RESUMEN
Chloral hydrate (CH) is a short-lived intermediate in the metabolism of trichloroethylene (TRI). TRI, CH, and two common metabolites, trichloroacetic acid (TCA) and dichloroacetic acid (DCA) have been shown to be hepatocarcinogenic in mice. To better understand the pharmacokinetics of these metabolites of TRI in humans, eight male volunteers, aged 24-39, were administered single doses of 500 or 1,500 mg or a series of three doses of 500 mg given at 48 h intervals, in three separate experiments. Blood and urine were collected over a 7-day period and CH, DCA, TCA, free trichloroethanol (f-TCE), and total trichloroethanol (T-TCE=trichloroethanol and trichloroethanol-glucuronide [TCE-G]) were measured. DCA was detected in blood and urine only in trace quantities (<2 microM). TCA, on the other hand, had the highest plasma concentration and the largest AUC of any metabolite. The TCA elimination curve displayed an unusual concentration-time profile that contained three distinct compartments within the 7-day follow-up period. Previous work in rats has shown that the complex elimination curve for TCA results largely from the enterohepatic circulation of TCE-G and its subsequent conversion to TCA. As a result TCA had a very long residence time and this, in turn, led to a substantial enhancement of peak concentrations following the third dose in the multiple dose experiment. Approximately 59% of the AUC of plasma TCA following CH administration is produced via the enterohepatic circulation of TCE-G. The AUC for f-TCE was found to be positively correlated with serum bilirubin concentrations. This effect was greatest in one subject that was found to have serum bilirubin concentrations at the upper limit of the normal range in all three experiments. The AUC of f-TCE in the plasma of this individual was consistently about twice that of the other seven subjects. The kinetics of the other metabolites of CH was not significantly modified in this individual. These data indicate that individuals with a more impaired capacity for glucuronidation may be very sensitive to the central nervous system depressant effects of high doses of CH, which are commonly attributed to plasma levels of f-TCE.
Asunto(s)
Hidrato de Cloral/metabolismo , Hidrato de Cloral/farmacocinética , Hígado/metabolismo , Adulto , Hidrato de Cloral/sangre , Hidrato de Cloral/orina , Ácido Dicloroacético/sangre , Ácido Dicloroacético/metabolismo , Ácido Dicloroacético/orina , Etilenclorhidrina/análogos & derivados , Etilenclorhidrina/sangre , Etilenclorhidrina/metabolismo , Etilenclorhidrina/orina , Glucuronatos/sangre , Glucuronatos/metabolismo , Glucuronatos/orina , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Ácido Tricloroacético/sangre , Ácido Tricloroacético/metabolismo , Ácido Tricloroacético/orinaRESUMEN
Dichloroacetate (DCA) is a rodent carcinogen commonly found in municipal drinking water supplies. Toxicokinetic studies have established that elimination of DCA is controlled by liver metabolism, which occurs by the cytosolic enzyme glutathione-S-transferase-zeta (GST-zeta). DCA is also a mechanism based inhibitor of GST-zeta, and a loss in GST-zeta enzyme activity occurs following repeated doses or prolonged drinking water exposures. GST-zeta is identical to an enzyme that is part of the tyrosine catabolism pathway known as maleylacetoacetate isomerase (MAAI). In this pathway, GST-zeta plays a critical role in catalyzing the isomerization of maleylacetoacetate to fumarylacetoacetate. Disruption of tyrosine catabolism has been linked to increased cancer risk in humans. We studied the elimination of i.v. doses of DCA to young (10 week) and aged (60 week) mice previously treated with DCA in their drinking water for 2 and 56 weeks, respectively. The diurnal change in blood concentrations of DCA was also monitored in mice exposed to three different drinking water concentrations of DCA (2.0, 0.5 and 0.05 g/l). Additional experiments measured the in vitro metabolism of DCA in liver homogenates prepared from treated mice given various recovery times following treatment. The MAAI activity was also measured in liver cytosol obtained from treated mice. Results indicated young mice were the most sensitive to changes in DCA elimination after drinking water treatment. The in vitro metabolism of DCA was decreased at all treatment rates. Partial restoration ( approximately 65% of controls) of DCA elimination capacity and hepatic GST-zeta activity occurred after 48 h recovery from 14 d 2.0 g/l DCA drinking water treatments. Recovery from treatments could be blocked by interruption of protein synthesis with actinomycin D. MAAI activity was reduced over 80% in liver cytosol from 10-week-old mice. However, MAAI was unaffected in 60-week-old mice. These results indicate that in young mice, inactivation and re-synthesis of GST-zeta is a highly dynamic process and that exogenous factors that deplete or reduce GST-zeta levels will decrease DCA elimination and may increase the carcinogenic potency of DCA. As mice age, the elimination capacity for DCA is less affected by reduced liver metabolism and mice appear to develop some toxicokinetic adaptation(s) to allow elimination of DCA at rates comparable to naive animals. Reduced MAAI activity alone is unlikely to be the carcinogenic mode of action for DCA and may in fact, only be important during the early stages of DCA exposure.
Asunto(s)
Ácido Dicloroacético/farmacocinética , Ácido Dicloroacético/toxicidad , Tirosina/metabolismo , Administración Oral , Factores de Edad , Animales , Peso Corporal , Ritmo Circadiano/efectos de los fármacos , Citosol/efectos de los fármacos , Citosol/enzimología , Citosol/metabolismo , Ácido Dicloroacético/administración & dosificación , Ácido Dicloroacético/sangre , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos , Agua Dulce , Glutatión Transferasa/efectos de los fármacos , Glutatión Transferasa/metabolismo , Inyecciones Intravenosas , Cinética , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos , Factores de Tiempo , Tirosina/efectos de los fármacos , cis-trans-Isomerasas/análisisRESUMEN
The oral and i.v. elimination kinetics were investigated for bromodichloroacetate (BDCA), a haloacetate found in drinking water. The BDCA was administered at a dose of 5, 20 and 100 mg kg-1 to B6C3F1 mice and appears to distribute to the total body water with a mean volume of distribution of 427 +/- 79 ml kg-1. It is subject to first-pass hepatic metabolism with a range of bioavailabilities of 0.28-0.73. A mean terminal half-life of 1.37 +/- 0.21 h. was calculated from the two lower doses of both i.v. and oral administration. Non-linear behavior was exhibited at doses greater than 20 mg kg-1, with a much higher than expected area under the curve (AUC), a decrease in total body clearance (CL(b)) and an increase in the terminal half-life to 2.3 h at the highest dose. The average CL(b) was 220 ml h(-1) kg-1 for the lower two doses but decreased to 156 ml h(-1) kg-1 at the high dose. The BDCA is primarily eliminated by metabolism, with only 2.4% of the parent dose being recovered in the urine at the high dose. The unbound renal clearance, as calculated from the high dose, was 15.0 ml h(-1) kg-1. The BDCA is moderately bound to plasma proteins (f(u) = 0.28) and preferentially distributes to the plasma with a blood/plasma ratio of 0.88.
Asunto(s)
Acetatos/farmacocinética , Desinfectantes/farmacocinética , Acetatos/administración & dosificación , Administración Oral , Animales , Área Bajo la Curva , Desinfectantes/administración & dosificación , Relación Dosis-Respuesta a Droga , Semivida , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos , Abastecimiento de AguaRESUMEN
A commonly used endpoint in bioassays testing the estrogenicity of chemicals is the induction of the egg yolk precursor vitellogenin (VTG) in male fish. However, relatively little is known about the kinetics of induction and elimination of VTG in fish exposed to xenoestrogens. In this study, we administered graded intra-arterial doses (0.001, 0.1, 1.0 and 10.0 mg/kg) of 17alpha-ethynylestradiol (EE(2)) to male rainbow trout via a dorsal aortic cannula which allowed repetitive blood sampling from individual fish for up to 48 days after injection. The plasma concentrations of VTG was quantified using an enzyme-linked immunosorbent assay procedure and the simultaneous concentrations of EE(2) were determined by gas chromatography-mass spectrometry. The pattern of VTG induction was similar for all doses of EE(2), with a 12-h lag-time before increase from basal levels (0.006-0.008 microg/ml), then increasing sharply to maximum levels within 7-9 days (C(max)=0.05, 711, 1521 and 2547 microg/ml VTG for the 0.001, 0.1, 1.0 and 10.0 mg/kg doses, respectively). After induction by EE(2), VTG declined mono-exponentially with an elimination half-life of 42-49 h. The half-life of VTG increased to 145 h in the 10 mg/kg treated fish. The pharmacokinetics of EE(2) were distinctly nonlinear with substantial increases in the elimination half-life with increasing dose. The plasma concentration-time profiles of EE(2) were influenced by enterohepatic recirculation that caused multiple or secondary peaks in the profiles. In a separate experiment, the pharmacokinetics of purified VTG was characterized after intra-arterial injection in trout. After direct injection of VTG, plasma levels declined tri-exponentially with an apparent steady-state volume of distribution of 837 ml/kg; total body clearance was 31.1 ml/h per kg, and the elimination half-life was 43.7 h.
Asunto(s)
Congéneres del Estradiol/farmacología , Etinilestradiol/farmacología , Oncorhynchus mykiss/metabolismo , Vitelogeninas/farmacología , Animales , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Glucuronidasa/metabolismo , Inmunohistoquímica , Masculino , Vitelogeninas/inmunología , Vitelogeninas/farmacocinéticaRESUMEN
A key question in the risk assessment of trichloroethylene (TRI) is the extent to which its carcinogenic effects might depend on the formation of dichloroacetate (DCA) as a metabolite. One of the metabolic pathways proposed for the formation of DCA from TRI is by the reductive dehalogenation of trichloroacetate (TCA), via a free radical intermediate. Although proof of this radical has been elusive, the detection of fully dechlorinated metabolites in the urine and the formation of lipid peroxidation by-products in microsomal incubations with TCA argue for its existence. We report here the trapping of the dichloroacetate radical with the spin-trapping agent PBN, and its identification by GC/MS. The PBN/dichloroacetate radical adduct was found to undergo an intramolecular rearrangement during its extraction into organic solvent. An internal condensation reaction between the acetate and the nitroxide radical moieties is hypothesized to form a cyclic adduct with the elimination of an OH radical. The PBN/dichloroacetate radical adduct has been identified by GC/MS in both a chemical Fenton system and in rodent microsomal incubations with TCA as substrate.
Asunto(s)
Ácido Dicloroacético/metabolismo , Microsomas Hepáticos/metabolismo , Ácido Tricloroacético/metabolismo , Animales , Ácido Dicloroacético/química , Radicales Libres/metabolismo , Masculino , Ratones , Ratones Endogámicos , Modelos Químicos , Oxidación-Reducción , Ratas , Ratas Endogámicas F344RESUMEN
Chloro, bromo, and mixed bromochloro haloacetates (HAs) are by-products of drinking water disinfection and are hepatocarcinogenic in rodents. We compared the toxicokinetics of a series of di-HAs, dichloro (DCA), bromochloro (BCA), dibromo (DBA) and tri-HAs: trichloro (TCA), bromodichloro (BDCA), chlorodibromo (CDBA), and tribromo (TBA) after iv and oral dosing (500 micrometer/kg) in male F344 rats. The blood concentrations of the HAs after iv injection declined in a bi-exponential manner with a short but pronounced distributive phase. The structural features that had the greatest influence on the disposition of HAs were substitution of a halogen for a hydrogen and the degree of bromine substitution. All di-HAs had blood elimination half-lives of less than 4 h (DCA > DBA, BCA) compared to the tri-HAs, which had half-lives that varied from 0.6 to 8.0 h (TCA > BDCA > CDBA > TBA). The urinary excretion of all di-HAs was low and accounted for less than 3% of the dose in contrast to the tri-HAs, where urinary excretion accounted for at least 30% of the dose. Toxicokinetic analysis indicated the steady-state apparent volume of distribution varied between 301 and 881 ml/kg among the HAs, but the variation was not statistically significant (P > 0.17). The blood concentration-time profiles for all di-HAs after oral dosing was complex and exhibited multiple peaks. This did not appear to be due to enterohepatic recirculation, as bile duct cannulated animals also displayed similar profiles. In contrast, the profiles for the tri-HAs did not exhibit multiple peaking after oral dosing and could be described using a one-compartment pharmacokinetic model. The oral bioavailability of the HAs varied between 30% (DBA) and 116% (TCA), depending on the number of halogen substituents and the degree of bromine substitution. In general, three patterns of elimination for the HAs can be broadly described: low metabolism with moderate renal clearance (TCA), high metabolism and renal clearance (BDCA, CDBA, TBA), and high metabolism, low renal clearance (DCA, BCA, DBA).
Asunto(s)
Acetatos/farmacocinética , Ácidos/farmacocinética , Hidrocarburos Bromados/farmacocinética , Hidrocarburos Clorados/farmacocinética , Acetatos/sangre , Acetatos/orina , Ácidos/sangre , Ácidos/orina , Administración Oral , Animales , Disponibilidad Biológica , Semivida , Hidrocarburos Bromados/sangre , Hidrocarburos Bromados/orina , Hidrocarburos Clorados/sangre , Hidrocarburos Clorados/orina , Infusiones Intravenosas , Masculino , Unión Proteica , Ratas , Ratas Endogámicas F344 , Relación Estructura-Actividad , Distribución TisularRESUMEN
Chloral hydrate (CH) is a commonly found disinfection by-product in water purification, a metabolite of trichloroethylene, and a sedative/hypnotic drug. CH and two of its reported metabolites, trichloroacetic acid (TCA) and dichloroacetic acid (DCA), are hepatocarcinogenic in mice. Another metabolite of CH, trichloroethanol (TCE), is also metabolized into TCA, and the enterohepatic circulation (EHC) of TCE maintains a pool of metabolite for the eventual production of TCA. To gain insight on the effects of EHC on the kinetics of CH and on the formation of TCA and DCA, dual cannulated F344 rats were infused with 12, 48, or 192 mg/kg of CH and the blood, bile, urine, and feces were collected over a 48-h period. CH was cleared rapidly (>3000 ml/h/kg) and displayed biphasic elimination kinetics, with the first phase being elimination of the dose and the second phase exhibiting formation rate-limited kinetics relative to its TCE metabolite. The effects of EHC on metabolite kinetics were only significant at the highest dose, resulting in a 44% and 17% decrease in the area under the curve (AUC) of TCA and TCE, respectively. The renal clearance of CH, free TCE (f-TCE), and TCA of 2, 2.7, and 38 ml/h/kg, respectively, indicates an efficient reabsorption mechanism for all of these small chlorinated compounds. DCA was detected at only trace levels (<2 microM) as a metabolite of CH, TCA, or TCE.
Asunto(s)
Hidrato de Cloral/farmacocinética , Ácido Dicloroacético/metabolismo , Desinfectantes/farmacocinética , Hipnóticos y Sedantes/farmacocinética , Hígado/irrigación sanguínea , Ácido Tricloroacético/metabolismo , Animales , Área Bajo la Curva , Bilis/química , Intestino Delgado/irrigación sanguínea , Hígado/metabolismo , Masculino , Distribución Aleatoria , Ratas , Ratas Endogámicas F344RESUMEN
Dichloroacetate (DCA) and trichloroacetate (TCA) are prominent by-products of chlorination of drinking water. Both chemicals have been shown to be hepatic carcinogens in mice. Prior work has demonstrated that DCA inhibits its own metabolism in rats and humans. This study focuses on the effect of prior administration of DCA or TCA in drinking water on the pharmacokinetics of a subsequent challenge dose of DCA or TCA in male B6C3F1 mice. Mice were provided with DCA or TCA in their drinking water at 2 g/l for 14 days and then challenged with a 100 mg/kg i.v. (non-labeled) or gavage (14C-labeled) dose of DCA or TCA. The challenge dose was administered after 16 h fasting and removal of the haloacetate pre-treatment. The haloacetate blood concentration-time profile and the disposition of 14C were characterized and compared with controls. The effect of pre-treatment on the in vitro metabolism of DCA in hepatic S9 was also evaluated. Pre-treatment with DCA caused a significant increase in the blood concentration-time profiles of the challenge dose of DCA. No effect on the blood concentration-time profile of DCA was observed after pre-treatment with TCA. Pre-treatment with TCA had no effect on subsequent doses of DCA. Pre-treatment with DCA did not have a significant effect on the formation of 14CO2 from radiolabeled DCA. In vitro experiments with liver S9 from DCA-pre-treated mice demonstrated that DCA inhibits it own metabolism. These results indicate that DCA metabolism in mice is also susceptible to inhibition by prior treatment with DCA, however the impact on clearance is less marked in mice than in F344 rats. In contrast, the metabolism and pharmacokinetics of TCA is not affected by pre-treatment with either DCA or TCA.
Asunto(s)
Ácido Dicloroacético/administración & dosificación , Ácido Tricloroacético/administración & dosificación , Abastecimiento de Agua , Animales , Radioisótopos de Carbono , Cromatografía de Gases , Ácido Dicloroacético/farmacocinética , Masculino , Ratones , Ratas , Ácido Tricloroacético/farmacocinéticaRESUMEN
Conflicting data have been published related to the formation of dichloroacetate (DCA) from trichloroethylene (TRI), chloral hydrate (CH), or trichloroacetic acid (TCA) in B6C3F1 mice. TCA is usually indicated as the primary metabolic precursor to DCA. Model simulations based on the known pharmacokinetics of TCA and DCA predicted blood concentrations of DCA that were 10- to 100-fold lower than previously published reports. Because DCA has also been shown to form as an artifact during sample processing, we reevaluated the source of the reported DCA, i.e., whether it was metabolically derived or formed as an artifact. Male B6C3F1 mice were dosed with TRI, CH, trichloroethanol (TCE), or TCA and metabolic profiles of each were determined. DCA was not detected in any of these samples above the assay LOQ of 1.9 microM of whole blood. In order to slow the clearance of DCA, mice were pretreated for 2 weeks with 2 g/liter of DCA in their drinking water. Even under this pretreatment condition, no DCA was detected from a 100 mg/kg i.v. dose of TCA. Although there is significant uncertainty in the amount of DCA that could be generated from TRI or its metabolites, our experimental data and pharmacokinetic model simulations suggest that DCA is likely formed as a short-lived intermediate metabolite. However, its rapid elimination relative to its formation from TCA prevents the accumulation of measurable amounts of DCA in the blood.
Asunto(s)
Hidrato de Cloral/farmacocinética , Ácido Dicloroacético/metabolismo , Etilenclorhidrina/análogos & derivados , Ácido Tricloroacético/farmacocinética , Tricloroetileno/farmacocinética , Animales , Disponibilidad Biológica , Ácido Dicloroacético/sangre , Etilenclorhidrina/farmacocinética , Semivida , Masculino , Tasa de Depuración Metabólica , Ratones , Modelos BiológicosRESUMEN
Trichloroacetic acid (TCA) is a major metabolite of trichloroethylene (TRI) thought to contribute to its hepatocarcinogenic effects in mice. Recent studies have shown that peak blood concentrations of TCA in rats do not occur until approximately 12 hours following an oral dose of TRI. However, blood concentrations of TRI reach a maximum within an hour and are nondetectable after 2 hours. The results of a study which examined the enterohepatic recirculation (EHC) of the principle TRI metabolites was used to develop a physiologically-based pharmacokinetic model for TRI, which includes enterohepatic recirculation of its metabolites. The model quantitatively predicts the uptake, distribution and elimination of TRI, trichloroethanol, trichloroethanol-glucuronide, and TCA and includes production of metabolites through the enterohepatic recirculation pathway. Physiologic parameters used in the model were obtained from the literature. Parameters for TRI metabolism were taken from Fisher et al. Other kinetic parameters were found in the literature or estimated from experimental data. The model was calibrated to data from experiments of an earlier study where TRI was orally administered. Verification of the model was conducted using data on the enterohepatic recirculation of TCEOH and TCA, chloral hydrate data (infusion doses) from Merdink, and TRI data from Templin and Larson and Bull.
Asunto(s)
Modelos Biológicos , Tricloroetileno/farmacocinética , Animales , Proteínas Sanguíneas/metabolismo , Carcinógenos/metabolismo , Carcinógenos/farmacocinética , Carcinógenos/toxicidad , Circulación Enterohepática , Contaminantes Ambientales/metabolismo , Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/toxicidad , Neoplasias Hepáticas Experimentales/inducido químicamente , Ratones , Unión Proteica , Ratas , Ratas Endogámicas F344 , Riesgo , Ácido Tricloroacético/metabolismo , Ácido Tricloroacético/farmacocinética , Ácido Tricloroacético/toxicidad , Tricloroetileno/metabolismo , Tricloroetileno/toxicidadRESUMEN
Trichloroacetic acid (TCA) is a metabolite of trichloroethylene (TRI) thought to contribute to its hepatocarcinogenic effects in mice. Recent studies have shown that peak blood concentrations of TCA do not occur until approximately 12 hr after an oral dose of TRI; however, blood concentrations of TRI reach a maximum within 1 hr and is nondetectable after 2 hr. The objective of this study was to examine quantitatively enterohepatic recirculation of trichloroethanol (TCEOH) and TCA as a possible mechanism responsible for the delayed production of TCA. Jugular vein, duodenum, and bile duct-cannulated Fischer 344 rats were used, with the collection of blood, bile, urine, and feces samples after intraduodenal and intravenous dosing of animals with TRI, TCEOH, and TCA. Samples were analyzed by GC for TCA, total TCEOH, and free TCEOH. The results show that, after an intravenous dose of TCEOH (100 mg/kg), 36% of the TCEOH in blood is attributable to enterohepatic recirculation. With the same treatment, 76% of the TCA in blood is attributable to enterohepatic recirculation of metabolites. Peak concentrations of total TCEOH in bile, after an intraduodenal dose of TRI, are over 5 times higher than peak concentrations of total TCEOH in systemic blood. Peak concentrations of TCEOH glucuronide in bile are approximately 200 times higher than peak concentrations of TCEOH glucuronide in systemic blood.
Asunto(s)
Circulación Enterohepática , Etilenclorhidrina/análogos & derivados , Glucuronatos/metabolismo , Ácido Tricloroacético/metabolismo , Tricloroetileno/metabolismo , Animales , Bilis/química , Cromatografía de Gases , Etilenclorhidrina/análisis , Etilenclorhidrina/sangre , Etilenclorhidrina/farmacocinética , Glucuronatos/análisis , Glucuronatos/sangre , Masculino , Ratas , Ratas Endogámicas F344 , Ácido Tricloroacético/análisis , Ácido Tricloroacético/sangreRESUMEN
Nine male and five female human liver microsomal sample were examined for laurate 11- and 12-hydroxylase activities. The mean specific activities for the 11- and 12-hydroxylation reactions were 0.78 +/- 0.33 and 1.07 +/- 0.12 nmol/min/mg protein, respectively. Antibody inhibition experiments, using a polyclonal antibody to a cytochrome P450 (P450) isolated from diethylhexyl phthalate-treated rats, which recognizes forms P4504A1, P4504A2, and P4504A3 of the rate, inhibited the 12-hydroxylase activity by 65%, but did not affect 11-hydroxylase activity. Western-blot analyses of the 14 human liver microsomal samples identified one major protein band at 52 kDa that comigrated with human form 4A11. A correlation coefficient of only 0.19 was calculated when comparing laurate 12-hydroxylase activities and the densitometric values of the immunochemically reactive protein bands in the human liver microsomal samples, which strongly suggests that additional P450 forms also support the 12-hydroxylation of lauric acid. Laurate 11-hydroxylase activity was inhibited by diethyldithiocarbamate, an inhibitor of P4502E1-mediated reactions, and by chlorzoxazone, a P4502E1 substrate. A comparison of laurate 11-hydroxylase activities with densitometric values of the P4502E1 protein bands indicated a strong correlation existed (0.82). An analysis of microsomal samples containing expressed human forms P4501A2, P4502A6, P4502C8, P4502C9, P4502D6, P4502E1, and P4503A4 showed that only form P4502E1 supported the 11-hydroxylation reaction.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/enzimología , Oxigenasas de Función Mixta/metabolismo , Adolescente , Adulto , Animales , Citocromo P-450 CYP2E1 , Citocromo P-450 CYP4A , Sistema Enzimático del Citocromo P-450/fisiología , Femenino , Humanos , Hidroxilación , Ácidos Láuricos/metabolismo , Masculino , Persona de Mediana Edad , Oxidorreductasas N-Desmetilantes/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Fluoxymesterone, an anabolic steroid, is metabolized in man primarily by 6 beta-hydroxylation, 4-ene-reduction, 3-keto-reduction, and 11-hydroxy-oxidation. These pathways of metabolism are suggested by the positive identification of 4 metabolites and the tentative identification of 3 other metabolites. Detection of the drug in urine is possible for at least 5 days after a single 10 mg oral dose to previously untreated adult males, by monitoring the presence of 2 metabolites, since the parent drug is not detectable more than 1 day after the dose.
Asunto(s)
Fluoximesterona/farmacocinética , Adulto , Relación Dosis-Respuesta a Droga , Fluoximesterona/metabolismo , Fluoximesterona/orina , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Modelos Biológicos , Trastornos Relacionados con Sustancias/orinaRESUMEN
The equipment, methods, logistics, and results of doping-control analyses for the 1984 Los Angeles Olympic Games are discussed in this article. Within 15 days, 1510 different urine specimens underwent 9440 screening analyses by a combination of gas chromatography, gas chromatography-mass spectrometry, "high-performance" liquid chromatography, and radioimmunoassay. These tests covered more than 200 different drugs and metabolites, including psychomotor stimulants, sympathomimetic amines, central nervous system stimulants, narcotic analgesics, and anabolic steroids. The results are summarized by class of drug. Less than 2% of the samples were found to contain a banned drug.
Asunto(s)
Doping en los Deportes , Preparaciones Farmacéuticas/orina , Antagonistas Adrenérgicos beta/orina , Anabolizantes/orina , California , Fármacos del Sistema Nervioso Central/orina , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Cromatografía de Gases y Espectrometría de Masas , Humanos , Narcóticos/orina , Radioinmunoensayo , Simpatomiméticos/orinaRESUMEN
The pretreatment concentrations of polyamines were determined in the 24-hr urine of 14 patients with widespread non-Hodgkin's lymphoma. In ten of 14 patients, the ratio of N1-acetylspermidine to N8-acetylspermidine was significantly higher than the mean for normal subjects. These results confirm our previous observations that the urinary excretion of N1-acetylspermidine is increased in some patients with lymphoma and suggest that the determination of urinary acetyl polyamines may be useful in conjunction with other procedures in the diagnosis of lymphoma. The ratio of N1-acetylspermidine to N8-acetylspermidine in the postchemotherapy 24-hr urine was 25 in one patient who had diffuse histiocytic lymphoma. This is the highest ratio ever reported. The patient responded well to chemotherapy, and rapid lysis of lymphoma lesion was observed. The potential utility of the rapid increase in the ratio of N1-acetylspermidine to N8-acetylspermidine as a criterion of tumor lysis is of interest and is currently under further investigation.
Asunto(s)
Linfoma/tratamiento farmacológico , Poliaminas/orina , Cromatografía Líquida de Alta Presión , Humanos , Linfoma/patología , Linfoma/orina , Espermidina/análogos & derivados , Espermidina/orina , Factores de TiempoRESUMEN
A procedure is described for the determination of monoacetylputrescine, N1-acetyl-spermidine and N8-acetylspermidine in human urine. The procedure is based on the high-performance liquid chromatographic separation of the 5-dimethylaminonaphthalene-1-sulfonyl (dansyl) derivatives of these amines using two different chromatographic modes. Monoacetyl-1,6-diaminohexane was used as an internal standard. The amines were extracted from urine using a silica gel cartridge. The dansyl monoacetylpolyamines were separated from the mixture of dansyl derivatives of urinary amines on a bonded-phase CN column using a programmed solvent gradient elution. The dansyl acetylpolyamines were rechromatographed on a silica gel column. This chromatographic procedure was used for the determination of the concentration of N1-acetylspermidine, N8-acetylspermidine and monoacetylputrescine in the urine of healthy volunteers and cancer patients.