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Purpose: Metamizole can sterically inhibit aspirin (ASA) from binding to cyclooxygenase 1 (COX1). It is recommended that ASA should be taken 30 min prior to metamizole to maintain the irreversible inhibition of arachidonic acid (AA)-induced platelet aggregation. We aimed to analyse the inhibitory effect of ASA and metamizole on AA-induced platelet aggregation over the course of the day., Methods: We analysed hospitalized patients who ingested ASA at least 30 min prior to metamizole (recommended dosing group, n = 15), metamizole prior or simultaneously with ASA (not recommended dosing group, n = 16) and patients with unknown or mixed intake (mixed dosing group, n = 5). AA-induced light transmission (LTA) and impedance aggregometry (IA) were measured before, 1-2 and 5-6 h after the intake of ASA ± metamizole., Results: Maximum AA-induced LTA prior to the intake of ASA was significantly lower and the rate of high on treatment platelet reactivity (HTPR) higher in the recommended compared with the not recommended dosing group (19.6% vs. 46.9%, p = 0.011 and 4/15 vs. 12/16 patients, p = 0.017). There was no difference when IA was used. Maximum AA-induced LTA after the intake of ASA ± metamizole was lower in patients in the not recommended but not in the recommended dosing group. All patients with HTPR in the recommended dosing group had regular inhibition of AA-induced LTA after discontinuation of metamizole., Conclusion: Co-medication of ASA and metamizole significantly influences platelet inhibition with variations during the day and can cause HTPR in patients taking ASA prior to metamizole or simultaneously.

Aim: Metamizole is a frequently used antipyretic and analgesic prodrug, yet its pharmacokinetics has not been thoroughly studied in infants and with coadministered medications. Thus, an LC-MS/MS method was developed to quantify the four major metamizole metabolites in human plasma. Methodology: Pre- and postcolumn infusion was installed to enable robust analyte retention and electrospray ionization following deproteinization of plasma samples. Results: The method was linear (R > 0.996), accurate (93.1-106.0%) and precise (≤12.7%). Mean recovery was more than 91.8% and ion suppression less than 13.1% for all analytes. Pharmacokinetic profiles were reproducible after 4 years at -80°C except for the formylated metabolite (-22.2%). Conclusion: The method fulfilled pertinent criteria of validation guidelines and required only little sample volume. The method therefore qualifies for metamizole analyses in children.

Purpose: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3-72 months., Methods: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC 0-inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3-23 months, 2-6 years) and compared with the 80-125% range of adult dose-adjusted reference exposure (AUC ref ). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure., Results: A total of 25 children aged 5 months-5.8 years (7.8-24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC 0-inf of 4-methylaminoantipyrine in children 2-6 years was 29.9 mg/L/h (95% CI 23.4-38.2), significantly lower than AUC ref (80-125% range 39.2-61.2 mg/L/h). AUC 0-inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8-119.0), comparable with AUC ref , while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age., Conclusions: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight-based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10-20 mg/kg) to achieve equivalent adult exposure., Trial Registration: ClinicalTrials.gov identifier: NCT02660177 .

Metamizole (MT), an analgesic and antipyretic drug, is rapidly hydrolyzed to the active primary metabolite 4-methylaminoantipyrine (MAA) and relatively active secondary metabolite 4-aminoantipyrine (AA). The aim of this study was to assess the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.), intramuscular (i.m.), oral (p.o.), and rectal (RC) routes in dogs. Six dogs were randomly allocated to an open, single-dose, four-treatment, four-phase, unpaired, crossover study design. Blood was collected at predetermined times within 24 hr, and plasma was analyzed by a validated HPLC-UV method. Plasma concentrations of MAA and AA after i.v., i.m., p.o., and RC administrations of MT were detectable from 5 (i.v. and i.m.) or 30 (p.o. and RC) min to 24 hr in all dogs. The highest concentrations of MAA were found in the i.v., then i.m., p.o., and RC groups. Plasma concentrations of AA were similar for i.v., i.m., and RC, and the concentrations were approximately double those in the PO groups. The AUC EV/IV ratio for MAA was 0.75 ± 0.11, 0.59 ± 0.08, and 0.32 ± 0.05, for i.m., p.o., and RC, respectively. The AUC EV / IV ratio for AA was 1.21 ± 0.33, 2.17 ± 0.62, and 1.08 ± 0.19, for i.m., p.o., and RC, respectively. Although further studies are needed, rectal administration seems to be the least suitable route of administration for MT in the dog., (© 2018 John Wiley & Sons Ltd.)

This study was performed to determine pharmacokinetic profiles of the two active metabolites of the analgesic drug metamizole (dipyrone, MET), 4-methylaminoantipyrine (MAA), and 4-aminoantipyrine (AA), after intravenous (i.v., intramuscular (i.m.), and oral (p.o.) administration in cats. Six healthy mixed-breed cats were administered MET (25 mg/kg) by i.v., i.m., or p.o. routes in a crossover design. Adverse clinical signs, namely salivation and vomiting, were detected in all groups (i.v. 67%, i.m. 34%, and p.o. 15%). The mean maximal plasma concentration of MAA for i.v., i.m., and p.o. administrations was 148.63 ± 106.64, 18.74 ± 4.97, and 20.59 ± 15.29 μg/ml, respectively, with about 7 hr of half-life in all routes. Among the administration routes, the area under the plasma concentration curve (AUC) value was the lowest after i.m. administration and the AUC EV /i.v . ratio was higher in p.o. than the i.m. administration without statistical significance. The plasma concentration of AA was detectable up to 24 hr, and the mean plasma concentrations were smaller than MAA. The present results suggest that MET is converted into the active metabolites in cats as in humans. Further pharmacodynamics and safety studies should be performed before any clinical use., (© 2017 John Wiley & Sons Ltd.)

Mild analgesics have been associated with antiandrogenic effects, but there are no such studies on dipyrone, despite its high prevalence of use in many countries. We examined the production of steroid hormones in human H295R cells after exposure to dipyrone and two metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), as well as fetal testicular testosterone production in rats following maternal dipyrone exposure. Androgen agonistic/antagonistic effects were examined in vitro for dipyrone and its metabolites in the Yeast Androgen Screen (YAS) assay and in vivo for dipyrone through the Hershberger assay. In vitro we tested dipyrone, MAA, and AA (0.1-1000 μM) while in vivo we used dipyrone (50, 100, 200 mg/kg/day). In the H295R assay, dipyrone, MAA and AA reduced the production of androgens and corticosteroids. Testosterone was reduced at concentrations 4-13 times higher than the maximum plasma concentrations reported in humans for MAA and AA. No effects were observed in the fetal testosterone production assay. In the YAS and Hershberger assays, no androgen agonistic/antagonistic activities were observed. These results indicate that dipyrone and its metabolites do not interact with the androgen receptor, but have the potential to inhibit steroidogenesis, however only at concentrations that are not relevant under normal medical use., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The purpose of the study was to evaluate the impact of intravenous metamizole on platelet inhibition by aspirin in patients with coronary artery disease early after on-pump coronary artery bypass grafting (CABG)., Design: Prospective, single-blind, randomized trial., Setting: Tertiary referal hospital., Participants: The study comprised 43 patients with multivessel coronary artery disease undergoing CABG., Interventions: Patients were randomized to postoperative intravenous metamizole ± opioids (study group; n = 23) or opioids alone (control group; n = 20). Aspirin was withheld at least 7 days before the surgery and reinitiated (300 mg) immediately after the procedure prior to metamizole use, and continued daily thereafter (150 mg). Platelet function was evaluated using multielectrode impedance aggregometry (acid-induced platelet activation [ASPI] and collagen-induced platelet activation [COL] test), P-selectin expression and urinary 11-dehydro-thromboxane B 2 (11-DTXB 2 ) level at baseline, postoperative day (POD) 0, POD 1, POD 2, and POD 6. Residual platelet reactivity (RPR) was defined as ASPI test >400 AU*min., Measurements and Main Results: In all study participants, postoperative ASPI test value moderately decreased (1058.2 v 966.6 AU*min, p = 0.047), urinary 11-DTXB 2 level increased (923.4 v 4367.3 pg/mg, p < 0.001), and P-selectin expression and COL test value remained stable postprocedure. The decreases of ASPI (p = 0.146) and COL test (p = 0.642), and P-selectin expression (p = 0.318) did not differ between both groups. Patients in the control group had higher postoperative increase of urinary 11-DTXB 2 level (p = 0.001). The prevalence of RPR was high and comparable between study and control groups (day 1, 95.6% v 100%, p = 0.535; day 6, 100% v 90%, p = 0.21). Multivariate analysis revealed that metamizole use did not predict the fluctuations of ASPI and COL test values and P-selectin expression, yet it independently predicted postoperative change of 11-DTXB 2 level (b = -0.518, p = 0.001)., Conclusions: Intravenous metamizole preceded by a loading dose of aspirin did not modify platelet response to aspirin in the postoperative period after CABG., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America., Objective: Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients., Design: A case-control study., Setting: Primary care in one European university hospital centre., Patients: In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls., Main Outcome Measures: Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors., Results: Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ± 89 vs. 7 ± 1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin., Conclusions: Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients., Trial Registration: German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.

Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs. MT is rapidly hydrolysed to the active primary metabolite 4-methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared with other minor metabolites. Among the other secondary metabolites, 4-aminoantipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.) and intramuscular (i.m.) routes in healthy horses. Six horses were randomly allocated to two equally sized treatment groups according to a 2 × 2 crossover study design. Blood was collected at predetermined times within 24 h, and plasma was analysed by a validated HPLC-UV method. No behavioural changes or alterations in health parameters were observed in the i.v. or i.m. groups of animals during or after (up to 7 days) drug administration. Plasma concentrations of MAA after i.v. and i.m. administrations of MT were detectable from 5 min to 10 h in all the horses. Plasma concentrations of AA were detectable in the same range of time, but in smaller amounts. Maximum concentration (C max ), time to maximum concentration (T max ) and AUMC 0-last of MAA were statistically different between the i.v. and i.m. groups. The AUC IM /AUC IV ratio of MAA was 1.06. In contrast, AUC 0-last of AA was statistically different between the groups (P < 0.05) with an AUC IM /AUC IV ratio of 0.54. This study suggested that the differences in the MAA and AA plasma concentrations found after i.m. and i.v. administrations of MT might have minor consequences on the pharmacodynamics of the drug., (© 2016 John Wiley & Sons Ltd.)

Metamizole (MT) is a pyrazolone nonsteroidal anti-inflammatory drug labelled for humans and animals. The aim of this study was to assess the pharmacokinetics of its active metabolites 4-methylamino-antipyrine (MAA) and 4-amino-antipyrine (AA) in male piglets after a single intramuscular injection of MT. Eight healthy male piglets were administered MT (100 mg/kg) intramuscularly. Blood was sampled at scheduled time intervals, and drug plasma concentrations evaluated by a validated HPLC method. MAA and AA plasma concentrations were quantitatively detectable from 0.25 to 48 h and 0.50 to 72 h, respectively, in 6 of 8 and 7 of 8 animals. The average maximum concentrations of MAA and AA were of 47.59 and 4.94 mg/mL, respectively. The average half-lives were 8.57 and 13.3 h for MAA and AA, respectively. This study showed that the amount of MAA and AA produced in piglets is different to that in the animal species previously investigated. Further studies are necessary to understand whether these differences in MAA and AA plasma concentrations between animal species necessitate diverse therapeutic drug dosing., (© 2016 John Wiley & Sons Ltd.)

We have recently shown that dipyrone (metamizole), a non-opioid analgesic, can nullify aspirin (acetylsalicylic acid; ASA) antiplatelet effects in patients with coronary artery disease (CAD). In this study, we analysed the aspirin and dipyrone drug-drug interaction in order to identify strategies to prevent the dipyrone induced inhibition of asprin antiplatelet effects. Platelet function was measured by arachidonic acid-induced light-transmission aggregometry, thromboxane (TX) B2- formation by immunoassay. Dipyrone metabolite plasma levels were determined by high-performance-liquid-chromatography (HPLC). In seven healthy individuals, in vitro ASA (30 µM/ 100 µM/ 300 µM/ 1,000 µM) and dipyrone (10 µM) coincubation revealed, that the aspirin and dipyrone interaction can be overcome by increasing doses of aspirin. In 36 aspirin and dipyrone comedicated CAD patients, addition of ASA (30 µM/ 100 µM) in vitro inhibited, but did not completely overcome the dipyrone induced reduction of aspirin antiplatelet effects. Notably, the inhibition of thromboxane formation in aspirin and dipyrone comedicated CAD patients coincided with dipyrone plasma levels. In a cross-over designed study in four healthy individuals, we were able to prove that inhibition of aspirin (100 mg/ day) effects by dipyrone (750 mg/ day) was reversible. Furthermore, aspirin (100 mg/ day) medication prior to dipyrone (750 mg/ day) intake prevented the inhibition of antiplatelet effects by dipyrone in 12 healthy individuals. In conclusion, aspirin medication prior to dipyrone intake preserves antiplatelet effects, circumventing the pharmacodynamic drug-drug interaction at the level of cyclooxygenase-1.

Background and Purpose: The antipyretic and hypothermic prodrug dipyrone prevents PGE2 -dependent and -independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects., Experimental Approach: Male Wistar rats were treated i.p. with indomethacin (2 mg·kg(-1) ), dipyrone, 4-methylaminoantipyrine (4-MAA), 4-aminoantipyrine (4-AA) (60-360 mg·kg(-1) ), 4-formylaminoantipyrine, 4-acethylaminoantipyrine (120-360 mg·kg(-1) ) or vehicle 30 min before i.p. injection of LPS (50 μg·kg(-1) ), Tsv (150 μg·kg(-1) ) or saline. Rectal temperatures were measured by tele-thermometry and dipyrone metabolite concentrations determined in the plasma, CSF and hypothalamus by LC-MS/MS. PGE2 concentrations were determined in the CSF and hypothalamus by elisa., Key Results: In contrast to LPS, Tsv-induced fever was not followed by increased PGE2 in the CSF or hypothalamus. The antipyretic time-course of 4-MAA and 4-AA on LPS-induced fever overlapped with the period of the highest concentrations of 4-MAA and 4-AA in the hypothalamus, CSF and plasma. These metabolites reduced LPS-induced fever and the PGE2 increase in the plasma, CSF and hypothalamus. Only 4-MAA inhibited Tsv-induced fever. The higher doses of dipyrone and 4-MAA also induced hypothermia., Conclusions and Implications: The presence of 4-MAA and 4-AA in the CSF and hypothalamus was associated with PGE2 synthesis inhibition and a decrease in LPS-induced fever. 4-MAA was also shown to be an antipyretic metabolite for PGE2 -independent fever induced by Tsv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4-MAA is the hypothermic metabolite of dipyrone., (© 2014 The British Pharmacological Society.)

Background: After oral administration dipyrone is rapidly hydrolyzed to 4-methylaminoantipyrine, which is absorbed and further metabolized to 4-formylaminoantipyrine and to 4-aminoantipyrine, which is acetylated by a polymorphic N-acetyltransferase system to 4-acetylaminoantipyrine. To evaluate the presence of dipyrone metabolites in different rat matrices after intraperitoneal administration, an analytical method was developed and validated., Methodology: The four main dipyrone metabolites were extracted from plasma, cerebrospinal fluid and hypothalamus samples by LLE prior to LC-MS/MS., Results: Standard calibration graphs for all metabolites were linear (r > 0.99). The intra- and inter-day precision and accuracy values were both inferior to 15%., Conclusion: This method is simple and specific for studying dipyrone metabolites after intraperitoneal administration.

In order to evaluate the pharmacokinetics of metamizol in the presence of morphine in arthritic rats, after subcutaneous administration of the drugs, an easy, rapid, sensitive and selective analytical method was proposed and validated. The four main metamizol metabolites (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) were extracted from plasma samples (50-100μl) by a single solid-phase extraction method prior to reverse-phase high performance liquid chromatography with diode-array detection. Standard calibration graphs for all metabolites were linear within a range of 1-100μg/ml (r(2)≥0.99). The intra-day coefficients of variation (CV) were in the range of 1.3-8.4% and the inter-day CV ranged from 1.5 to 8.4%. The intra-day assay accuracy was in the range of 0.6-9.6% and the inter-day assay accuracy ranged from 0.9 to 7.5% of relative error. The lower limit of quantification was 1μg/ml for all metabolites using a plasma sample of 100μl. Plasma samples were stable at least for 4 weeks at -20°C. This method was found to be suitable for studying metamizol metabolites pharmacokinetics in arthritic rats, after simultaneous administration of metamizol and morphine, in single dose., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Dipyrone (metamizole) is a nonsteroidal anti-inflammatory drug used as an analgesic and antipyretic in both pediatric and adult patients. Dipyrone hydrolyses to 4-methylaminoantipyrine (MAA) in the stomach before absorption. There are several HPLC methods available for analysis of MAA from human plasma but no method has yet been developed on liquid chromatography-mass spectrometry (LC-MS) or LC tandem MS (LC-MS/MS), which are much more specific and sensitive techniques., Methodology: A high-performance LC-MS method for the quantification of 4-methylaminoantipyrine from human plasma has been developed, validated and applied to a pharmacokinetic study of 500 mg oral dose dipyrone. Following liquid-liquid extraction, the analyte was first separated on a reverse phase column using isocratic mobile phase and then analyzed by MS in selected ion monitoring mode using [M+H](+) ions, m/z 218.2 for 4-methylaminoantipyrine and 231.3 for 4-isopropylantipyrine (internal standard)., Results: The method exhibited a linear range from 0.2 to 10.0 µg/ml when only 100 µl human plasma sample was used. The lower limit of detection was 0.04 µg/ml (160 pg on column). The recovery was 80%. The accuracy and precision were obtained over the calibration curve range and were well within the limits specified under guidelines for bioanalytical method validation. The compound was stable under the experimental conditions., Conclusion: The method was demonstrated to be, simple, sensitive and rapid. It can be easily adopted in laboratories with access to LC-MS or MS/MS and applied to sample analysis in clinical settings where a large number of samples are generated.

Dipyrone (INN, metamizol) is a common analgesic used worldwide. Its widespread prescription or over-the-counter use in many countries (e.g., Brazil, Israel, Mexico, Russia, Spain) requires insight into its mode of action. This study therefore addressed the impact of its metabolites 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA) on peripheral cyclooxygenases (COX). Pharmacokinetics of metabolites and ex vivo COX inhibition were assessed in five volunteers receiving dipyrone at single oral doses of 500 or 1000 mg. Coagulation-induced thromboxane B2 formation and lipopolysaccharide-induced prostaglandin E2 synthesis were measured in vitro and ex vivo in human whole blood as indices of COX-1 and COX-2 activity. In vitro, metabolites elicited no substantial COX-1/COX-2 selectivity with MAA (IC50=2.55 micromol/L for COX-1; IC50=4.65 micromol/L for COX-2), being approximately 8.2- or 9-fold more potent than AA. After administration of dipyrone, MAA plasma concentrations remained above the IC50 values for each isoform for at least 8 h (500 mg) and 12 h (1000 mg) postdose. COX inhibition correlated with MAA plasma levels (ex vivo IC50 values of 1.03 micromol/L [COX-1] and 0.87 micromol/L [COX-2]). By contrast, plasma peak concentrations of AA after the 1000 mg dose were 2.8- and 6.5-fold below its IC50 values for COX-1 and COX-2, respectively. Maximal inhibitions of COX-1 and COX-2 were 94% and 87% (500 mg), 97% and 94% (1000 mg). Taken together, dipyrone elicits a substantial and virtually equipotent inhibition of COX isoforms via MAA. Given the profound COX-2 suppression by dipyrone, which was considerably above COX-2 inhibition by single analgesic doses of celecoxib and rofecoxib, a significant portion of its analgesic action may be ascribed to peripheral mechanisms. In view of the observed COX-1 suppression, physicochemical factors (lack of acidity) rather than differential COX-1 inhibition may be responsible for dipyrone's favorable gastrointestinal tolerability compared with acidic COX inhibitors.

Objective: The aim of this study was to investigate the extent and the rate of absorption of metamizole, appearing in blood as methylaminoantipyrine (MAA), from a new oral solution and a parenteral solution administered by the oral route relative to capsules., Methods: An open, randomized, 3 single-dose (2 g metamizole), crossover study with intervals of 7 days between periods was performed in 19 male and female healthy volunteers (age 22 - 45 years, body weight 49 - 88 kg, body height 156 - 189 cm). Metamizole metabolites were measured with an HPLC technique. The test formulations were considered bioequivalent with the reference formulation if the 90% confidence limits of the AUC0-->infinity and Cmax ratios and the tmax differences were within the range of 80 - 125%., Results: The 90% confidence limits of the comparisons between capsules (reference) and oral solution, capsules (reference) and ampoules, and ampoules (reference) and oral solution were 98.5 - 117.8, 99.5 - 132.6 and 81.3 - 105.8 for AUC0-->infinity 98.7 - 119, 101.7 to 129.2, and 82.1 - 104.8 for Cmax, and 84.4 to 115.6, 100 - 105.6 and 70.3 - 100 for tmax, respectively., Conclusion: The oral solution was bioequivalent to capsules with regard both to the extent and the rate of MAA absorption. Metamizole as oral solution was bioequivalent to reference ampoules in the extent of MAA absorption, but absorption rate was faster. Ampoules showed a higher MAA bioavailability than capsules.

A fatal suicidal intoxication with unusual drugs is reported. A 56-year-old man was found dead in his house; near by the corpse several empty drugs boxes were found. An autopsy was performed and the biological fluids were submitted to a full toxicological work-up. The analytical results supported the hypothesis of a death due to the acute baclofen (4-amino-3-(p-chlorophenyl)butyric acid) and dipyrone (sodium [N-(1,5-dimethyl-3-oxo-2-phenylpyrazolin-4-yl)-N-methylamino] methanesulfonate) intoxication.

Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) and the peak plasma concentration (Cmax) of 4-methylaminoantipyrine (MAA), an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336), measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC(0-infinity) and the Cmax of MAA can be accurately predicted (R2>0.95, bias <1.5%, precision between 3.1 and 8.3%) by LSS models based on two sampling times. Validation tests indicate that the most informative 2-point LSS models developed for one formulation provide good estimates (R2>0.85) of the AUC(0-infinity) or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h), but using different coefficients for AUC(0-infinity) and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R2>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4%) as well as for plasma concentration data sets generated by simulation (R2>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%). Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC(0-infinity) and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.

Objective: We previously found that, compared with healthy subjects. asymptomatic hepatitis-B virus (HBV) carriers displaying slow acetylator phenotype demonstrate a significant prolongation of the elimination half-life of 4-methylaminoantipyrine (MAA) and a decrease in the clearance of formation of 4-aminoantipyrine (AA) and 4-formylaminoantipyrine (FAA). However, the formation of 4-acetylaminoantipyrine (AAA) was unchanged. The present study was designed to examine the effect of the asymptomatic HBV carrier state on the metabolism of dipyrone. as a model drug, in rapid acetylators., Methods: The plasma and urine concentrations of the metabolites of dipyrone were measured in eight asymptomatic HBV carriers and eight healthy subjects who had normal liver function tests, all displaying the rapid acetylation phenotype and genotype, after the administration of a 1.0-g oral dose of dipyrone., Results: The following pharmacokinetic parameters were evaluated: peak plasma concentration, time to peak plasma concentration, elimination rate constant, area under the plasma concentration-time curve (0-->infinity), amount excreted (0-->infinity), renal and non-renal clearances for MAA and the clearances of formation for AA, FAA and AAA. No significant differences were found between the two subject groups., Conclusion: The effect of hepatic viral carrier state on drug metabolism may vary according to metabolic pathways and genetic polymorphism.

A novel chemiluminescence (CL) flow system for two sulfite-containing drugs, namely, menadione sodium bisulfite (MSB) and analgin is described. It is based on the weak chemiluminescence induced by the oxidation of sulfite group in drugs with dissolved oxygen in the presence of acidic Rh6G. Tween 80 surfactant micelles showed a strong enhancement effect on this weak chemiluminescence. For MSB analysis, online conversion of MSB in alkaline medium into sodium bisulfite was necessary, whereas analgin could be determined directly. The proposed method allowed the measurement of 0.05-50 microg/ml(-1) MSB and 0.05-10 microg/ml(-1) analgin. The limits of detection (3sigma) were 0.01 microg/ml(-1) MSB and 0.003 microg/ml(-1) analgin. The method was applied satisfactorily to pharmaceutical preparations as well as biological fluids.

Objective: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically., Methods: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly., Results: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA., Conclusion: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.

The pharmacokinetic behaviour of dipyrone metabolite 4-MAA in serum was determined in seven horses of different breeds after a single intravenous dose administration. A biexponential formula was fitted to the serum concentration vs. time data. The median half-life of the elimination phase (t1/2 beta) was 4.85 h (range 5.04 h), the median volume of distribution (Vd(area)) was 1.85 L/kg (range 3.2 L/kg) and median of total clearance was 4.0 mL/min/kg (range 2.3 mL/min/kg).

A new HPLC method for the determination of a metabolite of analgin, MAA (4-methylaminoantipyrine), in plasma and its application to determine the bioavailabilities of analgin nasal drops in human volunteers is reported in this paper. A Waters Model 481 instrument was used throughout the experiment. IAA (isopropylaminoantipyrine) was shown to be the most suitable internal standard at absorption wavelength of 254 nm. A mixture of phosphate buffer (pH 5.5) and methanol (68:32) was used as the mobile phase with a flow rate of 2 ml.min-1, and YWG-C18H37 as stationary phase. Calibration curve was linear (gamma = 0.9998) in the concentration range of 0.1-5 micrograms.ml-1. The within day and day-to-day precision (RSD) of this method were 2.35% and 2.61%, respectively, with average recoveries of 99.3%-103.9%. No interference was found in the body fluid. The plasma samples of healthy volunteers were treated with acid and extracted with ether. The system of mobile phase and the process of blood sample treatment were simpler than those reported in literature. So, the method is suitable for the study of pharmacokinetics and clinical determination of blood level of analgin. The studies on bioavailabilities of analgin nasal drops were carried out in 8 men relative to intramuscular injection and 6 men relative to oral tablets, respectively, at the dose of 250 mg analgin in different preparations administered by cross-over method. The main pharmacokinetic parameters were shown in Table 3. The results indicate that analgin nasal drops exhibited a higher bioavailability (relative to injection) and faster absorption (relative to tablet). So, analgin is suitable to be developed as a nasal preparation.

We evaluated the new commercially available enzymatic test kit for creatinine (Randox Laboratories Ltd. Ardmore, Crumlin, UK). The test correlated well with the reference HPLC method (yenz = 0.98x + 1.4; r = 1.00; n = 72). The correlations with the Jaffe method (yenz = 1.00x + 14.1; r = 0.99; n = 72) and the dry slide technique (yenz = 1.07x + 4.1; r = 1.00; n = 72) were also good, but these techniques gave slightly higher creatinine results than the HPLC or the Randox enzymatic method. This new test is insensitive to bilirubin interference. It has been reported that patients receiving metamizol showed unusually low values of creatinine, when determined enzymatically, but this drug does not interfere with the Randox method. The test evaluated is more specific than enzymatic methods published earlier and it provides an attractive alternative to the traditional picrate test.

A rapid solid-phase extraction (SPE) procedure was developed for the quantitative isolation of three important antipyrine (dipyrone) metabolites from human plasma: 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-methylaminoantipyrine (MAA). Separation and quantitation were performed using micellar liquid chromatography (MLC) with a 0.1 mol l-1 sodium dodecyl sulfate (SDS)-2.5% pentanol mobile phase and UV detection at 262 nm. The metabolites were well resolved in less than 5 min using an octadecyl silica-bonded stationary phase. The extraction procedure involved passing 0.3 ml of plasma sample through a disposable SPE cartridge packed with C18 bonded porous silica. The adsorbed metabolites were removed from the cartridge with methanol. The eluent was evaporated to dryness and the residue was reconstituted with mobile phase and injected into the chromatographic system. The cartridge blank interferent peaks, the effects on reproducibility of sample loading in the cartridge and volume needed for desorption of metabolites were evaluated. The concentration of metabolites ranged between 2.4 and 4 micrograms ml-1. The present procedure yields recoveries for the three metabolites ranging from 93 to 100%. The relative standard deviation (Sr) ranged between 1.2 and 13.6%. Limits of detection (LODs) were 10.5, 11.5 and 17.0 ng ml-1 for FAA, AA and MAA, respectively.

In order to eliminate positive interferences that take place with the Jaffé technique, the Kodak Ektachem and Boehringer Mannheim Companies have chosen an enzymatic method for the determination of creatinine in serum and urine. Pathological and clinical samples often contain metabolites in elevated concentrations or exogenous compounds such as drugs or toxic compounds. We noticed that patients receiving metamizol-containing drugs showed unusually low values of creatinine when determined with an Ektachem analyser. We investigated the effect of the main metabolites of this prodrug on the creatinine enzymatic methods of Kodak and Boehringer. We concluded that methyl-amino-antipyrine, the active substance after administration of metamizol (prop. INN) was responsible for the interference, and that no reliable determination of creatinine could be performed with these methods in the serum of patients receiving this drug.

We studied the effect in vitro and in vivo of dipyrone on the determination of several biochemical tests in two analyzers, a Hitachi 747 and a Kodak Ektachem 700. From studies in vitro, we found significant interference by dipyrone (P < 0.05) in the determination of creatine kinase (CK), lactate dehydrogenase (LD), uric acid, triglycerides, cholesterol, aspartate aminotransferase, alanine aminotransferase, and urea nitrogen with both instruments, and in the determination of creatinine in the Ektachem analyzer. We also studied the effect of intravenously administered dipyrone in 14 patients. Dipyrone interfered significantly (P < 0.05) in the determination of CK, LD, uric acid, triglycerides, and cholesterol with both instruments, and creatinine only with the Ektachem analyzer. Using high-performance liquid chromatography (HPLC), we measured concentrations of dipyrone in the serum of patients who had received the drug and observed a negative correlation between the concentrations of dipyrone in the blood and the percentage of each analyte concentration.

The formation and urinary excretion of the dipyrone metabolites, methylaminoantipyrine (MAA), aminoantipyrine (AA), formylaminoantipyrine (FAA) and acetylaminoantipyrine (AAA) were determined following administration of a single oral 1.0 g dose of dipyrone to 12 healthy volunteers. The AAA/AA plasma ratio showed that 3 subjects were slow and 9 were rapid acetylators. Pharmacokinetic parameters were determined separately for each group. A good correlation was found between the plasma and urine AAA/AA ratios. The renal clearance of the four metabolites was similar for both phenotypes. A significant difference in the rate of formation of dipyrone metabolites was found for AA, 0.25 (slow) vs 0.1 ml.min-1.kg-1 (rapid), and for AAA 0.75 (slow) vs 7.53 ml.min-1.kg-1 (rapid). There were comparable differences between slow and rapid acetylators in the AUC and the urinary excretion extrapolated to infinity for AA and AAA. The present results show that the kinetics of dipyrone metabolites in plasma and urine can provide a useful measure of the activity of the enzymes involved in their production.

Breast milk and plasma levels of dipyrone metabolites in 8 mothers given a single oral dose of the drug were determined by HPLC. Four metabolites were demonstrated by the analytical method: 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA). A good correlation was found between the plasma and milk concentrations of the metabolites. The mean (+/- SD) milk to plasma concentration ratios were: MAA = 1.37 +/- 0.28, AA = 1.15 +/- 0.40, FAA = 1.03 +/- 0.09, AAA = 0.97 +/- 0.24. The disposition pattern of the dipyrone metabolites in milk was studied in two mothers. None of the metabolites was detectable 48 h after drug administration.

The pharmacokinetic parameters were investigated after a single application of 1,0 g of Analgin to women in labour in comparison with a nonpregnant control group. During the late stage of pregnancy the distribution volume is only slightly increasing. For Analgin a fundamental influence on the level of serum concentration could not be shown. The biological half-life of Analgin shows remarkable individual differences and does not differ significantly between the two investigated groups. Therefore, during pregnancy a change of the applied dose is not indicated.

Pharmacokinetic investigations with the drug noramidopyrinmethansulfonatnatrium (Analgin) were performed in 8 patients who, for a longer period, had taken the progestagene derivative norethisterone acetate. The half life of elimination as expression of biotransformation is clearly increased after intake of norethisterone acetate. As Analgin undergoes an oxydative mechanism of disintegration, possible explanations for this prolongation of the half life of elimination are discussed in the light of relevant literature.

A simple, rapid, and sensitive procedure is described for the determination of the main metabolites of dipyrone in plasma and urine. After adding isopropyl aminoantipyrine as internal standard and a deproteinizer the plasma of urine samples are alkalized and extracted with chloroform. The residue of the evaporated organic phase is dissolved in mobile phase and separated by HPLC. The compounds are detected by ultraviolet light at 265 nm. The following metabolites can be determined selectively by this method: 4-methylamino-antipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine and 4-acetylaminoantipyrine. The detection limit for all four metabolites is 0.1 microgram/ml in plasma and 2 micrograms/ml in urine. The results of a human pharmacokinetic study are also presented.

The enzymatic determination of the uric acie concentration in urine and serum according to Kageyama ((1971), Clin. Chim. Acta 31, 421--426), which excludes the deproteinization of samples, was adapted to the C4 automatic analyzer (Perkin-Elmer). The reliability of this procedure and its correlation with an UV-method were investigated. The interaction from-sample-to-sample was considerable, but this could be reduced by the addition of Brij-35. The recovery of uric acid added to protein-containing samples (about 96%) was better than with the UV-method. Novaminsulfone was the only substance tested which interfered significantly.

The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml X min-1 X kg-1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml X min-1 X kg-1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methyl-aminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.

Twelve healthy volunteers were given a single oral dose of dipyrone 1 g, once while fasting and once after a standard breakfast. Plasma levels of the active dipyrone metabolite-Methylaminoantipyrine (MAA) were measured and the calculated pharmacokinetic parameters were compared. Taking dipyrone with food resulted in a small delay in the mean time to peak from 1.5 h to 1.9 h (p less than 0.01). However, there was no significant difference in AUC, Cmax or K(elim) between fasting and nonfasting conditions. The rate of absorption, expressed as the mean K(abs), was somewhat slower in the nonfasting state, but not significantly so. It is suggested that dipyrone may be taken regardless of the times of eating.

A sensitive radioimmunoassay for pyrazolone derivatives has been developed. Anti-antipyrine antisera were produced in rabbits by repeated immunization with 4-succinamidoantipyrine coupled to bovine serum albumin. Less than 1 ng of antipyrine could be detected by this procedure. Various substituents on the carbon-4 position of the pyrazolone ring decreased the affinity for the antibody. The concentrations in ng of various pyrazolone derivatives required to inhibit [3H]antipyrine binding by 50% were: antipyrine, 6.8; aminopropylon, 8.5; sulpyrine, 35.5; isopropylantipyrine, 1320; and aminopyrine, 2820. The antibody showed no cross-reactivity with any other antipyretics such as pyrazolidine or aniline derivatives. The determination of antipyrine and sulpyrine concentrations in rat serum after i.p administration was also carried out.

A simple, rapid, specific and sensitive colorimetric method is proposed for the quantitative estimation of noramido-pyrine methanesulfonate sodium in different dosage forms as well as in blood and urine samples. The method is based on the reaction of 3-sulfonic-5-amino-alpha-naphthol with formaldehyde liberated from noramidopyrine methanesulfonate sodium after treatment with conc. sulfuric acid where a yellow colour appeared immediately which turned to blue on dilution with water. The blue colour obeyed Beer's law (10--400 microgram) and remained stable for more than 1 h. The effect of other drugs, tablet excipients, parentral vehicles and suppository bases was studied.

New high-performance liquid chromatography methods were developed to measure dipyrone and its active metabolite 4-monomethylaminoantipyrine (MAA) in biological fluids. While no detectable level of the unchanged dipyrone was found in plasma of four subjects taking 1000-mg oral doses of the drug, values ranging from 1.25 to 14.99 micrograms/ml of MAA were observed. Twenty-four hour urinary excretion of MAA varied from 9.56 to 21.21 mg. Concentrations as low as 0.25 micrograms/ml of MAA can be measured with acceptable coefficients of variation. The method, therefore, is suitable for microquantification of MAA in biological fluid which enables convenient and rapid assessment of the drug disposition in body.

A TLC method for measurement of aminophenazone (1) and of its degradation products 4-methylaminophenazone (2) and 4-aminophenazone (3) in plasma was described. After chloroform extraction amd separation on Silufol plates the substances were stained by ferric chloride/potassium hexacyanotoferrate(III) and the area of the spots was measured. Concentrations from 1 to 25 micrograms 1, 2 and 3 per ml plasma could be estimated.

The pharmacokinetics of the dipyrone metabolites 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA) were evaluated following the administration of a single oral 1.0 g dose of dipyrone to 23 healthy volunteers. Twelve were slow and 11 were rapid acetylators as previously determined by dapsone phenotyping. For MAA and FAA the mean peak plasma concentrations were 10.5 +/- 2.8 micrograms/ml and 2.1 +/- 0.8 micrograms/ml and the half-lives were 3.3 +/- 1.0 and 10.1 +/- 1.8 h, respectively. No significant difference was found between rapid and slow acetylators in MAA and FAA kinetics. For AA, the mean peak plasma concentrations were 2.7 +/- 0.6 and 1.6 +/- 0.7 micrograms/ml (p less than 0.01), the peak times 6.7 +/- 2.1 and 3.1 +/- 1.1 h (p less than 0.01) and the half-lives were 5.5 +/- 1.0 and 3.8 +/- 1.2 h in slow and rapid acetylators, respectively. For AAA, the mean peak plasma concentrations were 1.6 +/- 0.4 and 4.4 +/- 1.1 micrograms/ml (p less than 0.01) and the peak time 16.1 +/- 5.1 and 10.0 +/- 2.6 h (p less than 0.01) in slow and rapid acetylators, respectively. There was no difference in the elimination half-life between the two groups (10.6 +/- 2.2 h). Thus, it has been demonstrated that the AAA/AA ratio is an indicator of the acetylation phenotype, as it is closely correlated with that determined by dapsone (r = 0.895, p less than 0.0005).

The pharmacokinetics of the dipyrone metabolite, 4-methylaminoantipyrine (MAA) was evaluated, following the administration of a single oral dose of dipyrone 1.0 g to 12 young (21-30 years) and 9 elderly (73-90 years) healthy volunteers. Maximal concentration, time to peak and absorption rate of MAA were similar for both groups. The elimination half-life was 2.6 (0.2) h for the young and 4.5 (0.5) h for the elderly subjects. Total clearance of MAA, corrected for lean body mass (LBM), was lower in the elderly than in the young 2.65 vs 3.97 ml.min-1.kg-1 LBM. There was no differences between the groups in the apparent volume of distribution. A good correlation was found between the total body clearance of MAA and the creatinine clearance, which was also reduced in the elderly (r = 0.61).