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PubMed1982

Simultaneous determination of antipyrine, 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine in urine by gas chromatography chemical ionization mass spectrometry.

A simple, accurate and precise procedure was developed to quantify, in a single run, antipyrine, 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine in urine. The stable isotope-labelled internal standards for the assay were obtained from a subject who ingested deuterium labelled antipyrine and produced urine containing the labelled drug and metabolites.

Antipyrine↗

PubMed1998

Separation of disaccharides by affinity capillary electrophoresis in lectin-containing electrophoretic solutions.

Separation of the 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatives of simple disaccharides (maltose, cellobiose, gentiobiose, lactose, and melibiose) by affinity capillary electrophoresis was investigated using lectin-containing neutral phosphate buffers, filled in a linear polyacrylamide-coated capillary. When Lens culinaris agglutinin (LCA) was added, the derivatives of glucobioses were retarded with varying magnitudes depending on the amount of LCA and were well separated from each other and from galactosyl glucose under optimized conditions. Addition of Ricinus communis 60 kDa agglutinin (RCA60) to the phosphate buffer gave a different migration profile, in which the derivatives of galactosyl glucoses were more retarded than those of glucobioses. However, addition of either lectin did not accomplish complete separation of the derivatives of all these disaccharides even under optimum conditions. The addition of two kinds of lectins in appropriate proportions improved separation. Thus, the binary system composed of LCA and RCA60, as well as LCA and soybean agglutinin from Glycine max (SBA), gave better separation of these derivatives, giving peak tops for all derivatives.

Antipyrine↗

PubMed1998

Separation of 1-phenyl-3-methyl-5-pyrazolone derivatives of monosaccharides by capillary electrochromatography.

1-Phenyl-3-methyl-5-pyrazolone (PMP) derivatives of component monosaccharides in glycoproteins (fucose, galactose, mannose, N-acetylgalactosamine and N-acetylglucosamine) and epimeric aldopentoses (arabinose, lyxose, ribose and xylose) were well separated from each other by capillary electrochromatography on a Hypersil ODS column with a mixture of 50 mM N-(2-hydroxyethyl)piperazine-2'-(2-ethanesulfonic acid) buffer, pH 6.0 to approximately 6.3, and acetonitrile (2.2:1 v/v) as eluent. The elution of these compounds showed relatively strong dependence on the pH and concentration of the buffer salts contained in the eluent, as compared to the elution by pressure-driven high-performance liquid chromatography (HPLC) on the same stationary phase, but separation of PMP-monosaccharides was better than that by HPLC. Retention times of PMP-monosaccharides were highly reproducible with a relative standard deviation (RSD) of approximately 0.6%, and quantification with an RSD less than 5% could be achieved using 3-O-methylglucose as an internal standard.

Antipyrine↗

PubMed2003

High-speed electrophoretic analysis of 1-phenyl-3-methyl-5-pyrazolone derivatives of monosaccharides on a quartz microchip with whole-channel UV detection.

1-Phenyl-3-methyl-5-pyrazolone (PMP) derivatives of monosaccharides were analyzed by electrophoresis on a quartz microchip with whole-channel UV detection. Rapid separation of PMP derivatives of aldopentoses was achieved by plain-zone electrophoresis in a neutral phosphate buffer with the height equivalent to a theoretical plate at the micrometer level. Zone electrophoresis as borate complexes was also successful for the separation of PMP derivatives of a few aldoses, which were separated within 1 min. Separation by microchip electrophoresis was compared to that by capillary electrophoresis, and the difference was discussed in terms of column efficiency and sample column capacity.

Antipyrine↗

PubMed2006

Chiral resolution of monosaccharides as 1-phenyl-3-methyl-5-pyrazolone derivatives by ligand-exchange CE using borate anion as a central ion of the chiral selector.

Six reducing monosaccharides (mannose, galactose, fucose, glucose, xylose, and arabinose) were derivatized with 1-phenyl-3-methyl-5-pyrazolone (PMP) and chiral resolution of these racemic PMP-monosaccharides was studied by ligand-exchange CE using borate anion as a central ion of the chiral selector and (S)-3-amino-1,2-propanediol (SAP) as a chiral selector ligand. PMP-mannose, PMP-galactose and PMP-fucose were successfully enantioseparated. Lowering the capillary temperature increased the resolution of PMP-mannose system, but decreased that of PMP-galactose and PMP-fucose systems. Whereas the maximum resolution was obtained at pH 8.9 in the PMP-mannose system, resolution increased gradually with pH in the PMP-galactose and PMP-fucose systems. Expecting the formation of the ternary borate complexes with SAP and PMP-monosaccharide in the CE experiments, the optimized structures of the borate diastereomers were obtained by semiempirical molecular orbital calculations to discuss the structural difference of the diastereomers in connection with the enantioseparation behaviors.

Anions↗

PubMed2001

Investigation of different combinations of derivatization, separation methods and electrospray ionization mass spectrometry for standard oligosaccharides and glycans from ovalbumin.

Derivatization procedures using 1-phenyl-3-methyl-5-pyrazolone (PMP) and 2-aminonaphthalene trisulfone (ANTS) were selected among a number of well known methods for labelling carbohydrates. PMP derivatives were selected owing to our laboratory's previous high-performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI-MS) experience with these, whereas the ANTS-labelled compounds were prepared for fluorophore-assisted carbohydrate electrophoresis (FACE) separation. ANTS-oligosaccharide standards were characterized to study their ionization patterns. Reversed-phase and normal-phase HPLC systems were coupled on-line with ESI-MS. Each necessitated its own mobile phase system which, in turn, imposed some important changes in the ionization conditions used and/or on the ionization patterns and spectra obtained. Following characterization of the intact glycoprotein ovalbumin with ESI-MS, its glycans were detached using the enzyme PNGase-F. The glycans were subjected to PMP and ANTS derivatization. It was very difficult to separate ANTS derivatives by reversed-phase HPLC owing to lack of retention, and normal-phase HPLC offered reasonable retention with limited separation. PMP compounds overall yielded better normal- and reversed-phase separations and improved sensitivity over the ANTS-labelled sugars, for which negative mode ESI had to be used. The combination of ESI of intact ovalbumin and ESI of PMP-glycans gave rise to the detection of over 20 different glycoforms, excluding the possible presence of structural isomers for each sugar composition detected.

Amidohydrolases↗

PubMed2002

Automated structural assignment of derivatized complex N-linked oligosaccharides from tandem mass spectra.

Glycoprotein function is controlled by several biological factors, one of them being the structure of carbohydrate chains (glycans) attached to specific amino acids of the protein backbone. Changes in glycan structures have been shown to modify the secondary and tertiary conformation of glycoproteins, thus their function. Powerful analytical tools are available for the characterization of sugar structures, and recently mass spectrometry (MS) has been increasingly useful for this purpose. Manual interpretation of tandem mass spectrum is possible but tedious. Automated interpretation should speed the analysis and enhance the results obtained. A new computer program for automated interpretation of tandem MS spectra of complex N-linked glycans oligosaccharides from mammals will be described. N-Linked oligosaccharides standards were derivatized with 1-phenyl-3-methyl-5-pyrazolone (PMP) and analyzed by matrix-assisted laser desorption/ionization (MALDI)-tandem MS. Simulated tandem mass spectra of other common glycans were also generated to test the algorithm. The MALDI-MS/MS spectra featured resolved isotopic distributions for the [M + H](+) and fragment ions of oligosaccharides. These isotopic distributions complicated the automated analysis of the spectra and were removed to leave only monoisotopic peaks. An algorithm was written for this purpose, yielding simplified tandem mass spectra. Another algorithm is then used to determine the structure of the oligosaccharide. A score is then given to each structure, depending on agreement with experimental results. The program successfully assigned the true structure in 24 out of the 28 cases (86%) and the true structure was among the three top scoring structures in all cases.

Algorithms↗

PubMed1995

Monosaccharide composition analysis of oligosaccharides and glycoproteins by high-performance liquid chromatography.

A simple and sensitive high-performance liquid chromatography (HPLC)-based method for complete monosaccharide composition analysis of oligosaccharides and glycoproteins is described. In this method, an oligosaccharide or glycoprotein is first hydrolyzed using an optimized method to give the constituent monosaccharides, which are subsequently labeled with 1-phenyl-3-methyl-5-pyrazolone (PMP) as previously described by Honda et al. (Anal, Biochem. 180, 351-357, (1989)). The labeled monosaccharides are separated by reverse-phase HPLC using a column developed especially for this purpose, monitored by uv absorbance at 245 nm, and quantitated by their integration values relative to standards. Sialic acids are acid-labile keto-sugars. They are, therefore, released with neuraminidases or by mild acid hydrolysis and then converted with neuraminic acid aldolase to their corresponding mannosamine derivatives, which are then PMP-labeled, separated, and quantitated as described above. Individual sialic acids including N-acetyl and N-glycolyl neuraminic acids are well resolved and quantitated by this method. This method has proven to be highly sensitive, requiring only 1 pmol for reliable detection. Quantitative analysis of neutral and amino sugars from both oligosaccharide and glycoprotein samples can be achieved using one acid hydrolysis and a set of equal molar monosaccharide standards. Similarly, quantitation of sialic acids works equally well with both free oligosaccharide and glycoprotein samples. Monosaccharide compositions of oligosaccharides and glycoproteins determined by this method were found to be highly accurate.

Antipyrine↗

PubMed1997

Oligosaccharide characterization and quantitation using 1-phenyl-3-methyl-5-pyrazolone derivatization and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

The 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatives of monosaccharides, maltooligosaccharides, and oligosaccharides enzymatically released from asparagine-linked sites in ribonuclease B and fetuin have been investigated using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Use of the matrix 2,6-dihydroxyacetophenone containing diammonium hydrogen citrate (DHAP/DAHC) resulted in predominance of protonated over sodiated pseudomolecular ions of PMP-derivatized oligosaccharides. By comparison, the matrices alpha-cyano-4-hydroxycinnamic acid and 2,5-dihydroxybenzoic acid resulted in predominantly sodiated pseudomolecular ions. In addition, tendencies for fragmentation of PMP-oligosaccharide derivatives were significantly lower with DHAP/DAHC which enabled meaningful data to be obtained in reflector mode, even for samples with high excipient levels. The relative magnitude of the ion signals for PMP-derivatized maltooligosaccharides and ribonuclease B oligosaccharides correlated well with the oligomer distribution apparent by HPLC. PMP-maltohexose was used as an internal standard to quantitate PMP-oligosaccharides from ribonuclease B and asialofetuin in crude derivatization mixtures. A linear relationship was observed between the ratio of the intensities of pseudomolecualr ions and the amount of glycoprotein derivatized. The limit of detection for the major oligosaccharide of each protein was reached with ca. 3 micrograms of glycoprotein but may be further enhanced by optimization of sample handling. PMP derivatives of sialylated fetuin oligosaccharides were readily detected as protonated pseudomolecular ions by linear mode analyses. By comparison, reflector mode analyses revealed substantially reduced magnitudes of protonated pseudomolecular ions and considerable post-source fragmentation of sialic acid residues. The PMP derivatives of fetuin oligosaccharides were also amenable to exoglycosidase treatment as shown by the mass shifts found upon treatment with sialidase.

Antipyrine↗

PubMed1999

Analysis of sialyllactoses in blood and urine by high-performance liquid chromatography.

A sensitive and highly selective high-performance liquid chromatography (HPLC)-based method has been developed for the analysis of oligosaccharides in biological fluids. In this method, a sample of biological fluid, such as blood serum or urine, is filtered through a 10,000 molecular weight cutoff filter cartridge to remove large molecules such as proteins and lipids. The carbohydrates in the filtrate are then derivatized with 1-phenyl-3-methyl-5-pyrazolone (PMP) as described previously [Anal. Biochem. 180, 351-357, (1989)]. The derivatized carbohydrates are separated by reverse-phase HPLC and monitored by UV absorbance at 245 nm. Quantitative analysis of the carbohydrates can be achieved based on their integration values relative to a standard calibration curve. Since neutral and acidic carbohydrates can be separated by using Dowex 1-X8 anion exchange resin, this method can be used specifically to analyze neutral, acidic, and total carbohydrates in the biological fluids. Because PMP specifically reacts with reducing aldoses, interference from noncarbohydrate components present in the biological fluids is essentially eliminated. This method has proven to be highly sensitive, requiring as little as 5 pmol of analyte for reliable analysis. It has also been used successfully for pharmacokinetic analysis of carbohydrate drugs in human blood and urine samples.

Antipyrine↗

PubMed2002

A study of immunoglobulin G glycosylation in monoclonal and polyclonal species by electrospray and matrix-assisted laser desorption/ionization mass spectrometry.

N-linked oligosaccharides were released from human and bovine polyclonal immunoglobulin G (IgG) obtained from commercial sources and also from a monoclonal IgG(1) secreted by murine B-lymphocyte hybridoma cells (CC9C10) grown under different serum-free conditions. These conditions differed according to their steady-state dissolved oxygen concentrations. This work is based on a previous quantitative study where released glycans were characterized by fluorophore-assisted carbohydrate electrophoresis (FACE) and high-pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) (J. P. Kunkel, D. C. H. Jan, J. C. Jamieson, and M. Butler, 1998, J. Biotechnol. 62, 55-71). In the present article, peptide-N-glycosidase F-released glycans from different species of polyclonal IgG and murine monoclonal IgG were characterized qualitatively by high-performance liquid chromatography (HPLC) coupled to electrospray ionization mass spectrometry (ESI-MS). The glycans were also analyzed by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). The MALDI mass spectrometer used allowed acquisition of MS and tandem MS data, which were useful in structural investigations at a more detailed level than allowed by FACE and HPAEC-PAD. Predominant N-linked structures, as determined by all techniques, were core-fucosyl asialyl biantennary chains with varying galactosylation. Minor amounts of afucosyl, bisected, and monosialyl oligosaccharides were also detected. In contrast to FACE and HPAEC-PAD, MALDI-double quadrupole/time-of-flight MS and HPLC/ESI-MS also detected low-abundance high-mannose and hybrid structures in some of the species under investigation.

Animals↗

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↗

PubMed1984

Influence of alaproclate on antipyrine metabolite formation in man.

Alaproclate, a selective serotonin reuptake inhibitor, presently undergoing clinical trial for the treatment of major depressive disorders, has been shown to inhibit hexobarbital metabolism in mice. In the present study the influence of oral alaproclate on the total plasma clearance of antipyrine and on the formation of its metabolites was investigated in 10 healthy volunteers. The peak level of alaproclate was reached after about 1.5 h, and after a distribution phase, its plasma elimination half-life was between 3.0 and 3.5 h. Antipyrine tests were performed before treatment, during the first four doses and after the seventh dose of alaproclate 200 mg/day. During treatment, total plasma antipyrine clearance and the clearance for production of all antipyrine metabolites were reduced by 30%, indicating non-selective inhibition of oxidative drug-metabolizing enzyme activity in man by alaproclate. After the last dose of alaproclate, antipyrine plasma clearance and the clearance to its metabolites returned to control values. In order to allow more detailed evaluation of the results, the time course of the clearances for production of metabolites was investigated. This revealed that the extent of inhibition of metabolite formation by alaproclate was dependent on the plasma alaproclate level, indicating a rapidly reversible inhibition.

Adult↗

PubMed1987

Pharmacogenetic differences in the inhibitory effect of cimetidine on the metabolism of antipyrine.

The relationship between acetylator phenotype and the inhibitory effect of cimetidine on the hepatic metabolism of antipyrine has been studied in 20 subjects. Cimetidine, 1,0 g/day resulted in a significant decrease in the metabolic clearance rate of antipyrine, but only in slow acetylators, as fast acetylators were less affected. No sex difference was observed. No major change occurred in the urinary excretion of D-glucaric acid, which means that cimetidine had not-affected that Phase II reaction. It did significantly decrease the urinary partial clearance rate of norantipyrine, leaving that of antipyrine and 4-OH-antipyrine unchanged, which suggests that cimetidine had preferentially inhibited the P450 isozyme that catalyses norantipyrine formation.

Acetylation↗

PubMedDate not supplied

The changes of LCGU and rCBF in the MCA occlusion-recirculation model in rats and the ameliorating effect of MCI-186, a novel free radical scavenger.

We examined the change of regional cerebral blood flow (rCBF) and local cerebral glucose utilization (LCGU) in the middle cerebral artery (MCA) occlusion or recirculation model of rats, and tested anti-ischemic effects of a free radical scavenger, 3-methyl-1-phenyl-pyrazolon-5-one (MCI-186). A remarkable increase in LCGU was observed in the cortex supplied by the anterior cerebral artery after recirculation. This hypermetabolism of glucose was at least partly caused by the postischemic oxidative injury, since MCI-186 ameliorated the high LCGU in this area. These results suggested the usefulness of this type of free radical scavenger for inhibiting the postischemic injury.

Animals↗

PubMed1993

Analysis of carbohydrates in glycoproteins by high-performance liquid chromatography and high-performance capillary electrophoresis.

We describe two methods for the analysis of oligosaccharide chains in glycoproteins by high-performance liquid chromatography (HPLC) and high-performance capillary electrophoresis (HPCE). O- and N-glycosidically linked oligosaccharides released from glycoproteins can be identified as their borohydride-reduced forms by anion-exchange HPLC with pulsed amperometric detection. N-Glycosidically linked oligosaccharides can also be analyzed as 2-aminopyridine derivatives by HPCE in direct zone electrophoresis mode in an acidic phosphate buffer and zone electrophoresis mode as borate complexes in an alkaline buffer. We also present a convenient procedure for the analysis of the constituent monosaccharides of these oligosaccharides chains by HPLC based on reversed-phase partition mode as 1-phenyl-3-methyl-5-pyrazolone derivatives.

Aminopyridines↗

PubMed2002

Contractile responses to reactive oxygen species in the canine basilar artery in vitro: selective inhibitory effect of MCI-186, a new hydroxyl radical scavenger.

BACKGROUND: Cerebral vasospasm is one of the important pathological phenomena which influence morbidity and mortality following subarachnoid haemorrhage. Reactive oxygen species (ROSs) generated by the autoxidation of oxyhemoglobin to methemoglobin may be one of the essential factors in the pathogenesis of cerebral vasospasm. The direct vasocontractile effects of hydrogen peroxide (H(2)O(2)), superoxide anion (O(2)(-)), and hydroxyl radical (*OH) on the canine basilar artery and the inhibitory effects of MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one), a new *OH scavenger, were investigated. METHOD: Isometric tension was recorded in basilar artery rings from dogs in vitro. H(2)O(2), pyrogallol (O(2)(-) donor), and vitamin C (VitC)/Fe(2+) (*OH-generating system) were used to generate the ROSs. FINDINGS: H(2)O(2) (10 micromol/L), pyrogallol (10 micromol/L), and VitC/Fe(2+) (100 micromol/L each) induced fast onset and transient, slow onset and transient, and sustained contraction, respectively, in the canine basilar artery. Contractions induced by H(2)O(2) were almost completely inhibited by pre-incubation with catalase (800 U/mL) and those by pyrogallol with superoxide dismutase (150 U/mL), but neither with MCI-186 (10 micromol/L). The contraction induced by VitC/Fe(2+) was clearly inhibited by pre-incubation with MCI-186, but not with catalase or superoxide dismutase. INTERPRETATION: ROSs have direct vasocontractile effects on the canine basilar artery in vitro, but different ROSs have different contractile characteristics. Such contractions might be related to the pathophysiology of cerebral vasospasm. MCI-186 had a clear and selective inhibitory effect against *OH-induced contraction in vitro. Comparison of different radical scavengers may be important in pharmacological assessment, especially targeted on cerebral vasospasm.

Animals↗