine accumulation in isolated canine gastric mucosal cells and compared with those of ranitidine and famotidine. The potency of T-593-inhibition of [14C]aminopyrine accumulation stimulated by 10(-4) M histamine, with an IC50 value of 1.85 x 10(-6) M, was approximately 5 times greater than that of ranitidine, but half that of famotidine. T-593 did not affect [14C]aminopyrine accumulation stimulated by carbachol or dibutyryl-cAMP. T-593 depressed the maximal response of the histamine concentration-response curve with a dose-related displacement to the right, indicating that the nature of the H2-receptor antagonism of T-593 was insurmountable and included non-competitive inhibition. The inhibitory efficacy of T-593 was time-dependent and was retained after the cells were washed. The inhibitory potency of (-)-S-T-593, one of the enantiomers, on the [14C]aminopyrine accumulation stimulated by histamine was approximately twice that of racemic T-593 and it also behaved as an insurmountable H2-receptor antagonist. However, the potency of (+)-R-T-593 was markedly weak. These results suggest that T-593 has H2-receptor antagonism that is insurmountable and this agent slowly associates and dissociates with the receptor in isolated canine gastric mucosal cells and that the specific substance causing H2-receptor antagonism is (-)-S-T-593.

Aminopyrine↗
PubMed1981

Bacterial degradation of aminopyrine.

1. Four strains of bacteria growing with aminopyrine as sole source of carbon were isolated from soil and were identified as strains of Phenylobacterium immobilis. 2. Strain M13 and strain E, the type species of Phenylobacterium immobilis (DSM 1986), which had been isolated by enrichment with chloridazon (5-amino-4-chloro-2-phenyl-2H-pyridazin-3-one) were used to investigate the bacterial degradation of aminopyrine. 3. Three metabolites were isolated and identified as: 4-(dimethylamino)-1,2-dihydro-1,5-dimethyl-2-(2,3-dihydro-2,3-dihydroxy-4,6-cyc lohexadien-1-yl)-3H-pyrazol-3-one, 4-(dimethylamino)-1,2-dihydro-1,5-dimethyl-2-(2,3-dihydroxyphenyl)-3H-pyrazol-3 -one and 4-(dimethylamino)-1,2-dihydro-1,5-dimethyl-3H-pyrazol-3-one. 4. An enzyme extract from cells of strain m13 was shown to further metabolize the catechol derivative of aminopyrine, with the formation of 2-pyrone-6-carboxylic acid. 5. Results indicate that the benzene ring of aminopyrine is the principal site of microbial metabolism.

Aminopyrine↗