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PubMedDate not supplied

Ibuprofen does not impair antipyrine clearance.

The influence of therapeutic doses of ibuprofen on the distribution and clearance of antipyrine in humans was evaluated in a series of healthy volunteers. Subjects received a single intravenous dose of antipyrine on two occasions, once in the drug-free control state and again during coadministration of ibuprofen, 1.6 to 2.4 Gm per day in divided doses. Compliance was verified by measurement of plasma ibuprofen levels, which averaged 22 micrograms/ml. Kinetic variables for antipyrine were determined from multiple plasma antipyrine concentrations measured during 24 hours after each dose. Between drug-free control and ibuprofen coadministration trials, there was no significant difference in antipyrine volume of distribution (0.69 vs. 0.69 liter/kg), elimination half-life (12.2 vs. 12.5 hours), or total metabolic clearance (0.69 vs. 0.70 ml/min/kg). Thus, ibuprofen does not impair the clearance of the marker compound antipyrine, often used as an index of drug oxidizing capacity in humans.

Adult↗
PubMed1990

Quinidine does not alter antipyrine metabolism.

Quinidine has been reported to be a potent inhibitor of a specific isozyme of cytochrome P-450 (P-450db 1) that is responsible for the metabolism of a select group of drugs. In order to investigate the potential for quinidine to inhibit other isozymes of cytochrome P-450 and to assess whether or not P-450db 1 plays any role in antipyrine metabolism, we studied the effects of quinidine pretreatment on the pharmacokinetics and metabolism of antipyrine in six healthy, male volunteers. Using a randomized, crossover study design with a 2-week washout period between treatments, subjects received a single 1 gram antipyrine dose alone or with quinidine sulfate 200 mg orally every 8 hours for 24 hours prior to the dose of antipyrine and over the 48 hours following antipyrine administration. Mean serum concentrations, apparent oral clearance (1.93 +/- 0.86 vs 2.06 +/- 1.06 L/hr with quinidine) and half-life (13.5 +/- 3.3 vs 12.4 +/- 3.6 hr with quinidine) were not significantly different between the two treatments. The fraction of the administered dose recovered as antipyrine and measured metabolites (56.7% vs 59% with quinidine) as well as the recovery of each individual metabolite was not altered with quinidine pretreatment. In addition, the mean formation clearances for norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine exhibited no change between treatment phases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Finasteride, a steroid 5 alpha-reductase inhibitor, does not affect the oxidative metabolism of antipyrine.

A single-blind study was conducted to investigate the effect of multiple doses of finasteride, a 5 alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia, on the single-dose pharmacokinetics of antipyrine. Twelve patients with benign prostatic hyperplasia received a total of four single oral doses of 18 mg/kg antipyrine before, during, and after treatment with 10 mg/day of finasteride for 28 days. Finasteride had no effect on antipyrine concentration profiles. There were also no changes in urinary excretion of three principal antipyrine metabolites. A slight increase in renal clearance of antipyrine was observed; however, this is not considered relevant because excretion of unchanged antipyrine represents a minor fraction of total elimination and is not directly related to oxidative metabolism. These results imply that significant interactions between finasteride and drugs metabolized by these cytochrome P-450 enzymes are unlikely.

Administration, Oral↗
PubMed1992

Disposition of antipyrine in patients with extensive metastatic liver disease.

In the present study the effect of metastatic liver disease on hepatic drug metabolism has been examined by studying the pharmacokinetics of antipyrine and the urinary excretion of antipyrine and its three major metabolites (4-hydroxyantipyrine, norantipyrine, and 3-hydroxymethylantipyrine) in 12 patients with extensive metastatic liver disease, and in 12 matched healthy controls. In the patients total liver volume, the volume of the liver parenchyma, and the volume of the liver metastases were determined by computed tomography. The volume of liver metastases always exceeded 35% of the total liver volume. There were no significant differences between the patients and controls in plasma half-life, plasma clearance, or apparent volume of distribution of antipyrine. The cumulative urinary excretion of antipyrine and its three major metabolites was significantly lower in patients [44 (18) %] than in controls [71 (8) %]. The excretion of antipyrine itself was unchanged and the decrease in cumulative excretion was due to reduced excretion of the three metabolites. The results show that the activity of the hepatic mixed function oxidases was not impaired even in patients with extensive metastatic liver disease. This may be because liver metastases do not cause a corresponding reduction in the volume of normal hepatic parenchyma. The decreased urinary excretion of the three major metabolites of antipyrine, which are mainly glucuronidated, may have been due to an alteration in the process of conjugation.

Adenocarcinoma↗
PubMed1985

Antipyrine metabolite formation and excretion in patients with chronic renal failure.

In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides the parent drug, 3-hydroxymethylantipyrine (HMA) was present in plasma in the free and conjugated forms, whereas 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) were found only in the conjugated form. The same was true for urine. The plasma concentrations of these metabolites are too low to be measured in subjects with normal renal function. Plasma antipyrine clearance in the patients was in the same range as in healthy subjects. Investigation of metabolite kinetics, however, revealed that the rate of formation of NORA was preferentially decreased, whereas that of OHA and HMA were unaltered. Renal clearance of the metabolites of antipyrine was severely impaired in patients with renal insufficiency, and the resulting accumulation made it possible for the first-time to measure the antipyrine metabolites in plasma. Mean residence times of metabolites were longer than that of the parent compound. Renal clearances of the conjugates were correlated with the creatinine clearance, but were somewhat higher. Renal clearance of free HMA was lower and was also correlated with creatinine clearance. The mean clearance for glucuronidation of HMA was 93.1 ml/min. The results suggest that in healthy subjects Phase I metabolism is the rate-limiting step in the elimination of antipyrine, which is essential for its application as a model drug in metabolism studies.

Adult↗
PubMed1985

Influence of cimetidine on steady state concentration and metabolite formation from antipyrine infused with a rectal osmotic mini pump.

The utility of an osmotic rectal drug delivery system as a tool in steady-state pharmacokinetic interaction studies has been investigated using the cimetidine-antipyrine interaction. Antipyrine was administered to six healthy male volunteers at the rate of 15 mg/h until steady-state was reached. Cimetidine 400 mg was then given followed by 200 mg cimetidine after 2, 4 and 6 h. Antipyrine kinetics in plasma and saliva were assessed, and metabolite excretion was determined in urine. Antipyrine levels in plasma and saliva increased shortly after cimetidine administration, indicating inhibition of antipyrine metabolizing enzymes. From the metabolite data it was concluded that all major metabolic pathways of antipyrine were affected to the same extent. The effect lasted somewhat longer than anticipated on the basis of the plasma cimetidine concentrations, but it had disappeared within 48 hours after cessation of treatment. It is concluded that the osmotic rectal drug delivery system is a useful tool in pharmacokinetic interaction studies, because it provides very constant steady-state concentrations, thus permitting investigation of the time course of drug interactions.

Adult↗
PubMed1975

Normal antipyrine metabolism in patients with cholesterol cholelithiasis. Evidence that the disease is not due to generalized hepatic microsomal dysfunction.

Plasma antipyrine half-lives and metabolic clearances were measured after a single oral dose of antipyrine in 10 control subjects, 12 patients with gallstones, and 9 patients having undergone cholecystectomy for cholesterol cholelithiasis, to determine whether impairment of hepatic antipyrine metabolism occurs in patients with cholesterol cholelithiasis. The plasma antipyrine half-life and metabolic clearances in the control subjects were 11.7 plus or minus 1.3 hours and 42.5 plus or minus 3.3 ml/min, respectively; in patients with gallstones, 12.3 plus or minus 1.3 hours and 36.0 plus or minus 3.2 ml/min, respectively; and in patients having undergone cholecystectomy, 13.2 plus or minus 1.8 hours and 33.8 plus or minus 4.2 ml/min, respectively. Values for antipyrine half-life and metabolic clearance were not statistically different in these three groups. This study suggests the presence of normal hepatic antipyrine metablosim in patients with cholesterolcholelithiasis.

Adult↗
PubMedDate not supplied

Comparison of MEGX (monoethylglycinexylidide) and antipyrine tests in patients with liver cirrhosis.

The aim of the study was to compare the feasibility of the MEGX (monoethylglycinexylidide) and antipyrine tests in reference to standard biochemical parameters used for liver assessment in cirrhotic patients. The study was carried out in 44 subjects: 14 healthy controls and 30 cirrhotic patients classified according to the Child-Pugh's score to subgroups A (n=11), B (n=12) and C (n=7). All subjects underwent two dynamic liver tests, i.e. MEGX (monoethylglycinexylidide) and antipyrine test in a crossover schedule with at least 5-day interval. For the MEGX, lidocaine was administrated intravenously, at a dose of 1 mg/kg, and blood samples for MEGX assay were collected after 15 minutes. MEGX concentrations were measured by fluorescence polarization immunoassay. The antipyrine concentrations were evaluated following a single oral administration of 1000 mg antipyrine. The blood was sampled for 24 hours after the drug administration, and antipyrine concentrations were measured spectrophotometrically. Standard biochemical parameters used for liver assessment were measured by means of routine laboratory methods. It was concluded that in patients liver with cirrhosis, liver dynamic tests were better predictors of hepatic function. The MEGX test was more feasible in clinical setting, but it was noted that antipyrine test was more sensitive in staging liver cirrhosis.

Adult↗
PubMedDate not supplied

Induction of hepatic and presystemic metabolism of antipyrine in the mice: rifampicin versus rifabutin.

The effects of hepatic and presystemic enzyme induction on the bioavailability (F) and disposition of antipyrine after repeated rifampicin (RFM) and rifabutin (RBT) exposure were studied in mice. ICR mice were divided to receive 4 daily oral dosing of either the dosing vehicle or 50 mg/kg of REM or RBT. At the completion of rifamycin dosing, the pharmacokinetics of antipyrine were assessed following either a single 50 mg/kg oral dose or a 20 mg/kg intravenous dose. Blood samples were collected (n=4/timepoint) over a 6 h period. The content of P450 in the liver and small intestine (GI) was also assessed in parallel. Systemic antipyrine clearance (CL) increased from 31.8 ml/min/kg (controls) by 64% and 42% following repeated exposure to RFM and RBT, respectively. Estimate of F for antipyrine decreased from 0.97 in controls to 0.58 and 0.82 in animals treated with RFM and RBT, respectively. The content of P450 (nmol/mg protein) in the liver increased from 0.61 (control) to 1.36 following RFM and 0.82 for RBT, while no significant changes were observed for the GI tract. The i.v. dosing data confirmed the induction of antipyrine metabolism in the liver by both rifamycins yet the induction potential was approximately 1/3 lower for RBT. This difference was consistent with the changes observed in the hepatic P450 protein content, but this alone could not account for the reduction in the F for antipyrine. Therefore, predictions for changes in F of an interacting agent should not be judged solely on the basis of the metabolic status of the liver. The relative contribution of metabolic induction and presystemic drug loss to bioavailability/absorption should also be further delineated for its relevance to poly-pharmacy in patients likely to receive long-term rifamycin based treatment.

Administration, Oral↗
PubMed1998

The effect of physical conditioning on antipyrine clearance.

The effects of physical conditioning on antipyrine clearance were studied in two groups of subjects. Healthy men not engaged in the systematic practice of any sport were compared with endurance runners (defined as men running > 80 km/week). Studies were carried out at three different periods of the annual plan training at 4-month intervals. Antipyrine was administered orally and pharmacokinetic parameters were obtained from saliva samples by the multiple-sample method. Endurance performance, expressed in terms of the maximal oxygen uptake (VO2max), the ventilatory threshold and the 4-mM x l(-1) lactate threshold (OBLA), was higher in trained than in control subjects at each of the three periods. Antipyrine clearance was also significantly elevated and antipyrine half-life reduced in runners during all periods. No significant difference in VO2max or antipyrine clearance was found between the various periods in either trained or control subjects. Both ventilatory threshold and OBLA increased significantly along the training period in conditioned subjects. Significant correlations were found between antipyrine clearance and VO2max, ventilatory threshold and OBLA. In summary, these results indicate an association between aerobic conditioning and increased hepatic oxidative metabolism of low-clearance drugs.

Adult↗
PubMed1986

Effect of antipyrine on prostaglandin levels and uterine and umbilical blood flow.

Antipyrine and 4-aminoantipyrine have been used for approximately 20 years to measure uterine and umbilical blood flow. Fetal infusion of 4-aminoantipyrine has been shown to decrease myometrial activity and to significantly lower prostaglandin F2 alpha metabolite levels. Since prostaglandins are thought to be important in regulating uterine and umbilical blood flow, their decrease could cause significant changes in blood flow. The purpose of the present study was to evaluate the effects of antipyrine on uterine and umbilical blood flow as measured with electromagnetic flow probes and to determine whether antipyrine causes significant changes in levels of prostaglandin E2, prostaglandin F2 alpha metabolite, and prostaglandin I2 measured as 6-keto-prostaglandin F1 alpha. Antipyrine infusion produced significant reductions in the uterine venous levels of prostaglandin E2 and prostaglandin F2 alpha metabolite (p less than 0.05). These reductions in prostaglandin levels were not associated with any significant changes in maternal blood pressure, heart rate, uterine blood flow, or oxygen content. Although fetal prostaglandin levels tended to decrease during the antipyrine infusion, these changes were not significant. Fetal blood pressure, heart rate, umbilical blood flow, PaO2, and oxygen content were not significantly altered. These data suggest that the antipyrine method does not affect basal blood flow in the uterine or umbilical circulation even though uterine prostaglandin levels are significantly decreased.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Metabolism of metronidazole and antipyrine in isolated rat hepatocytes. Influence of sex and enzyme induction and inhibition.

The metabolism of metronidazole and antipyrine was investigated in freshly isolated hepatocytes from 7 male and 6 female control Wistar rats, 8 males and 5 females pretreated with phenobarbital (PB) and 3 males pretreated with 3-methylcholanthrene (MC). Pretreatment with PB increased the intrinsic clearance (CLi = Vmax/Km) of metronidazole to its acetic acid (MAA) and hydroxy metabolite (HM) 7- and 2.8-fold in the males and 3.2- and 3.0-fold in the females, whereas MC treatment increased the values 9- and 10-fold, respectively (P less than 0.05). The CLi of metronidazole to HM and its glucuronide conjugate was higher in the control and PB treated male than in the corresponding female groups, whereas the rank order was reversed for sulphate formation (P less than 0.05). SKF 525A was a more potent inhibitor of MAA formation than of HM formation, except in the PB treated male group. Pretreatment with MC increased the inhibitory potency of alpha-naphthoflavone and antipyrine toward MAA and HM formation. In male rats PB treatment increased the CLi of antipyrine to 3-hydroxymethyl-(HMAP), nor-(NORAP) and 4-hydroxyantipyrine (OHAP) 2.5-, 2.1- and 4.5-fold, respectively (P less than 0.05). Pretreatment with MC in male and with PB in female rats had no significant effect on antipyrine metabolism. SKF 525A was a more potent inhibitor of HMAP and OHAP formation than of NORAP formation. Treatment with MC increased the inhibitory potency of alpha-naphthoflavone toward the formation of all antipyrine metabolites. Metronidazole increased the formation rate of HMAP, but inhibited the formation of NORAP and OHAP, particularly the latter. The results suggest that the formation of MAA, HM, HMAP, NORAP and OHAP from metronidazole and antipyrine is catalyzed by different cytochrome P-450 isozymes, which may be supplemented or substituted by PB or MC induced species. The involved P-450 isozymes have more or less overlapping substrate and product specificity. Metronidazole appears to be a sensitive probe for detection and identification of PB and MC type induction.

Acetates↗
PubMed1983

Serum folic acid levels and antipyrine clearance rates in smokers and non-smokers.

Serum folic acid (FA) levels and antipyrine clearance rates were determined in 15 healthy male subjects who had not been administered any drug and alcohol for a month preceding the study. Eight of the 15 subjects smoked cigarettes daily while the remaining seven did not. The serum FA levels were measured by Lactobacillus casei bioassay. The antipyrine clearance rates were estimated in plasma or saliva obtained after oral administration of antipyrine for evaluating the activity of hepatic microsomal oxidase. The serum FA levels in the smokers were significantly lower than those in the non-smokers and the antipyrine clearance rates were significantly higher in the smokers compared with the non-smokers. The increase of the antipyrine clearance rates in the smokers was supposed to be caused by an increase in the activity of hepatic microsomal oxidase since it has been established that polycyclic aromatic hydrocarbons contained in cigarette smoke induce these enzymes. The association of the decrease in the serum FA levels and the increase of the antipyrine clearance rates was investigated.

Adult↗
PubMed1996

Accuracy of the one-sample method for determination of antipyrine clearance in elderly subjects.

The purpose of this study was to evaluate the validity of the one-sample abbreviated method for determination of the pharmacokinetic parameters of antipyrine in the elderly. Antipyrine pharmacokinetics were studied in 15 elderly women (mean age 86 years). Antipyrine (1 g) was administered orally and pharmacokinetic parameters were determined by the one-sample (24 h) and multiple-sample (3, 6, 9, 12 and 24 h) methods. Mean antipyrine clearance for the one-sample study (19.72 +/- 1.51) was almost identical to that obtained with the multiple-sample approach (20.73 +/- 1.57), and the two methods were very well correlated (r = 0.989). Relative standard deviations between individual clearances values for multiple-sample vs. one-sample studies averaged 1.6%. Values of elimination half-life were likewise very similar for the abbreviated (17.41 +/- 1.21) and complete (17.99 +/- 1.09) methods, with a significant correlation (r = 0.857). Although values were underestimated by 10% in the one-sample approach, no difference in the volume of distribution with the multiple-sample study was observed. When the unbiased volume of distribution value was determined from the total elimination curve against time, the influence of biased volume of distribution resulted in a 5.1% deviation in antipyrine clearance in the one sample method. The findings indicate that antipyrine pharmacokinetic parameters can be estimated with reasonable precision and accuracy in the elderly using a simplified one-sample procedure.

Administration, Oral↗
PubMed2005

Antipyrine test predicts pharmacodynamics in docetaxel and cisplatin combination chemotherapy.

To clarify the role of cytochrome P450 in docetaxel and cisplatin combination chemotherapy, cytochrome P450 activity was measured by simple antipyrine test, and its correlation with the drugs' pharmacodynamics was assessed. Twenty-five patients with advanced non-small cell lung cancer received an antipyrine test and were treated with docetaxel and cisplatin. Plasma antipyrine concentration (C) was measured 4 and 24h after oral administration of 500 mg antipyrine. Antipyrine disappearance rate (ADR) was calculated by: [(C(4h)-C(24h))/C(4h)]x100. ADR correlated significantly with neutropenia nadir. ADR and alpha(1)-acid glycoprotein were selected for independent predictors of neutropenia by multiple regression analysis. In addition, 25 patients were separated into "low ADR" (<40%) and "high ADR" groups (>40%). Grade 3--4 neutropenia was observed in 7/9 "low ADR" patients (77%), whereas grade 3--4 neutropenia was observed in 5/16 "high ADR" patients (31%). We concluded that antipyrine test and cytochrome P450 play an important role in predicting toxicities of docetaxel and cisplatin combination chemotherapy.

Adenocarcinoma↗
PubMed1985

Antipyrine elimination in patients with obstructive jaundice: a predictor of outcome.

A number of factors are known to be related to increased mortality of surgery in obstructive jaundice, yet precise identification of patients at greatest risk is difficult. We have studied the elimination of the minor analgesic antipyrine as a dynamic measure of hepatic metabolic function in patients with obstructive jaundice undergoing percutaneous transhepatic biliary drainage. Of 46 patients in whom antipyrine clearance was measured, 21 had an antipyrine half-life less than 15 hours and 2 died in the hospital. Of 25 who had an antipyrine half-life greater than 15 hours, 10 died in the hospital, 4 before undergoing surgery. The difference in mortality is significant (p less than 0.05). Of 15 patients who had serial antipyrine tests, only 4 showed an improvement during percutaneous transhepatic biliary drainage. The antipyrine test may be a useful predictor of outcome in obstructive jaundice, and this study suggests that hepatic function does not improve in all patients undergoing preoperative percutaneous transhepatic biliary drainage.

Adult↗
PubMed1996

Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation.

BACKGROUND AND OBJECTIVE: Antipyrine has been widely used as a probe drug for human oxidative drug metabolism. To evaluate the role of antipyrine as a model drug, we have identified the cytochrome P450 enzymes involved in 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. METHODS: We used the following methods for this study: (1) determination of enzyme kinetics for antipyrine metabolite formation in human liver microsomes, (2) inhibition studies with antibodies and inhibitors, and (3) formation of metabolites by stable expressed human P450 enzymes. RESULTS: Antipyrine biotransformation could be described by Michaelis-Menten kinetics: norantipyrine: maximum rate of metabolite formation (Vmax), 0.91 +/- 0.04 nmol . mg-1 . min-1; Michaelis-Menten constant (Km), 19.0 +/- 0.8 mmol/L; 4-hydroxyantipyrine: Vmax, 1.54 +/- 0.08 nmol . mg-1 . min-1;Km,39.6 +/- 2.5 mmol/L. Antibodies against CYP3A4 inhibited the formation of 4-hydroxyantipyrine by 25% to 65%. LKM-2 antibodies (anti-CYP2C) caused a 75% to 100% inhibition of norantipyrine and a 58% to 80% inhibition of 3-hydroxymethylantipyrine formation. Sulfaphenazole inhibited the formation of 3-hydroxymethylantipyrine and norantipyrine by about 50%. Furafylline and fluvoxamine inhibited norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine formation by about 30%, 30%, and 50%, respectively. Ketoconazole reduced formation of norantipyrine, 3-hydroxymethylantipyrine, and 4-hydroxyantipyrine by up to 80%. Formation in stable expressed enzymes indicated involvement of CYP1A2, CYP2B6, CYP2C, and CYP3A4 in metabolite formation. CONCLUSION: Antipyrine metabolites are formed by at least six hepatic cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP3A4). 4-Hydroxylation is mainly catalyzed by CYP3A4 and, to a lesser extent, by CYP1A2. The CYP2C subfamily contains the predominant enzymes for norantipyrine formation, and CYP1A2 is also involved. Formation of 3-hydroxymethylantipyrine is mediated by CYP1A2 and CYP2C9. Because several cytochrome P450 enzymes are involved in the formation of each metabolite, antipyrine is not well suited as a probe for distinct human cytochrome P450 enzymes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Effect of age on the pharmacokinetics of antipyrine in calves.

Single doses of 15 mg kg-1 antipyrine were given intravenously to 10 female calves of the black and white breed at one, two, four, six, eight and 12 weeks of age, and the concentrations of antipyrine, 4-hydroxyantipyrine (4-OHA), 3-hydroxymethyl-antipyrine (HMA) and norantipyrine (NORA) were measured in plasma and urine by high performance liquid chromatography. The first three months of life were characterised by a steady decrease in the apparent volume of distribution (aVd) and half-life (t0.5) of antipyrine. The systemic clearance (CIs) of antipyrine per unit bodyweight increased significantly between one and 12 weeks of age. Age did not influence the excretion of HMA and NORA in urine, but the excretion of 4-OHA by 12-week-old calves was significantly greater than by one-week-old calves. There was an age-related change in the partial clearances of the antipyrine metabolites when expressed per unit bodyweight.

Aging↗