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PubMed1995

Metabolism of aminopyrine and derivatives in man: in vivo study of monomorphic and polymorphic metabolic pathways.

1. The main metabolic pathways involved in the biodisposition of aminopyrine have been monitored in vivo in 60 healthy volunteers by measuring the amount of parent drug and metabolites recovered in the urine 24 h after oral administration of 250 mg aminopyrine. 2. The amount of metabolites in the 24-h urine was (mean +/- SD of 60 individuals): unchanged aminopyrine, 0.2 +/- 0.2 mg; methyl aminoantipyrine, 4.5 +/- 2.8 mg; formyl aminoantipyrine, 18.5 +/- 10.1 mg; aminoantipyrine, 9.2 +/- 6.6 mg; and acetyl aminoantipyrine, 31.8 +/- 21.1 mg. 3. Large interindividual differences (12-200-fold changes) are present in all the metabolic steps involved in aminopyrine biotransformation. These differences are not related to gender, intake of caffeine or alcohol, or known drug-metabolizing polymorphisms such as those involved in debrisoquine or mephenytoin metabolism. In contrast, smoking resulted in a decrease in the N(4)-demethylation ratio (p = 0.011). 4. The interindividual differences followed an apparently normal distribution in the N(4)- and N(2)-dimethylation and formylation pathways (p > 0.1). In contrast, acetylation follows a polymorphic distribution (p < 0.03), with an apparent antimode ratio close to 4. With the exception of the acetylation pathway, all of the metabolic ratios correlated between themselves (p < 0.001).

Administration, Oral↗
PubMed1989

Cholecystokinin and gastrin inhibit histamine stimulated aminopyrine uptake in isolated rabbit gastric glands.

In the present study we have analyzed if cholecystokinin (CCK) or gastrin (G) can inhibit acid production in isolated rabbit gastric glands as revealed by the aminopyrine technique. The results show that G 17 I, CCK 8 NS, CCK 8 S, ceruletide and CCK 39 significantly inhibit histamine induced aminopyrine accumulation. No significant inhibition was noted for G 4, G 34 and NT G 1-13. As a group the CCK peptides were more effective than the gastrin peptides in inhibiting the aminopyrine uptake. CCK 8 S and ceruletide, the most potent inhibitors, reduced histamine induced aminopyrine accumulation with an ED50 of 10(-9) and 10(-10) M respectively. These potencies are similar to those by which CCK peptides stimulate isolated pancreatic acini to secrete amylase. Inhibition evoked by CCK 8 S was most effective following 20-40 min of incubation time, possibly indicating that the effect is mediated by the release of an intermediate substance. The results may therefore indicate a role for cholecystokinin as a physiological inhibitor of acid secretion in the rabbit. The results may also contribute to explain why the potent gastric secretagogue gastrin per se fails to stimulate acid formation in gastric glands isolated from the rabbit.

Aminopyrine↗
PubMed1986

[The role of plasma alpha 1-glycoprotein acid in the binding of aminopyrine].

Under certain pathological conditions the binding of various substances by serum proteins is altered. The plasma concentrations of alpha 1-acid glycoprotein, also known as orosomucoid are reported to be elevated in stressful situation and in certain disease states like acute myocardial infarction. The binding of aminopyrine to serum proteins and alpha 1-acid glycoprotein was determined using equilibrium dialysis. It appears that alpha 1-acid glycoprotein has specific binding sites for aminopyrine. Aminopyrine was also bound to other serum proteins. On addition the results indicate that an increase of alpha 1-acid glycoprotein to concentrations such as those seen in some pathological states does not really alter the percent of aminopyrine bind to serum proteins.

Aminopyrine↗
PubMed1976

Evaluation of (14C)aminopyrine clearance for determination of gastric mucosal blood flow.

This study has demonstrated high correlation between the radiometric and spectrophotometric determinations of gastric mucosal aminopyrine clearance. The radiometric method is technically easier, allows a larger number of samples to be determined and is safer to the subject. The clearance of small amounts of [14C]aminopyrine was unaffected by large doses of unlabeled aminopyrine showing that mucosal extraction is not concentration limited. Small amounts of [14C]aminopyrine may provide an excellent tool for examining the role of mucosal blood flow in the pathogenesis of gastric disease in man.

Aminopyrine↗
PubMed1975

Quantitative assessment of hepatic function by breath analysis after oral administration of (14C)aminopyrine.

The rate of hepatic metabolism of dimethylaminoantipyrine (aminopyrine), which occurs primarily through N-demethylation, was assessed by measurement of the specific activity of 14CO2 excreted in breath samples obtained 2 hours after oral administration of a trace dose of [14C]aminopyrine. The percentage of administered 14C excreted in 14CO2 in 2 hours was 7.0 +/- 1.3 (SD)% in control patients, and significantly less (P less than 0.01) in patients with portal cirrhosis (2.6 +/- 1.2%), fatty liver (4.7 +/- 1.1%), hepatitis (2.6 +/- 1.4%), and hepatic malignancy (3.5 +/- 1.8%). In 16 of 24 subjects with cholestasis not caused by malignant disease the mean 14CO2 excretion was normal. The 14CO2 excretion in patients with portal cirrhosis correlated highly with aminopyrine metabolic clearance rate (r equals 0.92), serum albumin (r equals 0.75), and retention of bromsulphalein (r equals 0.73). Abnormal 14CO2 excretion returned to normal in patients with hepatitis, when the hepatitis resolved. The data suggest that the aminopyrine breath test is a safe, simple, qualitative and quantitative liver function test.

Administration, Oral↗
PubMed1992

A comparison between antipyrine and aminopyrine blood clearances.

The purpose of this study was to investigate the relationship between two quantitative liver functions, that is, antipyrine blood clearance and aminopyrine blood clearance, in normal subjects and in patients with liver cirrhosis. The mean blood clearances of antipyrine and aminopyrine in cirrhotic patients (0.220 +/- 0.085 ml/min/kg and 1.13 +/- 0.56 ml/min/kg; n = 64) was 50% and 38% of that of normal subjects (0.440 +/- 0.110 ml/min/kg and 2.95 +/- 0.59 ml/min/kg; n = 11). While no significant correlation was demonstrated between these two values in normal subjects (n = 11, r = -0.107, p greater than 0.10), a strong positive correlation was observed between antipyrine and aminopyrine blood clearances in cirrhotic patients (n = 64, r = 0.846, p less than 0.001). These results suggest that both antipyrine and aminopyrine blood clearances may be valuable indicators for assessing the total hepatic functioning mass in cirrhotics.

Adult↗
PubMedDate not supplied

[Characteristics of induced aminopyrine N-demethylase].

The study of the inducing effect of phenobarbital on the activity of N-demethylase of aminopyrine in the rat liver microsomes revealed the correlation of the rate of enzymic reaction with the changes in the maximum binding of aminopyrine by cytochrome P-450 rather than with the content of hemoprotein itself. The comparison of the activity of N-demethylation of aminopyrine in control and phenobarbital-induced rats showed the quantitative correspondence of the yield of products of the reaction--formaldehyde in the liver microsomes and 4-aminoantipyrine in the urine samples. Self-induction of N-demethylating activity at repeated aminopyrine administration to rats and the dose dependence of this phenomenon were found.

Aminopyrine N-Demethylase↗
PubMed1979

The effect of lead on aminopyrine N-demethylation.

The effect of various lead salts on "in vitro" aminopyrine N-demethylation was investigated. Lead was administered to male rats as a 1% solution in the drinking water. After seven days of lead treatment it was found that lead chloride and lead acetate had no effect on microsomal aminopyrine N-demethylation while lead nitrate increased aminopyrine metabolism. Intraperitoneal administration of either lead chloride or lead nitrate at a dose of 20 mg./kg. decreased metabolism. Lead chloride by oral administration did not suppress phenobarbital induction of aminopyrine metabolism in rats.

Acetates↗
PubMed1983

[Experiences with the 14C-aminopyrine breath test in liver cirrhosis and under the effect of sodium diclofenac (Voltaren)].

The 14C-aminopyrine breath test is a simple procedure for the non-invasive determination of the microsomal function of the liver. After the oral administration of a tracer dose of 2 microCi (74 kBq) of 14C-aminopyrine the 14CO2 activity of the expired breath air is determined in hourly intervals. There is a close correlation between its decrease and the elimination of aminopyrine from the plasma. Both the elimination constant of 14CO2 (Kbreath) and the maximal specific 14CO2 activity are useful quantitative parameters of the test. They allow conclusions as to the hepatic demethylation capacity. Both parameters were significantly lower in 15 patients with liver cirrhosis than in 12 control patients. The non-steroidal anti-inflammatory drug diclofenacsodium (Voltaren) did not significantly influence the demethylation of 14C-aminopyrine in 5 patients with rheumatic diseases and in 2 healthy probands. Further experiences with the breath test are necessary, especially with respect to its suitability for prospective investigations.

Adult↗
PubMed1983

Abnormalities in liver function and morphology and impaired aminopyrine metabolism in hereditary hepatic porphyrias.

The aminopyrine breath test and measurement of postprandial serum bile acids were performed in 67 patients with well-documented hereditary hepatic porphyria. Elevated postprandial serum bile acids levels were found in 75% and the aminopyrine breath test was abnormal in 42% of the patients studied. These function tests exhibited a statistically significant correlation with the excretion of porphyrin precursors in patients with acute intermittent porphyria. Furthermore, all 12 patients with acute intermittent porphyria who had a liver biopsy because of abnormalities in the aminopyrine breath test or postprandial serum bile acids measurement, or both, were found to have diffuse, moderately severe, but nonspecific ultrastructural changes of hepatocytes, indicative of significant subcellular damage. While a direct relationship between functional and morphologic abnormalities is speculative, it is possible that the defective heme biosynthesis, perhaps related to the reduced aminopyrine demethylation, could form the basis for the ultrastructural hepatic changes in porphyria. This, in turn, could be the cause of the elevated postprandial serum bile acids levels.

Adult↗
PubMed1981

[The antipyretic effects of aminopyrine and sodium acetylsalicylate on endotoxin-induced fever in rabbits (author's transl)].

The antipyretic effects of aminopyrine and sodium acetylsalicylate on endotoxin-induced fever in rabbits were studied relative to the route and dose of administration. Intravenous administration of aminopyrine produced a marked antipyretic effect, intracisternal administration produced a lesser effect and i.v. was the effective route. Similar results were obtained in the nonfebrile rabbits. On the contrary, the intracisternal administration of sodium acetylsalicylate reduced the body temperature to the same degree both in febrile and nonfebrile rabbits, but sodium acetylsalicylate given i.v. to nonfebrile rabbits did not reduce the body temperature. 4-aminoantipyrine and N-acetyl-4-aminoantipyrine, the major metabolites of aminopyrine had a lesser effect in the febrile rabbits. Antipyretic effects of sodium salicylate, the metabolite of sodium acetylsalicylate were similar to the effects of sodium acetylsalicylate. These data suggest that the antipyretic effects of aminopyrine may not be involved in the CNS, while the antipyretic effects of salicylate may be due to a direct action on the CNS.

Aminopyrine↗
PubMed1995

Aminopyrine metabolism in man: the acetylation of aminoantipyrine cosegregates with acetylation of caffeine.

Aminopyrine and caffeine metabolism was evaluated in vivo in 21 healthy volunteers in order to elucidate whether the acetylation capacity of the two substances correlates. The ratio of the aminopyrine metabolites 4-acetylaminoantipyrine (AAA)/4-aminoantipyrine (AA) was compared with the ratios of caffeine metabolites AAMU/1-X and AAMU/(AAMU + 1-X + 1-U). All the subjects phenotyped as slow acetylators with caffeine displayed AAA/AA ratios lower than 3.4, whereas the extensive acetylators had ratios higher than 3.8. Therefore, the acetylator phenotype determined with caffeine cosegregated with the capacity to acetylate the aminopyrine metabolite AA. The N-demethylation of aminopyrine and caffeine correlated strongly in the subjects studied (p < 0.001). A highly significant correlation (r = 0.92; p < 0.001) was also observed between caffeine N(1)- and N(7)-demethylation activities. In addition, most N-demethylation steps of both drugs significantly correlated, suggesting partial contributions by identical or closely related enzymes in their metabolism.

Acetylation↗
PubMedDate not supplied

The aminopyrine breath test.

The metabolic basis and clinical application of the aminopyrine breath test (ABT) as a measure of liver function is reviewed in this article. Several papers have been published in the 20 years that have elapsed since the test was validated in man by Hepner and Vesell. Nevertheless, even if the aminopyrine breath test has been shown to be a non-invasive, reliable and semiquantitative liver function test with diagnostic and prognostic accuracy, it is not yet extensively used in clinical practice, probably because it is not widely known to clinicians. The aminopyrine breath test, like other newer tests (phenacetin, caffeine and erythromycin breath tests), allows the effects of drugs on hepatic cytochrome P-450 to be explored both in normal subjects and in liver patients. This interesting field of application is sure to expand the appeal of the aminopyrine breath test in the future.

Aminopyrine↗
PubMedDate not supplied

Action of methotrexate on cytochrome P-450 monooxygenases in rats. Study performed with [13C]-aminopyrine micro breath test.

The aim of this work was to study the action of methotrexate on the cytochrome P-450 hepatic monooxygenases and to follow the evolution of the metabolic processes with time, after oral and intra-peritoneal administration of these drugs to rats. In order to perform this study, we used a new technique the [13C]-aminopyrine breath test (ABT). At the end of the in vivo study, the rats were sacrificed and the cytochrome P-450 concentration as well as microsomal enzymatic activities of aminopyrine N-demethylase, 7-ethoxyresorufin desalkylase, 7-ethoxycoumarin desalkylase, 7-pentoxyresorufin desalkylase were determined. A histological study of the liver was also carried out. Finally, haematological and biochemical parameters were also determined. In this study, 3 series of 6 rats were used: a control group, a group receiving 70 mg/kg of methotrexate by intra-peritoneal route, and a group of rats treated orally with 1 mg/kg of methotrexate every 2 days. For each observation, the variation of the ABT scores and of the cytochrome P-450 amounts as well as the microsomal aminopyrine N-demethylase activity were in good agreement.

Administration, Oral↗
PubMed1986

Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests.

The effects of low- and high-protein diets on theophylline kinetics and the time course of changes in 13C-labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low-protein diet, mean theophylline clearance fell 21% (P less than 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P less than 0.02). With a high-protein diet, mean theophylline clearance rose 26% (P less than 0.004) and the t1/2 shortened to 7.4 hours (P less than 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low-protein diet. Theophylline clearance correlated with caffeine breath test values during the low- (r = 0.73) and high- (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low- (r = 0.47) and high- (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.

Adult↗
PubMed1994

Short report: interferon-alpha decreases 14C-aminopyrine breath test values in patients with chronic hepatitis C.

OBJECTIVE: To investigate the effect of interferon-alpha on cytochrome P-450 dependent microsomal function. METHODS: The 14C-aminopyrine breath test was performed before, during and after a standard dose of interferon-alpha (3,000,000 units three times per week) was administered for at least six months (nine patients with chronic hepatitis C). RESULTS: Mean aminopyrine breath test values obtained during therapy were significantly lower than either pre- or post-treatment, the degree of reduction varying widely between individuals. Pre- and post-treatment aminopyrine breath test values did not differ significantly. CONCLUSION: Interferon therapy is associated with a significant and transient inhibition of cytochrome P-450 activity, which should be taken into account when prescribing concurrent therapy with drugs metabolized by this pathway.

Adult↗
PubMed1984

Renal aminopyrine demethylation in several species determined by a sensitive radiometric method.

Renal microsomal aminopyrine demethylation activities of several species were measured by a sensitive radiometric method using [dimethylamino-14C-]aminopyrine as a substrate and 2,4-dinitrophenylhydrazine as a trapping agent for the formaldehyde formed. The activity was highest in hamsters (0.75 nmol min-1 mg-1 protein) and that in rabbits, rats, mice, and guinea-pigs was 19.7, 7.0, 4.5 and 3.7%, respectively, of the hamster values. These species differences did not correlate with species differences in cytochrome P-450 content or in NADPH cytochrome c reductase activity. Aminopyrine demethylation activities in sliced renal tissues of several species were also compared. This activity was also found highest in hamsters (0.54 nmol min-1 g-1 wet tissue) and the activities in rabbits, rats, and guinea-pigs were 9.2, 1.8 and 2.5%, respectively, of the hamster values.

Aminopyrine↗
PubMedDate not supplied

Caffeine demethylase activity in human and Dark Agouti rat liver microsomes. Comparison with aminopyrine N-demethylase activity.

Human and Dark Agouti rat liver microsomes were analyzed for caffeine metabolism focusing on demethylase activity by using a simplified isocratic HPLC method. Results showed that, despite interspecies quantitative and qualitative differences on caffeine metabolism, mainly demethylated caffeine metabolites were detected in both species. Humans showed interindividual quantitative differences in caffeine demethylase activity in contrast to rats and, in both cases, the proportion of metabolites remained constant. In addition, aminopyrine N-demethylase activity was assayed, showing a direct correlation with caffeine demethylase activity in humans (r = 0.71) that is reported here for the first time, but not in rats (r = 0.21). These results indicate that, in human liver microsomes, caffeine and aminopyrine could be demethylated by the same or by closely related enzymes; whereas in Dark Agouti rats, there is no apparent relation between caffeine and aminopyrine demethylation pathways.

Aminopyrine↗