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1.
J Sep Sci ; 32(18): 3074-83, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19697309

RESUMEN

LC coupled to single (LC-MS) and tandem (LC-MS/MS) mass spectrometry is recognized as the most powerful analytical tools for metabolic studies in drug discovery. In this article, we describe five cases illustrating the utility of screening xenobiotic metabolites in routine analysis of forensic samples using LC-MS/MS. Analyses were performed using a previously published LC-MS/MS general unknown screening (GUS) procedure developed using a hybrid linear IT-tandem mass spectrometer. In each of the cases presented, the presence of metabolites of xenobiotics was suspected after analyzing urine samples. In two cases, the parent drug was also detected and the metabolites were merely useful to confirm drug intake, but in three other cases, metabolite detection was of actual forensic interest. The presented results indicate that: (i) the GUS procedure developed is useful to detect a large variety of drug metabolites, which would have been hardly detected using targeted methods in the context of clinical or forensic toxicology; (ii) metabolite structure can generally be inferred from their "enhanced" product ion scan spectra; and (iii) structure confirmation can be achieved through in vitro metabolic experiments or through the analysis of urine samples from individuals taking the parent drug.


Asunto(s)
Dibenzotiazepinas/orina , Noscapina/orina , Oxazinas/orina , Prazepam/orina , Trazodona/orina , Cromatografía Líquida de Alta Presión , Dibenzotiazepinas/metabolismo , Descubrimiento de Drogas , Toxicología Forense , Humanos , Noscapina/metabolismo , Oxazinas/metabolismo , Prazepam/metabolismo , Fumarato de Quetiapina , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem , Trazodona/metabolismo
2.
J Mass Spectrom ; 40(4): 516-26, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15712230

RESUMEN

A method was developed and fully validated for the quantitation of prazepam and its major metabolites, oxazepam and nordiazepam, in human plasma. Sample pretreatment was achieved by solid-phase extraction using Oasis HLB cartridges. The extracts were analysed by high-performance liquid chromatography (HPLC) coupled with single-quadrupole mass spectrometry (MS) with an electrospray ionization interface. The MS system was operated in the selected ion monitoring mode. HPLC was performed isocratically on a reversed-phase XTerra MS C18 analytical column (150 x 3.0 mm i.d., particle size 5 microm). Diazepam was used as the internal standard for quantitation. The assay was linear over a concentration range of 5.0-1000 ng ml(-1) for all compounds analyzed. The limit of quantitation was 5 ng ml(-1) for all compounds. Quality control samples (5, 10, 300 and 1000 ng ml(-1)) in five replicates from three different runs of analysis demonstrated an intra-assay precision (CV) of < or = 9.1%, an inter-assay precision of < or = 6.0% and an overall accuracy (relative error) of < 4.6%. The method can be used to quantify prazepam and its metabolites in human plasma covering a variety of pharmacokinetic or bioequivalence studies.


Asunto(s)
Cromatografía Liquida/métodos , Prazepam/sangre , Prazepam/metabolismo , Espectrometría de Masa por Ionización de Electrospray/métodos , Calibración , Diazepam/sangre , Humanos , Estructura Molecular , Nordazepam/sangre , Oxazepam/sangre , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
3.
Clin Pharmacol Ther ; 28(2): 196-202, 1980 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6772370

RESUMEN

Our subjects were 15 young (aged 22 to 42 yr) and 14 elderly (aged 62 to 85 yr) people who took single oral doses of 20 mg prazepam. Plasma desmethyldiazepam (DMDZ) concentrations were determined in venous blood samples drawn up to 9 days after the dose. Appearance in blood of DMDZ was slow, with peak plasma levels reached in an average of 10 to 20 hr. First-order DMDZ appearance was observed in only 17 subjects. Volume of distribution of total DMDZ (range, 1.33 to 6.30 l/kg) and of unbound DMDZ after correction for protein binding (range, 43 to 243 l/kg) was larger in women than in men of all ages, and in the elderly as opposed to the young. Elimination half-life (range, 29 to 224 hr) rose with age in men (r = 0.66, p < 0.01) but not in women (r = -0.02). Clearance of unbound DMDZ (range, 2.9 to 31.2 ml/min/kg) was greater in women than in men of all ages, and declined with age in men (r = -0.40) but not in women (r = -0.06). As in the case of diazepam, age can influence DMDZ kinetics, but changes in drug disposition with age may differ between sexes.


Asunto(s)
Diazepam/análogos & derivados , Nordazepam/metabolismo , Prazepam/metabolismo , Adulto , Factores de Edad , Anciano , Proteínas Sanguíneas/metabolismo , Femenino , Semivida , Humanos , Cinética , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Nordazepam/sangre , Unión Proteica , Análisis de Regresión , Factores Sexuales , Fumar/fisiopatología
4.
Biochem Pharmacol ; 43(6): 1377-80, 1992 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-1562288

RESUMEN

Phenobarbitone-pretreated male Sprague-Dawley rat liver microsomes were used to examine C3-hydroxylation and N-dealkylation of four clinically important benzodiazepines: diazepam (DZP), prazepam (PZP), pinazepam (PIN) and halazepam (HZP). These substrates differ only in the nature of the N-substituent of the B ring and N-desmethyldiazepam (DMD) is the N-dealkylation product in each case. C3-Hydroxylation was accordingly also studied with DMD as substrate. All monooxygenations were studied with substrates at a concentration of 10 microM, in the absence of solubilizing agents, and under conditions where the production of secondary metabolites was minimized. A 20-fold variation in the rate of C3-hydroxylation was recorded across the five substrates with HZP showing the highest rate and DMD showing the lowest rate. An almost equally large range of variation was shown for the N-dealkylation reaction, with PZP undergoing this biotransformation more than 17 times faster than DZP. Log P values (a measure of lipophilicity) for the five substrates were determined using an HPLC method and a remarkable lack of correspondence between this substrate parameter and either of the monooxygenations was noted. This suggests that multiple substrate determinants govern the relative rates of these monooxygenations. It was, however, notable that the additive rate of metabolism of these substrates by both monooxygenase routes did show an excellent correlation with substrate lipophilicity.


Asunto(s)
Ansiolíticos , Benzodiazepinas , Microsomas Hepáticos/efectos de los fármacos , Nordazepam/metabolismo , Fenobarbital/farmacología , Animales , Benzodiazepinonas/metabolismo , Diazepam/metabolismo , Hidroxilación , Masculino , Metilación , Microsomas Hepáticos/metabolismo , Prazepam/metabolismo , Ratas , Ratas Endogámicas , Relación Estructura-Actividad
5.
J Clin Pharmacol ; 24(10): 446-51, 1984 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-6150943

RESUMEN

Twelve healthy volunteers received a single 40-mg oral dose of the benzodiazepine derivative oxazolam, which serves primarily as a precursor of the active substance desmethyldiazepam (DMDZ). Concentrations of DMDZ were measured in multiple serum samples drawn for up to two weeks after the dose. Peak serum DMDZ concentrations averaged 115 ng/ml, measured at 8.6 hours after dosage. Mean DMDZ elimination half-life averaged 61 hours. Three of the subjects also received 40 mg each of prazepam and clorazepate, two other DMDZ precursors, on separate occasions. Although DMDZ elimination half-life was similar, total area under the curve (AUC) for DMDZ was larger for clorazepate, known to be completely transformed into DMDZ, than for oxazolam or prazepam the extent of whose conversion to DMDZ has not been previously established. After correcting for the different molar equivalent of DMDZ available from each preparation, the DMDZ ratio averaged 0.22 for oxazolam vs. clorazepate and 0.51 for prazepam vs. clorazepate. Thus, both oxazolam and prazepam lead to slow appearance of DMDZ in the systemic circulation. Furthermore the extent of DMDZ formation from oxazolam and prazepam is either incomplete or the drugs are incompletely absorbed. Equivalent doses of oxazolam, prazepam, and clorazepate should not be interchanged in clinical practice.


Asunto(s)
Ansiolíticos/metabolismo , Benzodiazepinas , Benzodiazepinonas/metabolismo , Clorazepato Dipotásico/metabolismo , Diazepam/análogos & derivados , Nordazepam/metabolismo , Prazepam/metabolismo , Adulto , Femenino , Humanos , Cinética , Masculino , Peso Molecular
6.
Forensic Sci Int ; 22(2-3): 243-8, 1983.
Artículo en Inglés | MEDLINE | ID: mdl-6416955

RESUMEN

The development of a radioimmunoassay for the analysis of prazepam and its metabolites is described. It includes the preparation of the immunogen, immunization and measurement of specificity and sensitivity.


Asunto(s)
Prazepam/análisis , Animales , Nordazepam/análisis , Oxazepam/análisis , Prazepam/metabolismo , Conejos , Radioinmunoensayo
7.
Encephale ; 10(3): 135-8, 1984.
Artículo en Francés | MEDLINE | ID: mdl-6389091

RESUMEN

Anxiolytic effects and tolerance of a four weeks treatment with prazepam (single dose of 40 mg in the evening) and with lorazepam (3 daily doses of 1.25 mg) are compared in a double blind study. Patients were treated by psychiatrists and were suffering from neurotic anxiety. Evaluation for therapeutic efficacy used a clinical global improvement scale and the Hamilton Anxiety Scale. Evaluation for side effects used the side effects symptoms check list. Anxiolytic effects of prazepam and lorazepam are not significantly different. Tolerance of the two treatments is comparable. The side effects are essentially an undesirable sedative action.


Asunto(s)
Trastornos de Ansiedad/tratamiento farmacológico , Lorazepam/uso terapéutico , Prazepam/administración & dosificación , Adolescente , Adulto , Anciano , Trastornos de Ansiedad/psicología , Ensayos Clínicos como Asunto , Método Doble Ciego , Femenino , Semivida , Humanos , Lorazepam/efectos adversos , Masculino , Persona de Mediana Edad , Prazepam/efectos adversos , Prazepam/metabolismo , Prazepam/uso terapéutico , Escalas de Valoración Psiquiátrica
16.
Arzneimittelforschung ; 29(9): 1317-25, 1979.
Artículo en Alemán | MEDLINE | ID: mdl-583236

RESUMEN

The article describes analytical data (TLC, IR, MS) of 7-chloro-1-methyl-1,3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one (3-hydroxydiazepam) and 7-cyclopropyl-methyl-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazpin-2-one (3-hydroxy-prazepam). Analytical properties of important derivatives (N-oxides, 3-acetoxy compounds, re-arrangement products) are also reported. Besides preparation methods are given for the synthesis of these substances, considering in particular preparation as solution-reactions as well as reaction on the TLC-plate.


Asunto(s)
Benzodiazepinonas/análisis , Benzodiazepinonas/síntesis química , Biotransformación , Diazepam/metabolismo , Hidrólisis , Oxidación-Reducción , Prazepam/metabolismo
17.
Mol Pharmacol ; 36(6): 932-8, 1989 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-2601688

RESUMEN

The metabolism of prazepam (7-chloro-1-(cyclopropylmethyl)-1,3-dihydro-2H-1, 4-benzodiazepin-2-one) (PZ) was studied using liver microsomes prepared from untreated, phenobarbital (PB)-treated, and 3-methylcholanthrene (3MC)-treated male Sprague-Dawley rats. Relative rates of PZ metabolism by liver microsomes prepared from rats were PB-treated greater than untreated greater than 3MC-treated. Metabolites of PZ were separated by normal phase high performance liquid chromatography and the relative amounts of major metabolites were found to be N-desalkylprazepam (also known as N-desmethyldiazepam and nordiazepam) greater than 3-hydroxy-PZ (3-OH-PZ) greater than oxazepam. Enantiomers of 3-OH-PZ were resolved by high performance liquid chromatography on an analytical column packed with Pirkle's chiral stationary phase, (R)-N-(3,5-dinitrobenzoyl)phenylglycine covalently bonded to spherical particles of gamma-aminopropylsilanized silica. 3-OH-PZ formed in the metabolism of PZ by liver microsomes prepared from rats was found to have 3R/3S enantiomer ratios of 84:16 (untreated), 85:15 (PB-treated), and 84:16 (3MC-treated), respectively. Relative rates of N-dealkylation of PZ by three rat liver microsomal preparations were PB-treated greater than untreated greater than 3MC-treated. N-Dealkylation of 3-OH-PZ by rat liver microsomes was substrate enantioselective; the 3S-enantiomer was N-dealkylated faster than the 3R-enantiomer. The results indicated that both C3-hydroxylation of PZ and N-dealkylation of 3-OH-PZ catalyzed by rat liver microsomes were stereoselective, resulting in the formation of a 3-OH-PZ highly enriched in the 3R-enantiomer.


Asunto(s)
Microsomas Hepáticos/metabolismo , Prazepam/metabolismo , Animales , Remoción de Radical Alquila , Inducción Enzimática , Hidroxilación , Técnicas In Vitro , Masculino , Ratas , Ratas Endogámicas , Estereoisomerismo
18.
Drug Metab Dispos ; 19(3): 637-42, 1991.
Artículo en Inglés | MEDLINE | ID: mdl-1680631

RESUMEN

Metabolism of prazepam [PZ, 7-chloro-1,3-dihydro-5-phenyl-1- (cyclopropylmethyl)-2H-1,4-benzodiazepin-2-one] and halazepam [HZ,7- chloro-1,3-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-2H-1,4- benzodizepin-2-one] was investigated in microsomes prepared from the livers of two male and one female subjects who died of head injuries. PZ (or HZ) and its metabolites were analyzed by normal phase and chiral stationary phase HPLC. The relative amount of products formed in the metabolism of PZ was found to be N-desalkylprazepam (NDZ, also known as N-desmethyldiazepam and nordiazepam) greater than 3-hydroxy-PZ (3-OH-PZ) much greater than oxazepam (OX). In contrast, the relative amount of products formed in the metabolism of HZ was found to be 3-OH-HZ much greater than NDZ greater than OX. Enantiomers of 3-OH-PZ and 3-OH-HZ were resolved by HPLC on an analytical column packed with the chiral stationary phase R-N-(3,5-dinitrobenzoyl)phenylglycine covalently bound to spherical particles of gamma-aminopropylsilanized silica. The 3-OH-PZ formed in the metabolism of PZ by three human liver microsomal preparations were found to have 3R/3S enantiomer ratios of 65:35, 61:39, and 62:38. In the metabolism of HZ, the enzymatically formed 3-OH-HZ had 3R/3S enantiomer ratios of 67:33, 60:40, and 62:38. N-Dealkylations of racemic 3-OH-PZ and 3-OH-HZ by human liver microsomal preparations were substrate-enantioselective; 3S-OH-PZ and 3R-OH-HZ were each N-dealkylated slightly faster than the corresponding antipode. The results indicated that both C3-hydroxylation of PZ and HZ as well as N-dealkylation of 3-OH-PZ and 3-OH-HZ catalyzed by human liver microsomes were stereoselective, resulting in the formation of a C3-hydroxylated product enriched (60-67%) in the 3R-enantiomer.


Asunto(s)
Ansiolíticos , Benzodiazepinas , Benzodiazepinonas/metabolismo , Microsomas Hepáticos/metabolismo , Prazepam/metabolismo , Adolescente , Preescolar , Cromatografía Líquida de Alta Presión , Remoción de Radical Alquila , Femenino , Humanos , Hidroxilación , Técnicas In Vitro , Estereoisomerismo
19.
J Chromatogr ; 146(2): 227-39, 1978 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-701422

RESUMEN

Methods have been developed for the determination of the benzodiazepine tranquilizer prazepam and its metabolites desmethyl diazepam, 3-hydroxy-prazepam and oxazepam by electron capture gas chromatography and selected ion monitoring with diazepam as the internal standard. The benzodiazepines were isolated from blood serum or homogenized tissue samples, either by extraction with ethyl acetate or on small Extrelut columns packed with porous silica. The concentrated extracts were directly injected into the gas chromatograph equipped with an electron capture detector. Following trimethylsilylation, analysis on a gas chromatography--mass spectrometry--computer system operated in the selected ion-monitoring mode was performed. Using 50--200 mg (microliter) biological material, concentrations of prazepam and metabolites of 5 ng/g(ml) could be determined with signal-to-noise ratios of greater than 10. Using 1 g(ml) samples, the same signal-to-noise ratios were obtained with 1 ng/g(ml) concentrations. The methods developed were applied to the analysis of the diaplacental transfer of prazepam and desmethyl diazepam in early human pregnancy. Furthermore, prazepam metabolism in human fetal liver and cell cultures was studied.


Asunto(s)
Hígado/metabolismo , Prazepam/análisis , Células Cultivadas , Cromatografía de Gases/métodos , Femenino , Humanos , Hígado/embriología , Espectrometría de Masas , Intercambio Materno-Fetal , Técnicas de Cultivo de Órganos , Prazepam/metabolismo , Embarazo , Primer Trimestre del Embarazo
20.
Fortschr Med ; 99(22): 874-9, 1981 Jun 11.
Artículo en Alemán | MEDLINE | ID: mdl-6790396

RESUMEN

The biotransformation pathways following oral administration of prazepam are characterized. The time course of the active metabolite descyclopropylmethylprazepam (= norprazepam), representing 80-90% of all prazepam metabolites in plasma, can be described by an open one compartment model with a mean elimination half life of 70 h and a plasma clearance of 1.0-1.4 l/h. 3-5 h after single doses of 20 mg prazepam, the corresponding peak levels of norprazepam are 120-160 ng/ml. There is only a slight uptake of norprazepam into red blood cells and a relative low secretion into breast milk. Following repeated doses of daily 20 mg prazepam steady state levels of norprazepam are 600-800 ng/ml. The slow build-up of the active metabolite and the long elimination half life ensure continuous plasma levels with small fluctuations.


Asunto(s)
Prazepam/metabolismo , Administración Oral , Biotransformación , Semivida , Humanos , Cinética , Tasa de Depuración Metabólica , Nordazepam/metabolismo , Oxazepam/metabolismo , Prazepam/farmacología
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