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PubMed1983

Effects of xylene exposure on the metabolism of antipyrine in vitro and in vivo in the rat.

Exposure of male rats to different concentrations of xylene for 3 days induced, in a dose-dependent way, the in vitro liver microsomal metabolism of antipyrine. The degree of induction was statistically significant at an exposure level of 250 ppm and maximal (2.5-fold increase) at 2000 ppm. This increase was of the same magnitude as after phenobarbital treatment. Female rats had a lower basal antipyrine metabolism than males, but exhibited a greater relative increase in antipyrine metabolism following xylene exposure. Cytochrome P-450 isozymes, purified from xylene- and phenobarbital-treated animals, were efficient catalysts of antipyrine metabolism, with turnover numbers of 33.3 and 21.1, respectively. A reduction in the half-life of antipyrine to 39% of preexposure values occurred after exposure of male rats to 1000 ppm of xylene for 3 days. Exposure to lower xylene levels did not produce significant alterations in antipyrine elimination half-life. In vitro, xylene was shown to be a non-competitive metabolic inhibitor of antipyrine. Experiments in vivo indicated that inhibition is not important at relatively low xylene exposure levels. It is concluded that induction of hepatic monooxygenases by xylene can be demonstrated, with antipyrine as a test drug, both in vitro and in vivo.

Animals↗
PubMed2002

Diabetes and elimination of antipyrine in man: an analysis of 298 patients classified by type of diabetes, age, sex, duration of disease and liver involvement.

UNLABELLED: Effects of diabetes on hepatic drug metabolism in man has not yet been adequately clarified. Two hundred ninety-eight diabetic patients, classified by type of the disease, age, gender, duration of therapy and liver involvement, were investigated. The antipyrine plasma clearance rate and cytochrome P450 content determinations in liver biopsies of subjects with diagnostic liver biopsy were used as indices of hepatic drug metabolising capacity. Drug metabolism was reduced as a function of age. Antipyrine elimination rate was dependent on the type of diabetes (type 1 versus type 2) and gender. Untreated type 1 patients eliminated antipyrine rapidly and insulin treatment normalised antipyrine elimination (clearance rates 89.5 +/- 20.3 versus 58.8 +/- 17.2 ml/min.; P<0.001). Males aged 16-59 years, but not over 60, who responded insufficiently to insulin therapy, had a rapid antipyrine elimination, which could be normalised by readjustment of insulin administration. Women with insufficient glucose control on insulin therapy had antipyrine elimination rate comparable to controls. Among type 2 diabetic patients, women metabolised antipyrine normally, but men over 40 years of age showed a reduced antipyrine metabolism. IN CONCLUSION: Drug metabolism in diabetes is affected by the type of disease, therapy and its effectiveness, and age and gender of the patients. These factors should be taken into account when evaluating overall drug metabolism in diabetic patients. This is especially important when investigating pharmacokinetics of new drugs for diabetic patients at different phases of the disease.

Adolescent↗
PubMed1980

Antipyrine metabolism during the menstrual cycle.

Two studies were initiated to determine the effect of the menstrual cycle on antipyrine metabolism. In the first study a relatively large oral dose of antipyrine (15 mg/kg) was given on days, 3, 5, 10, 14, 16, 20, and 25 after the onset of menstruation. Salivary antipyrine half-lifes (t1/2S) declined progressively, suggesting that the long-term administration of this dose had stimulated antipyrine metabolism. To minimize this possible induction, in the second study a much smaller dose of antipyrine (1 mg/kg) was given on the same days of the cycle as in the first study. There was no induction. In both experiments, the menstrual cycle had little or no effect on the mean salivary t1/2, mean metabolic clearance rate, or apparent volume of distribution of antipyrine. In the second, men served as controls. The mean kinetic parameters for the men did not differ from those for the women. Although individuals of each sex varied from day to day in each kinetic parameter, the magnitude of the intraindividual variability in antipyrine metabolism was the same for both. The mean intraindividual coefficient of variation for antipyrine t1/2S was 14.4 +/- 1.6% (SE) in women and 12.4 +/- 1.3% (SE) in men. No consistent pattern for either sex was observed in the day-to-day variations in the means of the kinetic parameters investigated. Several women in whom the t1/2 rose or fell at midcycle were found to have a different pattern when reexamined 6 mo later.

Adult↗
PubMed1981

Enflurane anesthesia and antipyrine metabolism.

To evaluate the influence of enflurane anesthesia on the hepatic drug-metabolizing capacity, antipyrine half-life was measured in 18 surgical patients before surgery and on days 4 and 8 after anesthesia. The effect of repeated administration of antipyrine on the rate of antipyrine metabolism was also evaluated in nine control subjects. Simultaneous measurement of plasma fluoride concentration allowed enflurane metabolism to be quantitated. Regardless of duration, enflurane anesthesia did not increase the rate of antipyrine metabolism as indicated by the absence of significant change in antipyrine half-life and clearance. Repeated doses of antipyrine to nine normal subjects did not influence the rate of antipyrine metabolism. Preanesthesia elimination rate of antipyrine did not indicate individual capacity to metabolize enflurane. Mean peak fluorides level (10.7 +/- 4.8 mM) was reached 3 hr after anethesia and did not appear to correlate with duration of exposure to enflurane.

Adolescent↗
PubMed1984

Sources of interindividual variations in acetaminophen and antipyrine metabolism.

Our goal was to compare and contrast in the same normal twins the relative contribution of genetic and environmental factors to large interindividual variations in the metabolism of acetaminophen (APAP) and antipyrine. These drugs were selected because they are biotransformed by different mechanisms. A single oral dose of APAP (10 mg/kg) was given to six sets of monozygotic (MZ) and six sets of dizygotic (DZ) twins. All were normal, nonsmoking, nonmedicated, and male. Among these 24 subjects, there were 300% interindividual variations in rate constants for formation of the sulfate and glucuronide conjugates, as well as in the overall rate constant for APAP elimination. Intratwin variations for each measurement were as large within MZ as within DZ twinships, suggesting that predominantly environmental rather than genetic factors maintained interindividual variations. Two other observations support this conclusion: Intraindividual variations were frequently as large as interindividual variations, and regardless of zygosity for twins living together, intratwin correlation coefficients were almost twice those of twins living apart. Quite different results were obtained when these twins received antipyrine. After a single oral dose of antipyrine (18 mg/kg), 500% interindividual variations in rate constants for formation of the three main oxidative metabolites of antipyrine appeared to be mainly under genetic control. Also for antipyrine and its principal metabolites, intraindividual variations were much smaller than interindividual variations. In contrast to the results with APAP, regardless of zygosity, intratwin correlation coefficients for antipyrine were similar for twins living apart and twins living together. This comparison between APAP and antipyrine metabolism in the same carefully selected normal twins under apparently uniform environmental conditions reveals that interindividual variations in APAP metabolism arise from certain unidentified environmental factors, whereas genetic factors cause the large interindividual variations that occur in antipyrine disposition.

Acetaminophen↗
PubMed1986

Diltiazem treatment impairs hepatic drug oxidation: studies of antipyrine.

To evaluate the effect of diltiazem on antipyrine disposition and metabolism, 10 healthy subjects received 1.2 gm antipyrine on two occasions, once while taking no other medications and once during long-term oral diltiazem, 120 mg three times daily. Antipyrine oral clearance was markedly reduced from (mean +/- SEM) 41.7 +/- 4.1 to 29.9 +/- 2.8 ml/min (P less than 0.01) during diltiazem treatment, resulting in prolongation of antipyrine elimination t1/2 from 12.2 +/- 1.0 to 16.7 +/- 1.3 hours (P less than 0.01), with no change in apparent volume of distribution (42.1 +/- 4.0 vs. 41.3 +/- 3.1 L; not significant). Measurement of urinary antipyrine and metabolites excreted in the urine during 24 hours after the antipyrine dose (percent of total 24-hour excretion) showed increased antipyrine (4.4% +/- 1.0% vs. 7.8% +/- 1.6%; P less than 0.01) during diltiazem treatment with no significant change in proportion of 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine excretion between trials. Chronic oral diltiazem in therapeutic doses markedly impairs antipyrine oxidation. Diltiazem may therefore impair the clearance of other coadministered drugs that undergo hepatic oxidation.

Administration, Oral↗
PubMed1981

Inhibition of antipyrine metabolism by beta-adrenoceptor antagonists.

1 The effects of two beta-adrenoceptor antagonists (propranolol and metoprolol), and of the beta-adrenoceptor agonist, terbutaline, on the plasma kinetics of antipyrine were studied in five normal subjects. In addition, the influence of propranolol on the clearance of antipyrine to three of its major metabolites was investigated. 2 At the same level of beta-adrenoceptor blockade, assessed by lowering of exercise tachycardia, propranolol decreased antipyrine clearance by 37.3 +/- 9.9 s.d. % (P less than 0.001) and metoprolol decreased it by 18.0 +/- 4.7 s.d. % (P less than 0.01). Terbutaline had no effect on antipyrine clearance. The volume of distribution of antipyrine was unchanged following treatment with all three drugs. 3 Only the metabolic clearance of antipyrine to its 3-hydroxymethyl product was impaired to a statistically significant degree by propranolol. However, four of the five subjects also showed impaired clearance to 4-hydroxyantipyrine and three of the five to norantipyrine after propranolol treatment. In four of the five subjects propranolol lowered the renal clearance of antipyrine. 4 Inhibition of the metabolism of antipyrine by beta-adrenoceptor antagonists may be related to their lipid-solubility and extent of metabolism and is independent of their effect on beta-adrenoreceptors.

Adrenergic beta-Antagonists↗
PubMed1983

Antipyrine metabolism in relation to polymorphic oxidations of sparteine and debrisoquine.

Thirty-five healthy subjects who had been classified as extensive or poor metabolizers of both sparteine and debrisoquine were given a single oral dose of antipyrine. Saliva concentration of antipyrine and urinary excretion of its three major oxidation metabolites were measured. All the parameters of antipyrine metabolism which were estimated had similar distributions in both the 28 EM and 7 PM genetic phenotypes defined by the metabolism of sparteine and debrisoquine. The clearance of antipyrine by the formation of 4-hydroxy-antipyrine and 3-hydroxy-antipyrine respectively were closely correlated (r = 0.83, P less than 0.001) and both were significantly higher in smokers than in non-smokers. Demethylation of antipyrine also seemed to be influenced by smoking, but not to a statistically significant extent. These findings confirm the influence of the environmental factor of smoking in antipyrine oxidative biotransformations.

Adult↗
PubMed1980

The effect of antineoplastic drugs on the pharmacokinetics of antipyrine in the rat.

The pharmacokinetics of antipyrine was investigated in individual rats pretreated with cyclophosphamide, 5-fluorouracil and methotrexate. Before oral dosing a complete emptying of the rat stomach was obtained by 24 hours of fasting and prevention of coprophagy. Antipyrine was given intravenously via a cannula in an inguinal vein and repeated samples of blood were drawn from a cannula in an inguinal artery. Systemic availability of oral antipyrine was studied in rats given the 14C-labelled drug intravenously and the 3H-labelled drug orally after pretreatment with cyclophosphamide. The log plasma concentration versus time curve of antipyrine given orally showed a short absorption and distribution phase followed by a linear elimination phase. Peak antipyrine concentrations were reached 3-6 minutes after oral dosing in control rats. The rate of absorption of antipyrine was moderately decreased by methotrexate. All drugs increased the area under the curve (AUC) of antipyrine. The systemic availability of oral antipyrine after cyclophosphamide pretreatment (0.88) was not changed, but the metabolic clearance of the drug was reduced. The apparent elimination rate constant was decreased by methotrexate and the apparent volume of distribution was decreased by cyclophosphamide and 5-fluorouracil. The results indicate that antineoplastic agents may change drug kinetics in different ways in rats.

Animals↗
PubMed1992

Distribution of antipyrine in the rat liver.

The rate and extent of hepatic distribution of antipyrine was examined in the rat isolated perfused liver. Tritiated water and [14C]antipyrine were injected simultaneously into the portal vein as a bolus using either Krebs-Ringer bicarbonate or rat plasma as the perfusate. The effluent profiles of each compound using the two perfusates were superimposable, a finding expected for water and consistent for antipyrine, which was negligibly bound in rat plasma. Although full recovery (97%) of administered material was achieved with both compounds, the fractional output profile for antipyrine peaked at a lower value (0.10 mL-1) and at a later time (24 s) than water (0.14 mL-1, 17.5 s), due to antipyrine having a larger volume of distribution (water 0.61 mL (g liver) -1); antipyrine 0.81 mL (g liver)-1). This observation is explained by antipyrine binding to, or partitioning into cellular components. Nonetheless, like water, distribution of antipyrine into hepatic cells is perfusion rate limited as evidenced by the superimposition of the dimensionless plots of fractional output vs time normalized to mean residence time.

Animals↗
PubMed1975

Anomalous results of studies on drug interaction in man. III. Disulfiram and antipyrine.

Disulfiram inhibited antipyrine metabolism reproducibly in three experiments utilizing three different groups of normal human volunteers. In these experiments disulfiram in a dose of 3.5 mg/kg body weight was given orally twice daily for 4 consecutive days and in two subsequent experiments for 10 consecutive days. In each experiment the mean antipyrine half-life was prolonged and the mean metabolic clearance rate of antipyrine was shortened by disulfiram. Large interindividual variations occurred; one volunteer with a very short initial plasma antipyrine half-life shortened, rather than prolonged, his antipyrine half-life after 10 days of disulfiram. In the first 10-day study the apparent volume of distribution of antipyrine was significantly increased in each volunteer after disulfiram administration, whereas in the second 10-day study, disulfiram failed to alter this value. Another anomalous result concerned attempts to determine whether a correlation existed between the initial antipyrine half-life and the percent change in this value produced by disulfiram administration. A significant correlation occurred in the initial 10-day study (4 = 0.71, p less than 0.05), whereas neither in the second 10-day study (r = 0.20, p greater than 0.05) nor in the 4-day study (r = 0.57, p greater than 0.05) was a significant correlation observed. Each of the three studies revealed no significant correlation between the initial metabolic clearance rate of antipyrine and the percent change in this value produced by disulfiram administration.

Administration, Oral↗
PubMed1975

Serial measurements of plasma half-lives and urinary excretion of antipyrine in low-birth-weight infants.

Antipyrine has been used previously to estimate total body water in infants. In the present study, antipyrine spaces were determined early on the first day of life and again at the end of the fourth day in 22 early mild-fed low-birth-weight babies as part of a study of serial measurements of water balance. This report deals with findings arising from analysis of disappearance rates of antipyrine in plasma used for the determination of antipyrine space (total body water estimation). Urine excretion of antipyrine was measured from 24-hour urine outputs in 9 of these babies. The data showed that: (1) wide individual variants of plasma antipyrine half-life times occurred on both the first and fourth days of life; (2) plasma half-life times in the low-birth-weight infants were usually much longer than those of adults; (3) half-life times on the first day of life were significantly longer than on the fourth day of life; (4) urine excretion of unchanged antipyrine was a significant factor in the disappearance rate of antipyrine from the body with between 7 and 36% of the dose appearing in the urine (average 21%) within 96 h of the initial injection.

Antipyrine↗
PubMed2002

Albendazole metabolism in patients with neurocysticercosis: antipyrine as a multifunctional marker drug of cytochrome P450.

The present study investigates the isoform(s) of cytochrome P450 (CYP) involved in the metabolism of albendazole sulfoxide (ASOX) to albendazole sulfone (ASON) in patients with neurocysticercosis using antipyrine as a multifunctional marker drug. The study was conducted on 11 patients with neurocysticercosis treated with a multiple dose regimen of albendazole for 8 days (5 mg/kg every 8 h). On the 5th day of albendazole treatment, 500 mg antipyrine was administered po. Blood and urine samples were collected up to 72 h after antipyrine administration. Plasma concentrations of (+)-ASOX, (-)-ASOX and ASON were determined by HPLC using a chiral phase column and detection by fluorescence. The apparent clearance (CL/f) of ASON and of the (+) and (-)-ASOX enantiomers were calculated and compared to total antipyrine clearance (CL(T)) and the clearance for the production of the three major antipyrine metabolites (CLm). A correlation (P<or=0.05) was obtained only between the CL(T) of antipyrine and the CL/f of ASON (r = 0.67). The existence of a correlation suggests the involvement of CYP isoforms common to the metabolism of antipyrine and of ASOX to ASON. Since the CL(T) of antipyrine is a general measure of CYP enzymes but with a slight to moderate weight toward CYP1A2, we suggest the involvement of this enzyme in ASOX to ASON metabolism in man. The study supports the establishment of a specific marker drug of CYP1A2 in the study of the in vivo metabolism of ASOX to ASON.

Adult↗
PubMed1993

Non-induction of extrahepatic antipyrine and metronidazole metabolism evaluated from partially hepatectomized rats.

1. The effect of beta-naphthoflavone (BNF), given i.p. (n = 9) and orally (n = 9), on the metabolism of antipyrine and metronidazole was investigated in rats. 2. The clearances of antipyrine and metronidazole were determined on a single saliva sample. The rates of formation of antipyrine and metronidazole metabolites were determined from a 20 h urine sample and saliva clearance. 3. Administration of beta-naphthoflavone i.p. was significantly more effective than oral dosage on the induction of antipyrine and metronidazole metabolism (p < 0.05). 4. The capacity of extrahepatic tissues to metabolize antipyrine and metronidazole was quantitatively assessed in rats with and without pretreatment with beta-naphthoflavone immediately after sham operation or 70% partial hepatectomy (n = 40). 5. Antipyrine and metronidazole clearances correlated with liver weight in induced and non-induced rats. Linear regression of antipyrine and metronidazole clearances did show a non-significant Y-intercept (p > 0.05), indicating a negligible extrahepatic metabolism in both induced and in non-induced rats. 6. From a quantitative point of view this study indicates that induction of extrahepatic cytochrome P450 metabolism of antipyrine and metronidazole is negligible.

Administration, Oral↗
PubMedDate not supplied

Effect of phenobarbital and spironolactone treatment on the oxidative metabolism of antipyrine by rat liver microsomes.

The effects of pretreating rats with the inducers, phenobarbital or spironolactone, on the formation rate of the three major oxidative metabolites of antipyrine in vitro by hepatic microsomal fractions have been investigated. Both inducers reduced the rate of 3-methylhydroxylation of antipyrine by approximately 50%. In contrast, N-demethylation and 4-hydroxylation were enhanced 1.7-fold and 3.4-fold, respectively, in case of phenobarbital induction and 1.4-fold and 2.6-fold, respectively, following spironolactone treatment. To elucidate the role of some cytochrome P450 isoenzymes in the production of the three major metabolites of antipyrine, the effects of form selective enzyme inhibitors on antipyrine oxidation were also studied. Troleandomycin did not alter 3-methylhydroxylation but reduced both N-demethylation and 4-hydroxylation of antipyrine in microsomes from induced rat liver. Cimetidine and chloramphenicol decreased the rate of formation of all three metabolites in microsomes from induced and uninduced animal livers as well. Chloramphenicol seemed to be the most potent inhibitor of in vitro antipyrine oxidation. Alpha-methyldopa significantly enhanced the rate of formation of 4-hydroxyantipyrine and slightly reduced the rate of N-demethylation and 3-methylhydroxylation. According to the data obtained with microsomes from uninduced rat livers, the formation of the three major metabolites of antipyrine is extensively mediated by CYP2C11/C6. In microsomes from induced animal liver, CYP2B and CYP3A may contribute to both N-demethylation and 4-hydroxylation of antipyrine.

Animals↗
PubMed1991

Changes in salivary antipyrine pharmacokinetics during adolescence, correlated with age, hormonal levels and Tanner stage.

To evaluate the effect of puberty on antipyrine metabolism, we measured antipyrine pharmacokinetics in 17 healthy subjects aged 6-21 years. The subjects received a single oral dose of antipyrine, 18 mg/kg. Salivary antipyrine levels were determined 3, 6, 9, 12 and 24 h after dosing. Age, weight, body surface area and Tanner stage were highly intercorrelated. Volume of distribution (liters) was highly correlated with all of these factors. The weight-corrected clearance of antipyrine declined significantly with age (r = 0.55, p less than 0.025). Patients were classified as immature and other based on serum hormone levels (immature = females with serum estradiol less than 25 pg/ml and males with serum testosterone less than 25 ng/dl). The uncorrected antipyrine clearance was significantly lower in the immature group (mean +/- SD 22.65 +/- 6.04 ml/min) than in others (mean +/- SD 41.30 +/- 13.26; p less than 0.01). This difference disappeared when the weight-corrected antipyrine clearance was compared for these two groups. The change in uncorrected antipyrine clearance with sexual maturation appeared to be due to increased body size, probably related to the adolescent growth spurt.

Adolescent↗
PubMed1982

Pharmacokinetics and metabolism of antipyrine (phenazone) after intravenous and oral administration.

To 12 healthy male volunteers, 6 smokers and 6 non-smokers, 10 mg/kg antipyrine (phenazone) was administered i.v. and p.o. in random order. Following i.v. administration, antipyrine kinetics could be described best by an open two-compartment model. Absolute bioavailability of an aqueous solution of antipyrine was on average 97%. Antipyrine half-life in smokers was significantly shorter (mean 9.7 h) as compared to non-smokers (mean 11.7 h). Smokers excreted significantly more 3-hydroxymethyl-antipyrine (17.2 +/- 2.4 vs. 14.2 +/- 1.9%) than non-smokers, and clearance to this metabolite was significantly increased in smokers. In addition, cumulative urinary excretion of 4-hydroxy-antipyrine, norantipyrine and 3-hydroxymethyl-antipyrine was on average higher in smokers (77.1 +/- 5.0%) as compared to non-smokers (69.5 +/- 10.8%). Thus, 3-hydroxymethyl-antipyrine formation is induced in smokers.

Administration, Oral↗
PubMed1995

Antipyrine repeatability and comparison of the powder and capsule formulations.

Twelve healthy subjects (6 females), who were drug-free and non alcoholic, age 21-40 years and weight 43-80 kg took part in the study which lasted about 4 weeks. The subjects were randomly assigned into 2 panels (of 6 subjects each) and took antipyrine (1,050 mg) orally either as powder made into solution or gelatin capsules on 3 consecutive trial occasions separated by 2-week intervals. Panel A had powder, powder and capsule formulations on trials 1, 2 and 3, respectively, and panel B had capsule, capsule and powder formulations on trials 1, 2 and 3, respectively. There were no significant differences in the saliva pharmacokinetic parameters of antipyrine in the 3 trials for both panels of subjects, except the half-lives in panel B which was significantly different at the 5% level. There were no significant differences in the amounts of antipyrine and its metabolites excreted in urine in the 3 trials. The saliva concentrations of antipyrine in the 3 trials were relatively comparable. The relative bioavailability of the capsule formulation of antipyrine was 97%. This study shows that the saliva pharmacokinetic parameters of antipyrine and the amounts of antipyrine metabolites excreted in urine are highly reproducible following repeated oral administration, either in solution or as capsules. The capsule formulation is fully bioavailable and should be suitable for oral administration in assessing the influence of drugs and environmental factors on antipyrine metabolism.

Adult↗