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1.
J Sep Sci ; 37(9-10): 1170-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24596062

RESUMO

Molecularly imprinted microspheres (MIMs) for the anticancer drug aminoglutethimide (AG) were synthesized by aqueous suspension polymerization. The expected size and diameter of MIMs are controlled easily by changing one of the surfactant types, ratio of organic-to-water phase or stirring rate during polymerization. The obtained MIMs exhibit specific affinity toward AG with imprinting factor of 3.11 evaluated with a chromatographic model. The resultant MIMs were used as the SPE materials for the extraction of AG from human urine. A molecularly imprinted SPE (MISPE) method coupled with HPLC has been developed for the extraction and detection of AG in urine. Our results showed that most impurities from urine can be removed effectively after a washing step and the AG has been enriched effectively after MISPE operation with the recovery of >90% (n = 3). The developed MISPE-HPLC method could be used for enrichment and detection of AG in human urine.


Assuntos
Aminoglutetimida/urina , Antineoplásicos/urina , Microesferas , Impressão Molecular , Extração em Fase Sólida , Aminoglutetimida/síntese química , Aminoglutetimida/química , Antineoplásicos/síntese química , Antineoplásicos/química , Humanos , Tamanho da Partícula , Polimerização , Propriedades de Superfície
2.
Rapid Commun Mass Spectrom ; 16(24): 2209-14, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12478562

RESUMO

Aminoglutethimide is used therapeutically as an aromatase inhibitor in the treatment of metastatic breast cancer in post-menopausal women. For doping purposes, aminoglutethimide may be used for treatment of adverse effects of an extensive abuse of anabolic androgenic steroids (gynaecomastia) and to increase the testosterone concentration and stimulation of testosterone biosynthesis. The use of aromatase inhibitors has been prohibited for male athletes since September 1, 2001. The purpose of this study was to develop methods for the identification of the parent compound or its main metabolite and the inclusion of this information into established screening procedures in doping analysis. An excretion study was conducted using oral application of one single therapeutic dose (500 mg) of Orimeten. The analysis was performed by gas chromatography/mass spectrometry (GC/MS). Aminoglutethimide is excreted almost totally as unconjugated parent compound and is detectable by different screening procedures for up to 165 h. Most suitable for the detection of aminoglutethimide is the screening procedure for heavy volatile nitrogen-containing drugs ('Screening 2'). However, since only competition samples are analysed in that screening procedure, the additional inclusion of aminoglutethimide in the screening procedure for anabolic androgenic agents ('Screening 4') is recommended. Full mass spectra and diagnostic ions for the analysis of aminoglutethimide are presented.


Assuntos
Aminoglutetimida/urina , Inibidores da Aromatase , Inibidores Enzimáticos/urina , Cromatografia Gasosa-Espectrometria de Massas/métodos , Adrenérgicos/urina , Aminoglutetimida/química , Anabolizantes/urina , Dopagem Esportivo , Humanos , Masculino , Programas de Rastreamento , Estrutura Molecular , Nitrogênio/urina , Volatilização
3.
J Clin Pharmacol ; 39(11): 1136-42, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10579143

RESUMO

This study was undertaken to examine the pharmacokinetics of both enantiomers of AG--that is, (R-AG) and (S-AG) and respective acetyl metabolites, R-AcAG and S-AcAG--in breast cancer patients. Six patients received a single dose (500 mg) of the racemic drug, and serial plasma samples and urine were collected over a 48-hour period. R-AG, S-AG, R-AcAG, and S-AcAg were measured simultaneously by high-performance liquid chromatography using two serial chiral separation columns with ultraviolet detection. The plasma concentrations of R-AG were about 1.5 times higher than those of S-AG, and the data for both enantiomers exhibited the characteristics of the one-compartment open model. There were no significant differences between R- and S-AG in ka, tmax, V/F, and t1/2. The formation of R- and S-AcAG was rapid, and no correlation was found between the t1/2 values of the AG enantiomers with that of their acetylated metabolites. Overall, 41% of the dose was excreted in urine as AG (15% R-AG and 26% S-AG) and 5.1% as AcAG (2.9% R-AcAG and 2.2% S-AcAG). Renal clearance of S-AG was significantly greater (i.e., 2.3-fold) than that of R-AG and appears to be most likely the cause for the other pharmacokinetic differences observed. Both enantiomers had low renal extraction ratios, suggesting extensive tubular reabsorption of the compounds. However, based on the data obtained, it was concluded that the main factor contributing to the therapeutic effectiveness of racemic AG is the large potency difference between the R- and S- forms (R > S). The pharmacokinetic differences between R-AG and S-AG appear to contribute only marginally to the activity of this drug as an aromatase inhibitor.


Assuntos
Aminoglutetimida/farmacocinética , Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/metabolismo , Adulto , Idoso , Aminoglutetimida/sangue , Aminoglutetimida/urina , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/urina , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pós-Menopausa , Estereoisomerismo , Fatores de Tempo
4.
Ther Drug Monit ; 17(5): 538-43, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8585120

RESUMO

An accurate and specific liquid chromatographic method for the separation and analysis of the R(+) and S(-) enantiomers of both aminoglutethimide (AG) and its acetylated metabolite (AcAG) in plasma, saliva, and urine is described. The separation was achieved by use of two serial Chiralcel OD columns [cellulose tris(3,5-dimethylphenyl carbamate)] with a mixture of hexane/isopropanol/methanol (65:17.5:17.5, per volume) as a mobile phase. The flow rate was 0.7 ml/min, and the compounds were detected in the effluent spectrophotometrically at 245 nm. The plasma, saliva, or urine sample (300 microliters) was extracted with dichloromethane after the addition of an equal volume of acetate buffer (pH 5.6) to the sample. The extraction recovery of the R(+) and S(-) enantiomers of AG and AcAG from plasma, saliva, and urine at different concentrations under these conditions was > 80.9%. No interference from any endogenous substance or concomitantly used drug was observed. The ratio of the peak area of R(+) and S(-) enantiomers of both AG and AcAG/internal standard was linearly (r > or = 0.995) related to concentration in the range 0.83-40.0 micrograms/ml, and the coefficient of variation (CV) at different concentrations was consistently < or = 13%. We are presently employing this method to study the pharmacokinetics of each of these enantiomers in breast cancer patients.


Assuntos
Aminoglutetimida/análogos & derivados , Aminoglutetimida/análise , Antineoplásicos Hormonais/análise , 1-Propanol/química , Acetilação , Aminoglutetimida/sangue , Aminoglutetimida/metabolismo , Aminoglutetimida/uso terapêutico , Aminoglutetimida/urina , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/urina , Neoplasias da Mama/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Feminino , Hexanos/química , Humanos , Concentração de Íons de Hidrogênio , Metanol/química , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Padrões de Referência , Reprodutibilidade dos Testes , Saliva/química , Saliva/metabolismo , Estereoisomerismo
5.
J Chromatogr ; 572(1-2): 143-57, 1991 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-1818050

RESUMO

The identification of metabolites from the pyridylglutarimide 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (PG, Rogletimide) was achieved using liquid chromatography-mass spectrometry with a thermospray interface (LC-TSP-MS). The urinary metabolites include PG N-oxide, the products of 4- and 5-hydroxylation in the piperidine residue (4- and 5-hydroxy-PG) and a gamma-butyrolactone derived via terminal hydroxylation in the ethyl residue. In addition to the above metabolites, several products of glutarimide ring-opening could be detected in the plasma extracts after multiple-dose treatment. Thus LC-TSP-MS is potentially a simple and rapid technique in studies of drug metabolism for the important glutarimide class of drug.


Assuntos
Aminoglutetimida/análogos & derivados , Antineoplásicos/metabolismo , Aminoglutetimida/sangue , Aminoglutetimida/metabolismo , Aminoglutetimida/uso terapêutico , Aminoglutetimida/urina , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Antineoplásicos/urina , Neoplasias da Mama/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Padrões de Referência
6.
Biomed Chromatogr ; 5(2): 74-7, 1991 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-1868261

RESUMO

A direct, isocratic, sensitive and precise liquid chromatographic method is presented for the enantiomeric separation of aminoglutethimide (AG) and its acetylated metabolite (AcAG) using cellulose tris-3,5-dimethyl phenyl carbamate (Chiralcel OD) and cellulose tris(4-methylphenyl benzoate) ester (Chiralcel OJ) columns in series. The enantiomeric elution order is determined by separate chromatography of the racemate AG and racemate AcAG and of their separate enantiomers under similar conditions. This method has been used to determine and identify the enantiomers of AG and AcAG in the urine sample collected from a metastatic breast cancer patient after administration of AG for 24 h. Large amounts of (+)-R-AG are excreted unchanged in the urine together with smaller quantities of (+)-R-AcAG, while most of the (-)-S-AG is metabolically converted into (-)-S-AcAG.


Assuntos
Aminoglutetimida/urina , Fenilcarbamatos , Aminoglutetimida/análogos & derivados , Aminoglutetimida/isolamento & purificação , Líquidos Corporais/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/urina , Carbamatos , Celulose/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Estereoisomerismo
7.
Clin Chim Acta ; 169(1): 99-108, 1987 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-3677440

RESUMO

Due to an unknown mechanism aminoglutethimide (AG) in urine samples is partly present in a form in which it is not detected. Though most evident if samples had been stored at -20 degrees C (about 60% trapped), it also occurred in fresh urine samples (about 20% trapped). Heating the urine sample for 15 min at 100 degrees C liberated all AG. This phenomenon has led to the underestimation of the excretion of unchanged AG in previous publications. This study shows that AG was excreted unchanged for 47.5 +/- 7.3% (mean +/- SD) in patients received 2 X 125 mg or 2 X 250 mg AG. Direct measurement of hydroxylaminoglutethimide (HxAG) was found difficult, due to its instability with respect to oxidation. We found azoxyG to be a stable oxidation product derived from HxAG. The concentration of azoxyG formed was proportional to the amount of HxAG converted. HxAG seemed subjected to the same phenomenon as AG. A conversion of HxAG into an unknown compound which seemed to occur very easily and which was even accelerated by heating, made it impossible to accurately measure the concentration of HxAG.


Assuntos
Aminoglutetimida/urina , Aminoglutetimida/administração & dosagem , Biotransformação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/urina , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Espectrometria de Massas , Métodos , Oxirredução , Manejo de Espécimes
9.
Br J Cancer ; 51(2): 259-62, 1985 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-3838134

RESUMO

Hydroxylaminoglutethimide [3-ethyl-3-(4-hydroxylaminophenyl)piperidine-2,6-dione] (HxAG), aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (AG) and N-acetyl-aminoglutethimide (N-AcAG) have been quantified by high performance liquid chromatography using m-aminoglutethimide (metaAG) as the internal standard in serial 24 h urine collections from a patient on chronic AG therapy without steroid supplementation. HxAG is the product of a major AG-induced metabolic pathway since the ratio [HxAG]/[AG] rises with time. In contrast the ratio [N-AcAG]/[AG] decreases with time. A rapid, simple colorimetric assay has been used to quantify HxAG in urine from both male and female patients receiving a range of doses of AG and to show that induced metabolism is a general phenomenon even at low doses (125 mg twice daily). AG therapy is known to alter the metabolic rate and plasma half-life of a number of coadministered compounds including dexamethasone and warfarin. Clinicians should remain alerted to this phenomenon.


Assuntos
Aminoglutetimida/análogos & derivados , Aminoglutetimida/metabolismo , Neoplasias da Mama/metabolismo , Aminoglutetimida/uso terapêutico , Aminoglutetimida/urina , Neoplasias da Mama/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Colorimetria , Feminino , Humanos , Masculino
10.
Cancer Chemother Pharmacol ; 15(2): 176-8, 1985.
Artigo em Inglês | MEDLINE | ID: mdl-4017167

RESUMO

A simple rapid high-performance liquid chromatographic assay for simultaneous estimation of aminoglutethimide and its acetylated metabolite acetylamidoglutethimide in plasma, saliva, and urine is described. This assay is suitable for pharmacokinetic studies in normal subjects and patients receiving other medication in addition to aminoglutethimide.


Assuntos
Aminoglutetimida/análogos & derivados , Aminoglutetimida/análise , Aminoglutetimida/sangue , Aminoglutetimida/urina , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Saliva/análise
12.
Drug Metab Dispos ; 12(4): 511-6, 1984.
Artigo em Inglês | MEDLINE | ID: mdl-6148221

RESUMO

Four new metabolites of aminoglutethimide have been identified in the urine of patients being treated chronically with the drug. These were products of hydroxylation of the 3-ethylpiperidine-2,6-dione residue, namely 3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione and its acetylamino analog, 3-(4-aminophenyl)-3-(1-hydroxyethyl)piperidine-2,6-dione, and 3-(4-aminophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, the lactone formed by rearrangement of 3-(4-aminophenyl)-3-(2-hydroxyethyl)piperidine-2,6-dione. The metabolites were isolated by reverse-phase thin layer chromatography and characterized by comparison of their mass spectra either with those of synthetic samples or with the mass spectra of analogous metabolites previously identified in the urine of rats. These new metabolites were minor constituents compared with aminoglutethimide and with the previously identified major metabolites 3-(4-acetylaminophenyl)-3-ethylpiperidine-2,6-dione and 3-(4-hydroxylaminophenyl)-3-ethylpiperidine-2,6-dione. There were marked species differences between rat and human inasmuch as almost all the metabolites in the urine of the rat were N-acetylated whereas most of the human metabolites were not. However, 5-hydroxylation of the piperidinedione residue was stereoselective in the same sense in both species, the cis isomer being formed exclusively. Synthetic cis-3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione did not inhibit the activity of the target enzyme systems desmolase and aromatase in vitro, and therefore, like other metabolites so far described, is an inactivation product of the drug.


Assuntos
Aminoglutetimida/urina , Acetilação , Biotransformação , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Humanos , Hidroxilação , Espectrometria de Massas
13.
J Chromatogr ; 307(1): 129-35, 1984 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-6725479

RESUMO

A rapid, sensitive and selective gas--liquid chromatographic assay for aminoglutethimide is described. The same extraction procedure may be employed prior to a high-performance liquid chromatographic assay for acetamidoglutethimide which is also detailed. Both assays are suitable for the study of the pharmacokinetics of aminoglutethimide and acetamidoglutethimide in biological fluids in man.


Assuntos
Aminoglutetimida/análise , Líquidos Corporais/análise , Aminoglutetimida/análogos & derivados , Aminoglutetimida/sangue , Aminoglutetimida/urina , Cromatografia Gasosa/métodos , Cromatografia Líquida de Alta Pressão , Humanos , Cinética , Saliva/análise
14.
Biomed Mass Spectrom ; 10(11): 620-5, 1983 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-6689274

RESUMO

Hydroxylaminoglutethimide (3-ethyl-3-(4-hydroxylaminophenyl)-2,6-piperidinedione) has been identified as a novel metabolite of aminoglutethimide (3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione) in the urine of patients treated chronically with this drug. The metabolite was isolated by reverse-phase thin-layer chromatography, and characterized by comparison of its mass spectrum and chromatographic properties with those of the synthetic compound. Hydroxylaminoglutethimide is unstable; it is readily oxidized to nitrosoglutethimide and disproportionates in the mass spectrometer into this compound and aminoglutethimide. In none of four patients studied was the metabolite detected in the urine after the first dose of the drug. In one patient it appeared after the second dose and in two more within seven to eight days suggesting that its formation is drug-induced, and that it may be the metabolite responsible for the diminished half-life of aminoglutethimide during chronic therapy. The profile of metabolites from one patient, examined by high-performance liquid chromatography after the first dose and again after six weeks of therapy afforded evidence that the formation of hydroxylaminoglutethimide was at the expense of a major metabolite N-acetylaminoglutethimide. Hydroxylaminoglutethimide was not an induced metabolite in the rat.


Assuntos
Aminoglutetimida/análogos & derivados , Aminoglutetimida/metabolismo , Aminoglutetimida/urina , Biotransformação , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Fina/métodos , Indução Enzimática , Humanos , Espectrometria de Massas/métodos
15.
Br J Cancer ; 46(3): 340-5, 1982 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7126424

RESUMO

The urinary excretion during 24 h of aminoglutethimide (AG) its major metabolite (N-acetylAG) and two minor metabolites (N-formylAG and nitroG) were measured in 10 volunteers given AG who had been typed for acetylator phenotype using sulphadimidine. The slow acetylators of sulphadimidine excreted more AG (mean 28% of the administered dose) than did the fast acetylators (12%), but the latter excreted more of the dose as N-acetylAG (8.8%) than did the former (3.9%). NitroG and N-formylAG were minor urinary metabolites of AG in humans. The former was more abundant in the urine of slow acetylators (0.10% of the dose) than in that of fast acetylators (0.047%), whereas the respective proportions of doses excreted as the N-formyl derivative (0.475 and 0.465%) were not significantly different for the two acetylator phenotypes. These results show that AG is among those drugs that are polymorphically acetylated in humans.


Assuntos
Aminoglutetimida/metabolismo , Polimorfismo Genético , Acetilação , Adulto , Aminoglutetimida/análogos & derivados , Aminoglutetimida/urina , Humanos , Fenótipo , Sulfametazina/metabolismo
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