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PubMed1994

Antipyrine Metabolism during Chemotherapy with 5-Fluorouracil Plus Folinic Acid in Patients with Liver Metastases from Primary Colorectal Cancer.

Current evidence suggests that the drug-metabolizing capacity of the liver can be altered by neoplastic lesions and by the chemotherapeutic agents used to treat them. Antipyrine metabolism is a widely used dynamic test for assessing mixed hepatic oxidase system activity in humans. This study was conducted to determine the effects of 5-fluorouracil-folinic acid chemotherapy on hepatic drug metabolization in patients with diffuse liver metastases from colorectal tumors using antipyrine metabolism as an index. Twenty-three patients, all with diffuse liver metastases from primary colorectal tumors and normal liver function tests, were treated with 5-day cycles of 5-fluorouracil (5-FU) (370 mg m(minus sign2) day(minus sign1) I.V.) and folinic acid (200 mg m(minus sign2) day(minus sign1) I.V.) administered every 28 days. Antipyrine metabolism was assessed before initiation of therapy and after each 5-day cycle to determine the effects of this chemotherapeutic protocol on the mixed-hepatic oxidase system. Response to treatment was assessed after 4 months. None of the patients displayed any change in antipyrine metabolism following treatment. There was no correlation between the ability to metabolize antipyrine and the response to chemotherapy. 5FU has been found to decrease antipyrine metabolism in rats with no liver disease. The absence of such an effect in our patients is thought to be due to inductive effects exerted by the metastases on the mixed hepatic oxidase system and modification of 5-FU metabolism by folinic acid. The liver appears to have an enormous functional reserve, even when there is massive tumor involvement.

Journal Article↗
PubMedDate not supplied

Antipyrine metabolite kinetics in rats: studies on dose and time dependence.

Antipyrine metabolite kinetics have been investigated in the rat with respect to dose and time dependence. The metabolic pathways, 4-hydroxylation, benzylic oxidation, and N-demethylation, are of equal quantitative importance (approximately 20 per cent of dose) and show no dose dependence over the range 25-500 mg kg-1. By using [N-methyl-14C]-antipyrine, the single carbon fragment lost by N-demethylation may be monitored as 14CO2. Serial sampling of 14CO2 exhalation rate provides a half-life estimate which, according to theoretical principles, reflects the antipyrine plasma half-life. When both half-lives were measured in the same animals a statistically significant correlation was evident. At doses of 250 mg kg-1 and 500 mg kg-1 there is an increase in CER half-life (218 and 303 min respectively) when compared to a dose below 100 mg kg-1 (152 min). The metabolite formation rate constants are decreased accordingly at the high doses but are invariant over the dose range 25-100 mg kg-1. Although inter-rat variation in antipyrine metabolite kinetics was substantial, intra-rat variability was small. The noninvasive nature of determining antipyrine metabolite kinetics via breath and urine analysis provides a potentially useful animal model system to investigate the factors influencing hepatic mixed function oxidase activity in vivo.

Animals↗
PubMedDate not supplied

The influence of vitamin C on antipyrine pharmacokinetics in elderly men.

The influence of vitamin C on the pharmacokinetics of antipyrine was investigated in eleven elderly men aged 65-74. Antipyrine (15 mg kg-1) was administered intravenously on three separate occasions over a 7-week period: (a) before dietary vitamin C restriction, (b) after approximately 5 weeks of dietary vitamin C restriction, and (c) after 2 weeks of vitamin C supplementation (500 mg orally twice daily). The mean plasma and leucocyte vitamin C levels (+/- S.D.) before vitamin C restriction were 1.26 +/- 0.31 mg dl-1 and 26.6 +/- 6.7 micrograms 10(-8) leucocytes, respectively. These values decreased and then increased significantly following vitamin C restriction and supplementation, respectively. The mean plasma half-life of antipyrine was 10.2 h and the mean plasma clearance was 2.561 h-1 1.73 m-2 before vitamin C restriction. No significant changes in the clearance, volume of distribution, or half-life of antipyrine occurred during the study, indicating that short-term alterations in vitamin C intake do not affect the pharmacokinetics of antipyrine in elderly males.

Aged↗
PubMed1995

Pharmacokinetic parameters of antipyrine in dog after hepatectomy.

Pharmacokinetic studies with antipyrine were carried out on beagle dogs to determine the consequence of hepatectomy on hepatic drug metabolizing capacity, the rate of hepatic regeneration, and the possible beneficial effect of hepatocellular transplantation. The drug (250 mg) was administered by short IV infusion in three groups of dogs (first group, 65% hepatectomy; second group, 65% hepatectomy with hepatocyte transplantation; third group 80% hepatectomy). Pharmacokinetic parameters of antipyrine were evaluated before surgery and within 10 d after surgery. Blood samples were taken at frequent intervals after drug administration and antipyrine was assayed in plasma by a specific HPLC method with UV detection. Before surgery, the mean elimination half-life was about 1.1 h and total clearance averaged 6 L h-1. In dogs with 65% hepatectomy, no statistical differences in pharmacokinetic parameters of antipyrine appeared before or after surgery. When 65% hepatectomy was associated with hepatocyte transplantation, a significant increase in elimination half-life and a significant decrease in total clearance were observed. The same statistical differences in the pharmacokinetic parameters were observed in the group with 80% hepatectomy. Transplantation of isolated hepatocytes into the spleen did not correct hepatocellular insufficiency. In this study, numerous laboratory tests were performed. A significant correlation was found between serum albumin, cholesterol, factor V, ALAT, total bilirubin, and ratio of amino acids and the pharmacokinetic parameters of antipyrine.

Alanine Transaminase↗
PubMedDate not supplied

Isolation and purification of three glucuronides of antipyrine. Proposal for an original analytical method for quantitation of sulpho- and glucuroconjugated metabolites.

The determination of the concentrations of antipyrine metabolites in biological fluids is hampered by the difficulty in obtaining pure conjugated compounds to be used as standards. Most authors have proposed determination of total forms by high performance liquid chromatography (HPLC) after deconjugation of these metabolites using chemical or enzymatic hydrolysis. Up to now there is no satisfactory hydrolysis method for the study of all antipyrine metabolites. The situation is further complicated by the fact that the deconjugated metabolites are highly unstable whichever technique is being used. Because of the lack of stability of all these molecules it has been necessary to isolate the glucuroconjugated compounds from urine. We describe a method which allows us to obtain highly purified glucuroconjugated metabolites of antipyrine. Sulphoconjugated compounds have been synthesized previously. We are thus able to propose a chromatographic procedure which allows us to determine simultaneously all stable phase I and phase II metabolites of antipyrine in biological fluids without any step of extraction. This analytical technique allows us to study the activity of the different isoenzymes implicated in the metabolism of antipyrine.

Antipyrine↗
PubMed1978

Racial differences in drug metabolizing ability: a study with antipyrine in the Sudan.

The kinetic disposition of antipyrine following oral administration of 1,200 mg has been investigated in 11 normal Sudanese subjects living in Sudan, 9 Sudanese subjects living in England for at least 2 yr, and 19 normal English subjects living in England. Sudanese subjects living in Sudan had significantly lower mean antipyrine clearance and higher volume of distribution than the English group (-28% and +30%, respectively). There was no significant difference for antipyrine clearance between English and Sudanese subjects living in England, but the volume of distribution of antipyrine was higher (16%) in the Sudanese subjects. The mean half-lives of the three groups differed significantly. We conclude that differences in disposition of antipyrine between native English and Sudanese populations was predominantly due to environmental factors.

Adolescent↗
PubMed1988

Pregnancy-specific changes of antipyrine pharmacokinetics correlate inversely with changes of estradiol/progesterone plasma concentration ratios.

Antipyrine pharmacokinetics as well as estradiol and progesterone concentrations were measured in plasma of 11 healthy pregnant women during the first two trimesters and again in the same patients 6 to 20 weeks after interruption of pregnancy. During pregnancy, the clearance of antipyrine increased and its half-life decreased in all but two instances. A significant inverse relationship was found between the degree of pregnancy-specific changes of plasma clearance of antipyrine and estradiol-progesterone plasma concentration ratios: high estradiol-progesterone ratios during pregnancy corresponded to decreased plasma clearance of antipyrine; low ratios of the two hormones during pregnancy corresponded to increased plasma clearance of antipyrine. The current results indicate that the balance between circulating estrogens and progesterone may be an appropriate indicator for pregnancy-specific changes of a particular hepatic drug metabolism during pregnancy.

Adult↗
PubMed1989

Comparative evaluation of the effects of labetalol, verapamil and diltiazem on antipyrine and indocyanine green clearances.

The effects of labetalol, diltiazem and verapamil on antipyrine and indocyanine green clearance were evaluated in a placebo-controlled, repeated measures evaluation. Twelve healthy subjects received either labetalol (200 mg every 12 hours), diltiazem (90 mg. every 8 hours), verapamil (80 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the morning of Day 3 immediately following their dose, the subjects assumed the supine position for 90 minutes, after which time a 0.5 mg/kg dose of indocyanine green was administered. Blood samples were obtained serially over a 20 minutes period for indocyanine green plasma concentration determinations by HPLC. Ten minutes later, subjects ingested a 1.2 Gm. dose of antipyrine and blood samples were obtained over a 48 hour period for antipyrine plasma concentration determinations by HPLC. A 2 week washout period separated treatment sequences. Mean (SD) antipyrine clearance (L/hr/kg) following diltiazem [0.028 (0.010)] and verapamil [0.030 (0.012)] treatment was significantly lower than that observed following placebo [0.039 (0.012)]. Antipyrine clearance following labetalol administration [0.033 (0.010)] was not significantly different from that observed following placebo, diltiazem or verapamil administration. No effects of these drugs on indocyanine green clearance could be detected.

Adult↗
PubMed1989

The influence of antineoplastic chemotherapy on antipyrine metabolism in man.

When either Doxorubicin or Mitomycin-C was administered to patients, antipyrine clearance was respectively unaltered or increased. Antipyrine was administered to patients two days prior to and one day after their first course of the chemotherapeutic drug. Antipyrine clearance increased an average of 11.2% in the 5 patients that received Doxorubicin (not significant) and 15.2% in the six patients that received Mitomycin-C (P = 0.033, students t-test). The altered clearance is likely due to a rapid induction of the mixed function oxidase system by the chemotherapy as other parameters that could influence clearance were stable throughout the study (volume of distribution, weight, creatinine clearance and liver function tests). It is unlikely that the prechemotherapy antipyrine dose accounted for this change. The administration of these two antitumor antibiotics in humans may modestly increase the mixed function oxidase activity that is responsible for the metabolism of antipyrine. These findings are in direct contrast to markedly decreased mixed-function oxidase activity observed in the rodent pretreated with the same chemotherapy.

Adult↗
PubMed1990

Effects of subchronic treatment with natural human interferons on antipyrine clearance and liver function in patients with chronic hepatitis.

To determine whether natural human interferon administered under the usual therapeutic dosing scheme would inhibit the hepatic drug metabolism, we performed an antipyrine test in eight patients with chronic B or non-A, non-B hepatitis before and after a subchronic interferon therapy (6 megaunits/day for 17 +/- 4 days, mean +/- SD). Six patients received interferon-beta and 2 received interferon-alpha. To circumvent a possible influence of interferon-induced fever on the hepatic drug metabolism, the antipyrine test during the interferon therapy was performed at least 14 days after the interferon-induced fever disappeared. The kinetic parameters of antipyrine were obtained from seven saliva samples over 32 hours postdose. There were no significant differences in any kinetic parameters of antipyrine observed before and during the interferon therapy. With the sample size of the study, there was only a 20% chance (i.e., beta-power = 0.8 at alpha = 0.05) that we might have missed a 17% reduction in antipyrine clearance by the interferon therapy (type II error). On the other hand, the subchronic interferon therapy lowered serum aminotransferases and DNA polymerase activity significantly (P less than .05) compared with the respective baseline values. Our results suggest that the subchronic therapeutic dosing scheme of interferon as conducted in the present study does not cause the inhibitory effect on the oxidative drug metabolism to a statistically significant or clinically relevant degree in patients with chronic hepatitis, while it improves their liver function. Further studies are required for determining if different types of interferons administered under the different dosing schemes would alter the hepatic drug metabolism and the inhibitory effect would be time-dependent.

Adult↗
PubMed1991

The effect of diltiazem on hepatic drug oxidation assessed by antipyrine and trimethadione.

The effect of pretreatment for 3 days with diltiazem 60 mg three times a day on the pharmacokinetics of 500-mg antipyrine and 250-mg trimethadione was studied in six healthy male subjects. Diltiazem decreased the total body clearance from 34.0 +/- 8.0 to 28.6 +/- 6.1 mL/min (P less than .01), and prolonged the elimination half-life from 12.6 +/- 3.0 to 14.3 +/- 2.5 hours (P less than .01) of antipyrine without any changes in volume of distribution. The cumulative renal excretion (% dose) of antipyrine was significantly increased from 2.23 +/- 0.73 to 2.78 +/- 0.83% (P less than .05). Clearances of production for three major antipyrine metabolites, norantipyrine (4.31 +/- 1.64 to 3.50 +/- 1.28 mL/min, P less than .01), 3-hydroxymethylantipyrine (4.67 +/- 1.63 to 3.82 +/- 1.34 mL/min, P less than .01) and 4-hydroxyantipyrine (10.47 +/- 3.41 to 8.16 +/- 2.82 mL/min, P less than .01) were reduced significantly by diltiazem. On the other hand, diltiazem did not produce any significant changes in pharmacokinetic parameters of trimethadione and plasma concentration ratio, oxidative major metabolite of trimethadione to trimethadione itself. These results suggest that other drugs metabolizing the same hepatic oxidative pathways as antipyrine, may be influenced by diltiazem.

Adult↗
PubMed1989

The effects of encainide versus diltiazem on the oxidative metabolic pathways of antipyrine.

The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p less than 0.05) and increased half-life from 12.7 to 15.9 hours (p less than 0.05). Diltiazem reduced the formation rate constants for 3-hydroxymethylantipyrine by 27% (p less than 0.05) and 4-hydroxyantipyrine by 37% (p less than 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 less than p less than 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half-life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.

Adult↗
PubMed1987

Comparison of effects of ozone, cadmium chloride and carbon tetrachloride on [14C]antipyrine metabolism in conscious rats.

Previously, Graham et al. found evidence that pentobarbital-induced sleeping time was enhanced in various animals following exposure to 1 ppm of ozone in air. The present study was undertaken to investigate whether similar ozone exposure would cause inhibition of metabolism of another model drug, [14C]antipyrine, in conscious rats. Furthermore, this study also investigated whether, like that of ozone, other lipid-peroxidizing agents such as cadmium and carbon tetrachloride would affect metabolism of [14C]antipyrine in conscious rats. The results showed no significant effect of ozone exposure on subsequent metabolism of [14C]antipyrine in conscious rats as revealed by very similar 14CO2 exhalation rate (CER)-time profiles before and after ozone treatment under various exposure protocols. Even though the exposure to ozone caused no inhibition of antipyrine metabolism in conscious rats, cadmium and carbon tetrachloride, on the other hand, markedly inhibited metabolism of this model drug. In agreement with the reported sex-difference in toxic effects of cadmium, during the present study the cadmium-induced inhibitory effect on the CER-time profiles was observed in male but not in female rats. In contrast, no clear sex-dependency was noted in the inhibitory effect of carbon tetrachloride on [14C]antipyrine metabolism.

Animals↗
PubMed1986

Characterization of antipyrine autoinduction in the rat utilizing a new microsampling technique for serial blood sample collections.

A new microsampling technique is described and applied to the collection of a large number of blood samples from individual rats receiving a chronic intravenous antipyrine infusion. From these samples, a detailed description of the time-course of antipyrine autoinduction of clearance in the rat was provided. Antipyrine clearance was increased 4-5-fold over 8 d of antipyrine administration, with the increase in clearance following a monoexponential process in all animals. The assumption that the time-course of induction should reflect the degradation rate of induced enzymes was examined by comparing the half-life of antipyrine autoinduction with in vitro estimates for the half-life of induced cytochrome P-450 enzymes. The results of this comparison are discussed with respect to utilizing this kinetic model to quantitate the turnover of drug metabolism enzymes in vivo.

Animals↗
PubMed1996

Lack of effect of zinc supplementation on antipyrine clearance in alcoholic liver disease.

METHODS: The effect of zinc supplementation on antipyrine clearance was evaluated in 14 outpatients with stable alcoholic liver disease, of whom nine had biopsy proven alcoholic cirrhosis. RESULTS: There was no change in antipyrine clearance after 14 days of zinc supplementation (median 12.5 vs 12.9 ml.min-1). However, a significant increase in P-prothrombin-proconvertin was found. There was a positive correlation between S-zinc and antipyrine clearance at inclusion (rs = 0.76) as well as after zinc supplementation (rs = 0.72). CONCLUSION: No effect of zinc supplementation on antipyrine clearance was found. The positive correlation between S-zinc and antipyrine clearance could be due to the confounding effect of alcoholic liver disease.

Adjuvants, Immunologic↗
PubMed1984

Antipyrine metabolism in patients with disseminated testicular cancer and the influence of cytostatic treatment.

Antipyrine plasma clearance and rates of metabolite formation were measured on four occasions in eight patients with disseminated nonseminomatous testicular cancer. Antipyrine tests were performed before, during (2X), and after treatment with a combination of cisplatin (P), vinblastin (V), and bleomycin (B). Pretreatment values were compared with a male control group (n = 14) matched for age and body weight. Antipyrine plasma clearance was 20% higher in patients with testicular cancer (first experiment) than in the control group. This difference was mainly due to a 35% higher clearance for production of 3-hydroxymethylantipyrine (HMA), while clearance for production of norantipyrine (NORA) and 4-hydroxyantipyrine (OHA) was not significantly different from the control group. A reduction in CLHMA was observed after complete remission (fourth experiment), indicating that the presence of the tumor may be related to a selective increase of HMA formation. Treatment with the PVB combination resulted in a 30% increase in antipyrine plasma clearance (second and third experiments), whereas the rates of formation of the main metabolites of antipyrine were all increased to the same extent. These accelerating effects of PVB treatment persisted for at least 6 weeks after the start of the last treatment cycle. The data presented in this paper demonstrate that the presence of a testicular tumor and the use of cytostatics can have an accelerating and partially selective effect on oxidative drug-metabolizing enzyme activity in man.

Adolescent↗
PubMed1988

Antipyrine and metronidazole metabolism during occupational exposure to gasoline.

Antipyrine and metronidazole clearance was measured in 18 fuel-filling attendants by the single-sample method while the attendants were being exposed occupationally to gasoline; the measurements were repeated after 2-4 weeks with no exposure. Eighteen office workers were investigated simultaneously. The median concentration of gasoline in the breathing zone of the fuel-filling attendants during filling and cleaning operations was 270 mgm-3 (range 18-1758 mgm-3). Antipyrine clearance was 18% higher during exposure to gasoline than after 2-4 weeks of vacation (P less than 0.01), while antipyrine clearance was unchanged in the office workers. No change was found in metronidazole clearance in either group. Antipyrine clearance was on average 26% higher in the smokers than in the nonsmokers (P less than 0.05), while metronidazole clearance was similar in smokers and nonsmokers. We conclude that gasoline is an inducer of antipyrine elimination, with no impact on metronidazole elimination. This indicates that gasoline has a differential inducing effect on the hepatic drug metabolizing enzymes of man.

Adult↗
PubMed1987

Pharmacokinetics of adriamycin, adriamycinol, and antipyrine in patients with moderate tumor involvement of the liver.

The pharmacokinetics of adriamycin, its metabolite adriamycinol, and antipyrine were studied in 17 patients with moderate tumor involvement of the liver and compared to that of 19 tumor patients with normal liver function (Preiss et al. 1985). The individual liver function parameters deviated from normal by a factor ranging from 2.5 to 12.2. The t1/2 alpha and t1/2 beta, the AUC (corrected for body weight and dose) and the total body clearance (CL, corrected for body weight) of adriamycin did not differ significantly between the two groups of patients. Likewise, there was no difference in the kinetic parameters of antipyrine between the two groups. Unlike adriamycin and antipyrine, adriamycinol was found to have a significantly longer t1/2term (60.5 vs 28.3 h, P less than 0.001), an increased AUC (3.00 vs 1.43 h/ug per ml, P less than 0.02), and a higher AUCadriamycinol/AUCadriamycin ratio (0.94 vs 0.52, P less than 0.02) in patients with moderate tumor involvement of the liver. The CL, the AUC, and t1/2 beta of adriamycin correlated significantly (P less than 0.001 and P less than 0.01) with the corresponding kinetic parameters of antipyrine, but not with the usual liver function parameters. No correlation could be found between the kinetic parameters of adriamycinol and those of antipyrine.

Adult↗