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PubMedDate not supplied

Salivary antipyrine half-life during injectable progestagen contraception.

Antipyrine pharmacokinetics were studied in 6 healthy women before and 2, 8 and 12 weeks after administering the injectable progestagen (progestin), norethisterone (norethindrone) enanthate 200mg intramuscularly. Additionally, antipyrine kinetics in 5 women who had previously used the injectable contraceptive for 8 to 14 months were compared with values obtained in 14 non-users. Antipyrine was measured in saliva using a spectrophotometric method, following an oral dose of 18 mg/kg bodyweight. In the 6 women studied prospectively the mean salivary antipyrine half-life was 14.91 +/- 1.5 hours (SEM) before administering the injection, and 13.56 +/- 0.73 at 2 weeks, 15.13 +/- 1.86 at 8 weeks and 15.21 +/- 2.46 hours at 12 weeks after the injection. The mean antipyrine half-life in the 5 long term users of injectable progestagen was 14.21 +/- 2.53 hours compared with 13.66 +/- 0.98 hours in non-users. The results of this study suggest that - in contrast to published data on combined oral contraceptives - neither short nor long term use of parenteral norethisterone enanthate in Indian women is associated with significant alterations in antipyrine clearance.

Adult↗
PubMed1979

Studies on the different metabolic pathways of antipyrine in rats: influence of phenobarbital and 3-methylcholanthrene treatment.

1. The amounts of antipyrine and its metabolites excreted in 24 h urine after i.v. injection of 10 mg antipyrine into male Wistar rats were quantified after enzymic hydrolysis with beta-glucuronidase/aryl sulphatase. In 24 h 2.7% of the administered dose was excreted as unchanged antipyrine, 13.3% as 4-hydroxyantipyrine, 7.4% as norantipyrine, 28.9% as 3-hydroxymethylantipyrine and 1.1% as 3-carboxyantipyrine. 2. Treatment with phenobarbital decreased the antipyrine half-life from 65 to 30 min, but did not significantly change the urinary metabolite profile. Only the amount of 3-carboxyantipyrine was significantly different and increased from 1.1 to 2.6% dose. 3. 3-Methylcholanthrene treatment resulted in a decrease of antipyrine half-life from 72 to 37 min. After treatment 4-hydroxyantipyrine was increased from 13.4% to 25.6% dose, whereas 3-hydroxymethylantipyrine was decreased from 26.8% to 8.5% and 3-carboxyantipyrine from 1.3% to 0.2% of the dose respectively; norantipyrine was unchanged. 4. It is concluded that different types of hepatic cytochrome P-450 may be involved in the formation of 4-hydroxyantipyrine on one hand and the formation of 6-hydroxymethylantipyrine on the other. Another possibility is that in methylcholanthrene-treated animals another haemoprotein is formed that results in the formation of more 4-hydroxyantipyrine and less 3-hydroxymethylantipyrine. In any case, the urinary metabolite profile of antipyrine can be used to study changes in the activity of different cytochromes in drug metabolism studies.

Animals↗
PubMed1983

Human metabolism of antipyrine labelled with 14C in the pyrazolone ring or in the N-methyl group.

After ingestion of [N-14CH3]antipyrine by two healthy male subjects, the urinary recoveries of radioactivity plus norantipyrine (non-radioactive) were 63 and 73%. After ingestion of [3-14C]antipyrine in the same two subjects, the urinary recoveries of radioactivity were 84 and 99%. Therefore, N-demethylated metabolites which have not been identified before, besides norantipyrine, must account for 21--26% of the dose. Serum half-lives of total 14C were about 50% greater than those of unchanged antipyrine. The difference was less in the saliva. Three major metabolites of antipyrine, norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine, in urine were determined by radio-t.l.c. and g.l.c. These three metabolites and antipyrine accounted for 50--69% of the administered dose. The urinary excretion half-lives of these three metabolites were similar to each other and to the serum half-life of antipyrine. 3-Hydroxymethylantipyrine in one subject was excreted more slowly than the other metabolites. The radioactive metabolite not extracted from urine by organic solvents was very polar, as judged by t.l.c.

Adult↗
PubMed1983

Influence of 9-hydroxyellipticine and 3-methylcholanthrene treatment on antipyrine metabolite formation in rats in vivo.

The influence of pretreatment of rats with 9-hydroxyellipticine and 3-methylcholanthrene on different enzymes of the hepatic mixed-function oxidase system were studied using antipyrine as model compound. Antipyrine half-lives and clearances were estimated in blood, and the metabolite profile was determined in urine. 3-Methylcholanthrene treatment resulted in an increase in antipyrine clearance from 17 to 75 ml/min per kg. Partial clearance of formation of 4-hydroxyantipyrine was selectively increased from 3.9 to 28.2 ml/min kg, whereas clearance of 3-hydroxymethylantipyrine was decreased from 3.2 to 1.2 ml/min per kg. Norantipyrine formation was increased from 2.7 to 7.2 ml/min per kg, while 4,4'-dihydroxyantipyrine formation was unchanged. 9-Hydroxyellipticine treatment resulted in no change in the total clearance, and only the clearance of 4,4'-dihydroxyantipyrine was decreased, from 2.5 to 1.5 ml/min per kg. After pretreatment with 3-methylcholanthrene, 9-hydroxyellipticine treatment resulted in a selective decrease in the clearances of 4-hydroxyantipyrine, from 28.2 to 15.8 ml/min per kg, and of 4,4'-hydroxyantipyrine, from 3.8 to 1.6 ml/min per kg. From these results it is concluded, that 9-hydroxyellipticine is a selective inhibitor of the activity of some of the cytochrome P-450s involved in antipyrine metabolism, though this inhibition does not effect all of these enzymes, nor is it restricted to polycyclic hydrocarbon-induced activity. These results further substantiate the value of antipyrine as a model substrate, for they indicate that the formation of all four metabolites of antipyrine in rats is mediated by different (iso-)enzymes.

Alkaloids↗
PubMed1983

Influence of allylisopropylacetamide and phenobarbital treatment on in vivo antipyrine metabolite formation in rats.

The influence of pretreatment with allylisopropylacetamide (AIA) and phenobarbital (PB) on the pharmacokinetics and metabolite profile of antipyrine was studied in rats in vivo. Antipyrine concentrations were measured in blood and urine, and four metabolites (4-hydroxyantipyrine, norantipyrine, 3-hydroxymethylantipyrine and 4,4'-dihydroxyantipyrine) were determined in urine. Treatment with PB increased antipyrine blood clearance from 11.1 to 59.1 ml/min per kg. The clearances for production of metabolites all increased between four- and five-fold, indicating non-selective induction. Treatment with AIA resulted in a reduction of antipyrine clearance to 5.6 ml/min per kg. The clearances to all four metabolites were decreased to about the same extent (52-65% of control values) indicating non-selective inhibition. Treatment with AIA after PB treatment strongly inhibited drug-metabolizing enzyme activity. Blood clearance of antipyrine was reduced from 59.1 to 12.3 ml/min per kg. Clearances to the metabolites were again inhibited non-selectively (to 20-28% of PB-induced values). In contrast to previous reports, AIA in this study inhibited non-induced oxidative microsomal enzyme activity. This inhibition closely resembled AIA inhibition of PB-induced cytochromes. Therefore it is concluded that in untreated rats antipyrine is predominantly metabolized by PB-types of cytochrome P-450.

Acetamides↗
PubMed1976

[Comparative study on the elimination of pindolol (visken) and antipyrin in patients with liver diseases].

25 patients suffering from different hepatic diseases were studied in order to investigate the elimination of the beta-receptor blocking drug pindolol in hepatic disease. Following an overnight fasting period the patients received simultaneously 3 mg pindolol intravenously and 1000 mg antipyrine orally. Plasma samples were taken at certain time intervals for 24 hs and urine was collected for 72 hs for the measurements of drug concentrations in plasma and urine. From these measurements different pharmacokinetic parameters were calculated for both drugs used in the present study according to a one-compartment open model. The total body clearance of antipyrine was selected as a parameter of the metabolic capacity of the liver microsomal enzyme system and was compared with the pharmacokinetic parameters calculated for pindolol by means of linear regression. There was no significant correlation between the total body clearance of antipyrine and the kinetic parameters of pindolol in any of the 25 patients irrespective of the differences in liver disease. On the other hand, 14 patients suffering from cirrhosis of the liver showed a significant correlation between the total body clearance of antipyrine and the overall elimination rate constant or metabolic clearance of pindolol. No correlation was found between antipyrine clearance and total body clearance of pindolol, as some patients with intact renal function excreted a higher proportion of pindolol in the urine as liver function decompensated. The mechanism of such compensatory elimination is unknown. In conclusion, the total body clearance of antipyrine known to represent metabolic liver function showed a significant correlation with the metabolic clearance of pindolol in patients with cirrhosis of the liver. For the other liver diseases investigated, too few patients were studied to calculate an adequate correlation.

Antipyrine↗
PubMed1992

Endogenous interferon plasma levels and antipyrine pharmacokinetics in patients with viral infections.

We investigated the pharmacokinetics of antipyrine and the endogenous plasma levels of interferon alpha (IFN alpha), interferon beta (IFN beta) and interferon gamma (IFN gamma) in 10 otherwise healthy volunteers before outbreak (baseline) and in the symptomatic interval of an acute viral respiratory infection, and also in HIV-1 infected homosexual patients in stadium WR 2-3 (n = 11) and WR 5-6 (n = 11) before and one day after application of the antiretroviral agent zidovudine 800 mg day-1 for 14 days. Interferons were measured by RIA or ELISA, respectively. The concentrations of antipyrine and its metabolites in serum and urine were measured by HPLC. Antipyrine is a pharmacokinetic model substance to estimate the cytochrome P 450 enzyme activity. The plasma levels of IFN alpha and IFN gamma in the symptomatic interval of an acute viral respiratory infection were elevated from 4.7 U ml-1 to 12.6 U ml-1 and from 0.3 U ml-1 to 3.4 U ml-1, respectively. The antipyrine clearance showed a significant decrease from 57.9 ml min-1 to 45.0 ml min-1. In the HIV-1 infected patients in stadium WR 2-3 no alterations in plasma levels of interferons or in the pharmacokinetics of antipyrine were observed after treatment with zidovudine. In contrast to these results, in patients in stadium WR 5-6 we found a significant decrease of IFN alpha and an elevation of the clearance and the clearances to metabolite of antipyrine by about 20 percent.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Effect of physical exercise on one-sample antipyrine clearance.

Moderate physical exercise for a few hours is not expected to reduce the hepatic elimination of drugs exhibiting capacity-limited metabolism (low-clearance drugs such as antipyrine). However, previous studies have shown that antipyrine half-life, measured by the multiple-sampling technique, is increased by exercise. A simplified one-sample procedure for antipyrine clearance determination is increasingly being used as a liver function test. The effects of exercise on this measurement have never been evaluated. We measured antipyrine clearance, using the one-sample, simplified procedure in a group of 50 young Italian army soldiers, while at rest and during a 6 hour march in the mountains (extra energy expenditure: 7.43 kjoule per min). Mean antipyrine clearance was on average 46.6 (SD 10.2) ml/min (range 30.5-65.4) while resting, and 46.2 (10.5) (range 25.5-64.8) while exercising (not different). No specific advice regarding physical exercise is needed whenever liver function is measured in outpatients by the one-sample, simplified antipyrine clearance test.

Adult↗
PubMed1977

Antipyrine metabolism and bronchogenic carcinoma.

Studies in animals indicate that tumor-bearing is associated with inhibition of hepatic drug metabolism. Our purpose was to determine the influence of a tumor on drug metabolism in man. The plasma clearance of antipyrine reflects the rate of its metabolism by the liver. Antipyrine clearance was measured in 7 patients with bronchogenic carcinoma and in 13 normal subjects and 7 patients with chronic lund disease. Mean (+/- SD) antipyrine clearance rates were 2.98 +/- 0.68 1/hr, 2.14 +/- 0.69 1/hr and 2.02 +/- 0.67 1/hr, respectively; indicating that bronchogenic carcinoma is associated with rapid, rather than slow, antipyrine metabolism. Antipyrine clearance (mean +/- SD) in 8 patients with bronchogenic carcinoma and evidence of liver metastases was 2.17 +/- 0.75 1/hr indicating that liver involvement by tumor decreased antipyrine clearance.

Adult↗
PubMed1987

[Evaluation of the functional status of hepatic microsomal enzymes in workers exposed to carbon dioxide and vinyl chloride by using the antipyrine test].

Examined were 42 CS2-exposed subjects, 34 CV-exposed subjects and 14 healthy people (control group) with no exposure to chemicals that might change the hepatic microsomal enzymes activity. All the subjects underwent antipyrine test (clearance and plasma half-time). The activities of AspAT and AlAT aminotransferases, alkaline phosphatase, gamma-glutamyl-transferase, and the value of thymol test and BSP were determined. Furthermore, in CV-exposed subjects, the organic clearance for N 2,4-dimethyl-acetanilide-iminodiacetic acid was determined. It was demonstrated that the mean value of antipyrine clearance was significantly reduced in CS2-exposed group, whereas in CV-exposed subjects the mean clearance value differed significantly from the control group value. The pathological values of antipyrine clearance were found in 12 CS2-exposed and only in 3 CV-exposed subjects. Pathological findings of the Hepida test were found in 3 CV-exposed subjects who exhibited normal antipyrine clearance values. This would imply that the Hepida test detects disturbances of different type in hepatic cells functioning, as compared to the antipyrine test. The studies confirmed that the antipyrine test performed in a simplified version (a single biological sampling) bears the same reference value for the detection of disturbances in hepatic microsomal enzymes as the traditional version of the test calling for repeated collection of blood or saliva.

Adult↗
PubMed1988

Effects of age, sex and breed on antipyrine disposition in calves.

In domestic animals relatively little is known about the functions of hepatic microsomal enzymes and their role in biotransformation. In this study, antipyrine was used to assess microsomal oxidative function and particularly to determine the effect of age, sex and breed on drug metabolising enzymes. At birth, the elimination rate of antipyrine was very low as reflected by a half-life of 24 hours. The first two months of life were characterised by a steady decrease of antipyrine half-life values of three to four hours being reached at six months. The decrease observed during early life was not identical in the two breeds used in this experiment. By six months the Friesian calves eliminated antipyrine twice as fast as the Blue White Belgian (BWB) breed: 2.1 +/- 0.3 hours and 4.9 +/- 0.3 hours, respectively. The BWB breed is characterised by muscular hypertrophy and by a relative imbalance in muscle:body ratio. The apparent volume of distribution of antipyrine did not vary with age, sex and breed. No differences in antipyrine clearance were found between male and female calves.

Age Factors↗
PubMedDate not supplied

Induction of hexobarbital and antipyrine metabolism by rifampicin treatment in the pig.

The rates of antipyrine and hexobarbital elimination from blood or plasma were used to determine whether the antibiotic rifampicin is an inducer of microsomal oxidative drug metabolism in the pig. Treatment with rifampicin (300 mg, po, twice daily for 7 days) decreased hexobarbital and antipyrine elimination half-lives by 65 and 62%, respectively. This was associated with an increase of the metabolic clearance by 222% for hexobarbital and 255% for antipyrine. However, not in all pigs was an increase of antipyrine clearance observed. The antipyrine metabolite profile was determined before and after rifampicin treatment. The partial clearance of 4-hydroxyantipyrine, as measured on the basis of urinary excretion data, increased about fourfold. Neither norantipyrine nor 3-hydroxymethylantipyrine were detectable in urine before rifampicin treatment. Only after rifampicin treatment could a small amount of 3-hydroxymethylantipyrine be measured. It is concluded that rifampicin is a potent inducer of microsomal oxidative drug metabolism in the pig. In contrast to other animal species, the pig seems to represent a suitable animal model for further study of rifampicin induction. Because of the increase of hexobarbital clearance in all cases and lack of increase of antipyrine clearance in some pigs, a similarity between the situation in man and pig seems to exist.

Animals↗
PubMed1983

Antipyrine clearance during occupational exposure to styrene.

Animal experiments have indicated that styrene, which is a widely used organic solvent, may induce the microsomal enzyme function of the liver. Thirteen workers with long-term exposure to styrene in a polyester plant were investigated. They worked at air concentrations about the maximal allowed time-weighted average concentration of styrene in most Western countries (50 ppm). The clearance of antipyrine was determined from saliva concentrations before and after three weeks free of exposure and then again three weeks after returning to work. Thirteen matched controls were investigated with similar intervals and methods. No significant differences were found between the half life, apparent volume of distribution, or clearance of antipyrine either within the groups or between the groups. The data exclude (95% confidence limit) the possibility that occupational exposure to styrene at concentrations about 50 ppm stimulates the microsomal enzyme function of the liver to a degree compatible with an increase in antipyrine clearance of more than 2 ml x min-1 (3%). While the first antipyrine estimation was carried out under medical supervision, the workers themselves managed to perform the antipyrine test correctly after verbal and written instructions. This has broadened the application of the antipyrine test.

Adolescent↗
PubMed1984

Influence of mild thyroid dysfunction on antipyrine clearance and metabolite formation in man.

The salivary kinetics and rates of metabolite formation of antipyrine were studied in 6 hyperthyroid and 6 hypothyroid out-patients on 2 occasions, on admission and when T3 and T4 levels had returned to normal after treatment with carbimazole (hyperthyroidism) or l-thyroxine (hyperthyroidism). In hyperthyroidism the half-life of antipyrine was significantly shorter (p less than 0.05) than after recovery (9.3 +/- 1.0 versus 10.6 +/- 0.9 h). Hypothyroid patients showed a significantly longer elimination half-life before treatment than after recovery (12.7 +/- 2.6 versus 10.3 +/- 2.6 h). Antipyrine clearance in hyperthyroid patients was decreased after treatment from 2.7 +/- 0.3 to 2.4 +/- 0.3 l/h, and it was increased in hypothyroid patients from 2.1 +/- 0.4 to 2.5 +/- 0.5 l/h (p less than 0.05). The changes in clearances for the production of the antipyrine metabolites 4-hydroxyantipyrine (OHA), norantipyrine (NORA) and 3-hydroxymethylantipyrine (HMA) were of the same order of magnitude as total antipyrine clearance, and no selectivity towards any of the metabolic pathways of antipyrine was apparent. Mild thyroid dysfunction seems to affect oxidative drug metabolizing enzyme activity in a non-selective manner and only to a small extent (10-30%). It is suggested that adjustment of the therapeutic regimens of various drugs in mild thyroid disease will only rarely by required on the basis of pharmacokinetic considerations.

Adult↗
PubMed1994

Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction.

Substituted benzimidazole inhibitors of the gastric H+/K(+)-ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs, as known for omeprazole. The primary aim of the present studies was to determine whether pantoprazole, a new, selective proton pump inhibitor, modifies the plasma concentrations of orally-administered antipyrine, a commonly used marker for mixed hepatic oxidase enzyme activity. In the acute study, 12 healthy male volunteers were given a) a single 30 mg i.v. doses of pantoprazole, b) a single 5 mg/kg oral dose of antipyrine, or c) coadministered pantoprazole and antipyrine according to a randomized three-period change-over design. In the chronic study, another 12 volunteers received 40 mg once-daily oral doses of pantoprazole on day 3 and on days 5-12, and a single oral 5 mg/kg dose of antipyrine on days 1, 12 and 14. Antipyrine plasma concentrations were measured without pantoprazole (day 1), on the last day of chronic dosing with pantoprazole (day 12) and 48 hours after the last dose of pantoprazole (day 14) to differentiate between inhibition and induction, respectively. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or laboratory parameters were observed during treatment. The point estimates of the respective AUC- and Cmax-ratios for antipyrine with and without pantoprazole were 0.99 and 0.98 in the acute study, and 1.01 and 0.93 on day 12, and 1.04 and 0.99 on day 14 of the chronic study.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMedDate not supplied

Inhibitory action of cimetidine on antipyrine metabolism.

The influence of cimetidine on the activity of microsomal enzymes in vivo using the simple one-sample antipyrine test was investigated. The calculated antipyrine clearance unequivocally indicates the dose-dependent effect of cimetidine on the microsomal biotransformation of antipyrine. The IC50 of cimetidine inhibitory effect was 39.9 mg/kg. The duration of the effect was approximately 12 h and the lowest antipyrine clearance was observed 0.5 h following cimetidine administration. The in vivo results were confirmed by an in vitro study. Km for global metabolic processes of antipyrine in vitro was 1.3 mM. Vmax 9.1 nM/mg/min for control was decreased to 3.1 nM/mg/min after addition of cimetidine (4 mM). The inhibition constant of cimetidine determined by the method of Dixon, was 2.8 mM. Inhibition of antipyrine metabolism by cimetidine was noncompetitive.

Animals↗
PubMed1996

Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction.

Substituted benzimidazole inhibitors of the gastric H+/K(+)-ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs, as known for omeprazole. The primary aim of the present studies was to determine whether pantoprazole, a new, selective proton pump inhibitor, modifies the plasma concentrations of orally-administered antipyrine, a commonly used marker for mixed hepatic oxidase enzyme activity. In the acute study, 12 healthy male volunteers were given a) a single 30 mg i.v. doses of pantoprazole, b) a single 5 mg/kg oral dose of antipyrine, or c) coadministered pantoprazole and antipyrine according to a randomized three-period change-over design. In the chronic study, another 12 volunteers received 40 mg once-daily oral doses of pantoprazole on day 3 and on days 5-12, and a single oral 5 mg/kg dose of antipyrine on days 1, 12 and 14. Antipyrine plasma concentrations were measured without pantoprazole (day 1), on the last day of chronic dosing with pantoprazole (day 12) and 48 hours after the last dose of pantoprazole (day 14) to differentiate between inhibition and induction, respectively. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or laboratory parameters were observed during treatment. The point estimates of the respective AUC-and Cmax-ratios for antipyrine with and without pantoprazole were 0.99 and 0.98 in the acute study, and 1.01 and 0.93 on day 12, and 1.04 and 0.99 on day 14 of the chronic study. The corresponding 90%-confidence intervals were all within the equivalence range of 0.8-1.25 so that lack of interaction either by inhibition or induction can be concluded.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMedDate not supplied

Effect of some anti-cancer drugs and combined chemotherapy on the pharmacokinetics of antipyrine in the rat.

The effect of anti-cancer drugs on the metabolic efficiency of the liver was evaluated by means of phenazone (antipyrine) kinetics individually in each rat. Chlormethine (nitrogranulogen, NG), methotrexate (MTX), floxuridine (fluorouracil, 5-fluorouracil, 5-FU), cyclophosphamide (CY, endoxan), and three cytostatics applied jointly (MTX + 5-FU + CY) were administered ip to the rats, while antipyrine was given intravenously. The anti-cancer drugs: NG, MTX, 5-FU, CY and MTX + 5-FU + CY delayed the elimination of antipyrine. Statistically significant prolongation of the half-life, decrease in the elimination rate constant and the clearance of antipyrine have been found in the rats receiving anti-cancer drugs, as compared to the controls. After the administration of MTX, 5-FU, CY and the joint administration of MTX + 5-FU + CY the volume of distribution did not change, while the volume of distribution of antipyrine decreased after the administration of NG. The activity of the investigated enzymes, i.e., alanine aminotransferase (ALAT), aspartic aminotransferase (AspAT), gamma-glutamyltransferase (GGT), alkaline phosphatase (AP), which are the indicators of various liver dysfunctions, did not change after the administration of NG, MTX, 5-FU, CY and MTX + 5-FU + CY. The administered antineoplastic drugs in mono and polytherapy changed the activity of oxidase mixed function responsible for the metabolism of antipyrine. CY administered to rats in polytherapy had less influence on liver metabolic efficiency than in monotherapy.

Animals↗