RESUMEN
Characterization of the pathophysiology of ARDS following chlorine gas inhalation in clinically relevant translational large animal models is essential, as the opportunity for clinical trials in this type of trauma is extremely limited. To investigate Cl2 concentration and gender-dependent ARDS severity. Sheep (n = 54) were exposed to air or Cl2 premixed in air at a concentration of 50, 100, 200, and 300 ppm for 30 min under anesthesia/analgesia and monitored for an additional 48 h in a conscious state. Cardiopulmonary variables and survival endpoints were compared between male and female sheep. Overall there were no significant differences in the responses of female and male sheep except pulmonary oxygenation tended to be better in the male sheep (300 ppm group), and the pulmonary arterial pressure was lower (200 ppm group). The onset of mild ARDS (200 < PaO2/FiO2 ≤ 300) was observed at 36 h post exposure in the 50 ppm group, whereas the 100 ppm group developed mild and moderate (100 ≤ PaO2/FiO2 ≤ 200) ARDS by 12 and 36 h after injury, respectively. The 200 ppm and 300 ppm groups developed moderate ARDS within 6 and 3 h after injury, respectively. The 300 ppm group progressed to severe (PaO2/FiO2 ≤ 100) ARDS at 18 h after injury. Increases in pPeak and pPlateau were noted in all injured animals. Compared to sham, inhalation of 200 ppm and 300 ppm Cl2 significantly increased lung extravascular water content. The thoracic cavity fluid accumulation dose-dependently increased with the severity of trauma as compared to sham. At necropsy, the lungs were red, heavy, solidified, and fluid filled; the injury severity grew with increasing Cl2 concentration. The severity of ARDS and mortality rate directly correlated to inhaled Cl2 concentrations. No significant sex-dependent differences were found in measured endpoint variables.
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Cloro , Síndrome de Dificultad Respiratoria , Masculino , Femenino , Animales , Ovinos , Cloro/toxicidad , Cloro/uso terapéutico , Pulmón , Administración por InhalaciónRESUMEN
In sepsis, microvascular hyperpermeability caused by oxidative/nitrosative stress (O&NS) plays an important role in tissue edema leading to multi-organ dysfunctions and increased mortality. We hypothesized that a novel compound R-107, a modulator of O&NS, effectively ameliorates the severity of microvascular hyperpermeability and preserves multi-organ function in ovine sepsis model. Sepsis was induced in twenty-two adult female Merino sheep by intravenous infusion of Pseudomonas aeruginosa (PA) (1 × 1010 CFUs). The animals were allocated into: 1) Control (n = 13): intramuscular injection (IM) of saline; and 2) Treatment (n = 9): IM of 50 mg/kg R-107. The treatment was given after the PA injection, and monitored for 24-h. R-107 treatment significantly reduced fluid requirement (15-24 h, P < 0.05), net fluid balance (9-24 h, P < 0.05), and water content in lung/heart/kidney (P = 0.02/0.04/0.01) compared to control. R-107 treatment significantly decreased lung injury score/modified sheep SOFA score at 24-h (P = 0.01/0.04), significantly lowered arterial lactate (21-24 h, P < 0.05), shed syndecan-1 (3-6 h, P < 0.05), interleukin-6 (6-12 h, P < 0.05) levels in plasma, and significantly attenuated lung tissue 3-nitrotyrosine and vascular endothelial growth factor-A expressions (P = 0.03/0.002) compared to control. There was no adverse effect in R-107 treatment. In conclusion, modulation of O&NS by R-107 reduced hyperpermeability markers and improved multi-organ function.
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Permeabilidad Capilar/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Estrés Nitrosativo/efectos de los fármacos , Infecciones por Pseudomonas , Pseudomonas aeruginosa/metabolismo , Sepsis , Animales , Modelos Animales de Enfermedad , Femenino , Infecciones por Pseudomonas/sangre , Infecciones por Pseudomonas/tratamiento farmacológico , Sepsis/sangre , Sepsis/tratamiento farmacológico , OvinosRESUMEN
Previously, we reported that prenatal exposure to 1-bromopropane (1-BP) causes the accumulation of bromide (Br-) in the brain of rat pups. Here, we aimed to investigate the effects of Br- accumulation in rat pups prenatally exposed to 1-BP vapor. Dam rats were exposed to 1-BP (400 or 700 ppm; 1-BP group) by inhalation, or to NaBr (20 mM; Br- group) in drinking water during gestation days 1-20. We also analyzed pentylenetetrazole (PTZ, 60 mg/kg, ip)-induced behavioral changes in pups prenatally exposed to 1-BP or Br- on postnatal day (PND) 14. PTZ-induced epileptic convulsions were inhibited in both 1-BP (700 ppm) and Br- groups. The inhibition of neuronal excitability induced by Br- was evaluated electrophysiologically using the hippocampal slices obtained from PND14-16 pups. PTZ (2 mM) failed to induce epileptiform discharge in the presence of 1.2 mM Br- in the slices obtained from the control group. However, it induced epileptiform discharge following the removal of Br-, by perfusing artificial cerebrospinal fluid into the slices obtained from the Br- group. Our results indicate that Br- accumulates in the brain of neonatal rat pups prenatally exposed to 1-BP vapor suppressed neuronal excitability.
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Bromuros , Efectos Tardíos de la Exposición Prenatal , Animales , Encéfalo , Femenino , Hidrocarburos Bromados , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas WistarRESUMEN
2',2'''-Dithiobisbenzanilide (DTBBA) is a high-production-volume chemical used as a peptizing agent for rubber. The disposition and metabolism of [14C]DTBBA were determined in male and female rats and mice following oral (4, 40, or 400 mg/kg) and intravenous (IV) (4 mg/kg) administration and dermal application (0.4 or 4 mg/kg). [14C]DTBBA was well absorbed following oral administration (> 60%) and dermal application (â¼40-50%) in rats and mice. Following oral administration, the majority of radioactivity was excreted in urine (29 - 70%) and feces (16 - 45%). Unlike rats, mice excreted â¼1-5% of the dose as exhaled CO2. The residual radioactivity in tissues was <1% in both species and sexes. The pattern of disposition following IV administration in male rats was similar to that following oral. When [14C]DTBBA was administered via IV to rats, a significant portion of the dose was recovered in bile (â¼13%) suggesting that at least a portion of the dose recovered in feces following oral administration was likely the absorbed dose. The profiles of urine from rats and mice were similar and consisted of four major metabolites and three minor metabolites. The predominant metabolite in urine was the S-glucuronide of the thiol/sulfide cleavage product N-(2-mercaptophenyl)benzamide, which accounted for more than 50% of radioactivity in the radiochromatogram.
RESUMEN
The specialty amine catalyst 2,2'-dimorpholinodiethyl ether (DMDEE) is a high-production volume chemical used in the production of flexible foam, high-resilient molded foam, and in coatings and adhesives. The disposition and metabolism of [14C]DMDEE (20 or 200 mg/kg) were determined in male ane female rats and mice after oral and intravenous administration and dermal application. In male and female rats, following a single oral administration, [14C]DMDEE was well-absorbed and excreted rapidly and extensively via urine (75-93%) and some in feces (â¼4-8%). The total radioactivity in tissues at 24 h and 72 h (males only) following oral administration was 8-10% and â¼4%, respectively, suggesting considerable tissue distribution. A moderate amount of the total tissue radioactivity in kidney and liver were unextractable suggesting covalent binding of [14C]DMDEE-derived products in tissue macromolecules. Absorption following a single dermal application in rats was significant (â¼64%) with a similar disposition pattern to oral. The oral and dermal disposition of [14C]DMDEE in male and female mice was similar to rats. Urinary products of DMDEE identified were oxidative metabolism of the morpholine ring. Coadministration of DMDEE with nitrite in rats didn't produce the rodent carcinogen, N-nitrosomorpholine.
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Aminas/metabolismo , Administración Cutánea , Administración Intravenosa , Administración Oral , Animales , Femenino , Hígado , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
2-Hydroxy-4-methoxybenzophenone (HMB) is a common ingredient in personal care products and used as an UV stabilizer. In these studies, disposition and metabolism of [14C]HMB in rats and mice was assessed following single gavage administration (10, 100, or 500 mg/kg), single IV administration (10 mg/kg), or dermal application (0.1, 1, 10, or 15 mg/kg).Following gavage administration, [14C]HMB was well absorbed and excreted mainly in urine (39-57%) and feces (24-42%) with no apparent difference between doses, species or sexes. Distribution of HMB in tissues was minimal in rats (0.36%) and mice (<0.55%).Distribution of HMB following dermal application was comparable to that following gavage administration; no differences between doses, sexes, or species were observed but absorption varied between dose vehicles. Light paraffin oil had the highest absorption and excretion (98% of the HMB dose absorbed).In rats, HMB slowly appeared in the systemic circulation (Tmax â¼2-6 h) and had poor bioavailability (F%<1).Urine metabolites for both species and all routes included HMB, HMB-glucuronide, 2,4-dihydroxybenzophenone (DHB), DHB-glucuronide, and DHB-sulfates, and novel minor dihydroxy metabolites including 2,5-dihydroxy-4-methoxybenzophenone.In vitro hepatic metabolism in mice differed from human and in vivo metabolism especially for phase II conjugates.
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Benzofenonas/metabolismo , Protectores Solares/metabolismo , Animales , Humanos , Ratones , Ratones Endogámicos , Ratas , Ratas Sprague-DawleyRESUMEN
Ketamine is a glutamate N-methyl-D-aspartate receptor antagonist that is a rapid-acting dissociative anesthetic. It has been proposed as an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well-characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the SOC. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography-mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non-compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 minutes allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co-administration with the SOC following nerve agent exposure in animal models.
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Anestésicos Disociativos/administración & dosificación , Anestésicos Disociativos/farmacocinética , Absorción Intramuscular/efectos de los fármacos , Ketamina/administración & dosificación , Ketamina/farmacocinética , Anestésicos Disociativos/sangre , Animales , Inyecciones Intramusculares/métodos , Absorción Intramuscular/fisiología , Ketamina/sangre , Masculino , Ratas , Ratas Endogámicas F344 , Espectrometría de Masas en Tándem/métodos , Espectrometría de Masas en Tándem/normasRESUMEN
ß-N-methylamino-l-alanine (L-BMAA) is produced by cyanobacteria (blue-green algae). Human exposure to L-BMAA occurs via consumption of L-BMAA-contaminated water and food. It is speculated that exposure to L-BMAA, and subsequent brain accumulation, may contribute to an increased incidence of neurodegenerative diseases indicating the need to evaluate risk of L-BMAA exposure to humans. As an initial step in this process, we have evaluated disposition following a single or repeated gavage administration of 1, 10 or 100mg/kg [14C]L-BMAA in rats and mice. L-BMAA was well absorbed following a single gavage administration with minimal dose, species, or sex-related effect. In both species, the main excretion route was as exhaled CO2 (46-61%) with 7-13% and 1.4-8% of the administered dose excreted in the urine and feces, respectively. L-BMAA was distributed to all tissues examined; the total radioactivity in tissues increased with the dose and was significant in both species (8-20%). In male rats, L-BMAA was slowly eliminated from blood and tissues (half-lives ≥48h). Following 1, 5 and 10days of dosing in male rats, levels in tissues increased with the number of doses demonstrating potential for accumulation of BMAA-derived equivalents. There was no greater affinity for accumulation in the brain compared to other organs and tissues. Following repeated exposure in rats, amino acid mass shifts associated with L-BMAA were detected in brain peptides. However, the low frequency of occurrence suggests that the substitution of an amino acid with L-BMAA is not significant relative to substitutions and/or modifications by other L-BMAA-derived equivalents.
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Aminoácidos Diaminos/administración & dosificación , Aminoácidos Diaminos/metabolismo , Agonistas de Aminoácidos Excitadores/administración & dosificación , Agonistas de Aminoácidos Excitadores/metabolismo , Neurotoxinas/administración & dosificación , Neurotoxinas/metabolismo , Administración Oral , Animales , Toxinas de Cianobacterias , Esquema de Medicación , Femenino , Masculino , Ratones , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Roedores , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiologíaRESUMEN
Neurotoxicity of 1-bromopropane (1-BP) has been reported in both human cases and animal studies. To date, neurotoxicity of 1-BP has been induced in rats but not in mice due to the lethal hepatotoxicity of 1-BP. Oxidization by cytochromes P450 and conjugation with glutathione (GSH) are two critical metabolism pathways of 1-BP and play important roles in toxicity of 1-BP. The aim of the present study was to establish a murine model of 1-BP neurotoxicity, by reducing the hepatotoxicity of 1-BP with 1-aminobenzotriazole (1-ABT); a commonly used nonspecific P450s inhibitor. The results showed that subcutaneous or intraperitoneal injection of 1-ABT at 50mg/kg body weight BID (100mg/kg BW/day) for 3days, inhibited about 92-96% of hepatic microsomal CYP2E1 activity, but only inhibited about 62-64% of CYP2E1 activity in brain microsomes. Mice treated with 1-ABT survived even after exposure to 1200ppm 1-BP for 4 weeks and histopathological studies showed that treatment with 1-ABT protected mice from 1-BP-induced hepatic necrosis, hepatocyte degeneration, and hemorrhage. After 4-week exposure to 1-BP, the brain weight of 1-ABT(+)/1200ppm 1-BP group was decreased significantly. In 1-ABT-treated groups, expression of hippocampal Ran protein and cerebral cortical GRP78 was dose-dependently increased by exposure to 1-BP. We conclude that the control of hepatic P450 activity allows the observation of effects of 1-BP on the murine brain at a higher concentration by reduction of hepatotoxicity. The study suggests that further experiments with liver-specific control of P450 activity using gene technology might provide better murine models for 1-bromopropane-induced neurotoxicity.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Modelos Animales de Enfermedad , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Solventes/toxicidad , Animales , Cámaras de Exposición Atmosférica , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/mortalidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Inhibidores Enzimáticos del Citocromo P-450/administración & dosificación , Inhibidores Enzimáticos del Citocromo P-450/uso terapéutico , Relación Dosis-Respuesta a Droga , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/agonistas , Proteínas de Choque Térmico/metabolismo , Hidrocarburos Bromados/administración & dosificación , Hidrocarburos Bromados/toxicidad , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Tamaño de los Órganos/efectos de los fármacos , Solventes/administración & dosificación , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Proteína de Unión al GTP ran/agonistas , Proteína de Unión al GTP ran/metabolismoRESUMEN
1-Bromopropane (1BP) is widely used as an alternative to ozone-depleting solvents. The present study investigated the role of P450s in 1BP-induced male reproductive toxicity. Mice co-treated with 1-aminobenzotriazole (ABT), a non-selective P450 inhibitor, were exposed to 1BP at 0, 50, 250, or 1200 ppm, while saline-treated control mice were exposed to 1BP at 0, 50, or 250 ppm, for 4 weeks. In the saline-treated mice, exposure to 1BP at 250 ppm decreased the sperm count and sperm motility. Histopathological examination showed that exposure to 1BP at 50 and 250 ppm increased the number of elongated spermatids retained at the basal region of stage IX, X and XI seminiferous tubules, while exposure to 1BP at 250 ppm increased the number of periodic acid-Schiff (PAS)-positive round structures in stage IX, X, and XI seminiferous tubules. Co-treatment with ABT prevented the above changes induced by exposure to 1BP at 50 or 250 ppm. However, ABT-treated mice exposed to 1BP in the 1200 ppm group showed decreases in the weights of reproductive organs, epididymal sperm count and motility, increases in epididymal sperm with abnormal heads, retained spermatids and PAS-positive round structures in stages IX-XI, depletion of spermatogenic cells in part of the seminiferous tubules, and a small number of round spermatids in stage VII seminiferous tubules. The results at 50 and 250 ppm of 1-BP exposure indicate that P450s play important roles in 1BP-induced testicular toxicity. The control of P450 activity reduced 1BP-induced male reproductive toxicities including spermiation failure, reduction of epididymal sperm count and motility, and formation of PAS-positive round structures at postspermiation stages.
RESUMEN
1-Bromopropane (1-BP) was introduced into the workplace as an alternative to ozone-depleting solvents and increasingly used in manufacturing industry. The potential exposure to 1-BP and the current reports of adverse effects associated with occupational exposure to high levels of 1-BP have increased the need to understand the mechanism of 1-BP toxicity in animal models as a mean of understanding risk in workers. Physiologically based pharmacokinetic (PBPK) model for 1-BP has been developed to examine 2 metabolic pathway assumptions for gas-uptake inhalation study. Based on previous gas-uptake experiments in the Fischer 344 rat, the PBPK model was developed by simulating the 1-BP concentration in a closed chamber. In the model, we tested the hypothesis that metabolism responsibilities were shared by the p450 CYP2E1 and glutathione (GSH) conjugation. The results showed that 2 metabolic pathways adequately simulated 1-BP closed chamber concentration. Furthermore, the above model was tested by simulating the gas-uptake data of the female rats pretreated with 1-aminobenzotrizole, a general P450 suicide inhibitor, or d,l-buthionine (S,R)-sulfoximine, an inhibitor of GSH synthesis, prior to exposure to 800 ppm 1-BP. The comparative investigation on the metabolic pathway of 1-BP through the PBPK modeling in both sexes provides critical information for understanding the role of p450 and GSH in the metabolism of 1-BP and eventually helps to quantitatively extrapolate current animal studies to human.
Asunto(s)
Gases , Modelos Biológicos , Animales , Femenino , Hidrocarburos Bromados/administración & dosificación , Hidrocarburos Bromados/farmacocinética , Exposición por Inhalación , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
Carbon dioxide (CO2) absorption with aqueous amine solvents is a method of carbon capture and sequestration (CCS) from flue gases. One concern is the possible release of amine solvents and degradation products into the atmosphere, warranting evaluation of potential pulmonary effects from inhalation. The CCS amines monoethanolamine (MEA), methyldiethanolamine (MDEA), and piperazine (PIP) underwent oxidative and CO2-mediated degradation for 75 days. C57bl/6N mice were exposed for 7 days by inhalation of 25 ppm neat amine or equivalant concentration in the degraded mixture. The aqueous solutions were nebulized to create the inhalation atmospheres. Pulmonary response was measured by changes in inflammatory cells in bronchoalveolar lavage fluid and cytokine expression in lung tissue. Ames mutagenicity and CHO-K1 micronucleus assays were applied to assess genotoxicity. Chemical analysis of the test atmosphere and liquid revealed complex mixtures, including acids, aldehydes, and other compounds. Exposure to oxidatively degraded MEA increased (p < 0.05) total cells, neutrophils, and lymphocytes compared to control mice and caused inflammatory cytokine expression (statistical increase at p < 0.05). MEA and CO2-degraded MEA were the only atmospheres to show statistical (p < 0.05) increase in oxidative stress. CO2 degradation resulted in a different composition, less degradation, and lower observed toxicity (less magnitude and number of effects) with no genotoxicity. Overall, oxidative degradation of the amines studied resulted in enhanced toxicity (increased magnitude and number of effects) compared to the neat chemicals.
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Aminas/toxicidad , Secuestro de Carbono , Carbono/análisis , Solventes/toxicidad , Pruebas de Toxicidad , Administración por Inhalación , Aminas/química , Animales , Cromatografía Liquida , Etanolamina/química , Etanolamina/toxicidad , Pulmón/metabolismo , Masculino , Espectrometría de Masas , Ratones Endogámicos C57BL , Mutágenos/toxicidad , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.
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Amidas/farmacología , Antibacterianos/farmacología , Pirroles/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Tiazoles/farmacología , Inhibidores de Topoisomerasa II/farmacología , Adenosina Trifosfatasas/antagonistas & inhibidores , Adenosina Trifosfatasas/metabolismo , Amidas/síntesis química , Amidas/química , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Noqueados , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
1. The objectives of the current studies were to evaluate the factors influencing the toxicokinetics of 1-bromopropane (1-BP) in rodents after intravenous (IV) and inhalation exposure. 2. F-344 rats were administered 1-BP via IV bolus injection at 5 and 20 mg/kg and blood concentration determined versus time. F-344 rats and B6C3F1 mice were also exposed to starting inhalation concentrations 70, 240, 800 and 2700 ppm 1-BP in a closed gas uptake system and chamber 1-BP levels were monitored for 6 h. Plasma bromide concentrations were determined to estimate total metabolized dose. Rats were pretreated with chemical inhibitors of cytochrome P450 and glutathione (GSH) synthesis, prior to exposure to 1-BP at 800 ppm within inhalation chambers. 3. Systemic clearance of 1-BP in rat was rapid and decreased with increasing dose. As inhalation chamber concentration of 1-BP increased, the terminal elimination rates decreased. Half-life of 1-BP in rats following inhibition of P450 (9.6 h) or depletion of GSH (4.1 h) increased relative to controls (2.0 h) at 800 ppm. The percentage of 1-BP metabolized decreased with increasing inhalation exposure. Hepatic levels of GSH were significantly lowered regardless of the exposure level in both rats and mice. Chamber concentration-time curves were fit to a two compartment model which was used to estimate metabolic rate constants. 4. These data suggest that in rat, 1-BP clearance is saturable and that elimination is highly dependent on both P450 and GSH-dependent metabolism. This investigation in rodents may provide an understanding of interspecies differences in toxicokinetics and eventually aid translation of animal studies to human risk assessment.
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Glutatión/metabolismo , Administración por Inhalación , Animales , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450 , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Hidrocarburos Bromados/administración & dosificación , Hidrocarburos Bromados/farmacocinética , Hidrocarburos Bromados/toxicidad , Inactivación Metabólica , Exposición por Inhalación , Inyecciones Intravenosas , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos , Ratas Endogámicas F344 , Factores Sexuales , Especificidad de la EspecieRESUMEN
Polybrominated diphenyl ethers (PBDEs) are used commercially as additive flame retardants and have been shown to transfer into environmental compartments, where they have the potential to bioaccumulate in wildlife and humans. Of the 209 possible PBDEs, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is usually the dominant congener found in human blood and milk samples. BDE-47 has been shown to have endocrine activity and produce developmental, reproductive, and neurotoxic effects. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for BDE-47 in male and female (pregnant and non-pregnant) adult rats to facilitate investigations of developmental exposure. This model consists of eight compartments: liver, brain, adipose tissue, kidney, placenta, fetus, blood, and the rest of the body. Concentrations of BDE-47 from the literature and from maternal-fetal pharmacokinetic studies conducted at RTI International were used to parameterize and evaluate the model. The results showed that the model simulated BDE-47 tissue concentrations in adult male, maternal, and fetal compartments within the standard deviations of the experimental data. The model's ability to estimate BDE-47 concentrations in the fetus after maternal exposure will be useful to design in utero exposure/effect studies. This PBPK model is the first one designed for any PBDE pharmaco/toxicokinetic description. The next steps will be to expand this model to simulate BDE-47 pharmacokinetics and distributions across species (mice), and then extrapolate it to humans. After mouse and human model development, additional PBDE congeners will be incorporated into the model and simulated as a mixture.
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Contaminantes Ambientales/farmacocinética , Exposición Materna , Intercambio Materno-Fetal , Modelos Biológicos , Bifenilos Polibrominados/farmacocinética , Animales , Femenino , Feto/metabolismo , Éteres Difenilos Halogenados , Humanos , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Distribución TisularRESUMEN
The objective of the study was to assess the degree of accuracy in human drug clearance prediction from two species using four different allometric approaches: simple allometry (SA), multiexponential allometry (ME), rule of exponents (ROE), and fixed exponents (FE) as suggested by Tang et al. There were 45 compounds in this analysis and the two species used were either rat-dog or rat-monkey. In addition, > or = 3 species scaling was also performed to evaluate the comparative accuracy in the prediction of human drug clearance between two or more than two-species scaling. The results of the study indicated that the two-species scaling with different methods provided different degrees of accuracy in the prediction of clearance. Prediction by a particular method was also species dependent. For example, a given drug with rat-dog scaling provided a reasonably accurate prediction of clearance whereas with rat-monkey scaling the prediction of clearance was highly erratic or vice versa. The results of the study indicated that the two-species scaling can be useful for prediction purposes but the prediction of clearance from > or = 3 species was far more accurate than two-species scaling.
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Evaluación Preclínica de Medicamentos/métodos , Tasa de Depuración Metabólica/fisiología , Preparaciones Farmacéuticas/metabolismo , Especificidad de la Especie , Algoritmos , Animales , Perros , Haplorrinos , Humanos , Modelos Estadísticos , RatasRESUMEN
PURPOSE: Pharmacokinetic/pharmacodynamic (PK/PD) models have been shown to be useful in predicting tumor growth rates in mouse xenografts. We applied novel PK/PD models to the published anticancer combination therapies of tumor growth inhibition to simulate synergistic changes in tumor growth rates. The parameters from the PK/PD model were further used to estimate clinical doses of the combination. METHODS: A PK/PD model was built that linked the dosing regimen of a compound to the inhibition of tumor growth in mouse xenograft models. Two subsequent PK/PD models were developed to simulate the published tumor growth profiles of combination treatments. Model I predicts the tumor growth curve assuming that the effect of two anticancer drugs, AZD7762 and irinotecan, is synergistic when given in combination. Model II predicts the tumor growth curve assuming that the effect of co-administering flavopiridol and irinotecan is maximally synergistic when dosed at an optimal interval. RESULTS: Model I was able to account for the synergistic effects of AZD7762 following the administration of irinotecan. When Model II was applied to the antitumor activity of irinotecan and flavopiridol combination therapy, the modeling was able to reproduce the optimal dosing interval between administrations of the compounds. Furthermore, Model II was able to estimate the biologically active dose of flavopiridol recommended for phase II studies. CONCLUSIONS: The timing of clinical combination therapy doses is often selected empirically. PK/PD models provide a theoretical structure useful in the design of the optimal clinical dose, frequency of administration and the optimal timing of administration between anticancer agents to maximize tumor suppression.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Algoritmos , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Proliferación Celular , Evaluación Preclínica de Medicamentos/métodos , Sinergismo Farmacológico , Flavonoides/administración & dosificación , Genes cdc/efectos de los fármacos , Inhibidores de Crecimiento/administración & dosificación , Humanos , Irinotecán , Ratones , Ratones Desnudos , Modelos Estadísticos , Trasplante de Neoplasias , Piperidinas/administración & dosificación , Valor Predictivo de las Pruebas , Tiofenos/administración & dosificación , Urea/administración & dosificación , Urea/análogos & derivados , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A multiexponential allometry (MA) method was developed to predict human drug clearance from preclinical data. Separate data sets containing clearances from human and preclinical species were chosen for the study. Human clearance was estimated using the MA technique according to the equation: CL = aBWb + cBWd, where CL is clearance in milliliters/minute, and a, b, c, and d are constants derived from preclinical pharmacokinetic data. Simple allometry (SA) gave the poorest prediction using any data set, and the percentage outliers remained larger than MA or monkey liver blood flow within 1.5-, 2-, and 3-fold error. Analysis of compounds common to both data sets suggested that MA could accurately predict human clearances within approximately 10% of 3-fold error. The analysis also showed that monkey is an important species for scaling, and MA is a better predictor of human clearance when the slope of SA is >0.7.
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Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Animales , Peso Corporal , Interpretación Estadística de Datos , Evaluación Preclínica de Medicamentos/métodos , Haplorrinos , Humanos , Circulación Hepática/fisiología , Especificidad de la EspecieRESUMEN
The role of the intestine in the elimination of (2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide (DPC 333), a potent inhibitor of tissue necrosis factor alpha-converting enzyme, was investigated in mice and rats in vivo and in vitro. In Madine-Darby canine kidney cells stably transfected with P-glycoprotein (P-gp) and DPC 333, the transport from B-->A reservoirs exceeded the transport from A-->B by approximately 7-fold. In Caco-2 monolayers and isolated rat ileal mucosa, DPC 333 was transported from basolateral to apical reservoirs in a concentration-dependent, saturable manner, and transport was blocked by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), confirming the contribution of P-gp/breast cancer resistance protein in B-->A efflux of DPC 333. In quantitative whole body autoradiography studies with [(14)C]DPC 333 in mice and rats, radioactivity was distributed throughout the small intestine in both species. In GF120918-pretreated bile duct-cannulated rats, radioactivity in feces was reduced 60%. Using the in situ perfused rat intestine model, approximately 20% of an i.v. dose of [(14)C]DPC 333 was measured in the intestinal lumen within 3 h postdose, 12% as parent. Kinetic analysis of data suggested that excreted DPC 333 may be further metabolized in the gut. Intestinal clearance was 0.2 to 0.35 l/h/kg. The above data suggest that in the rodent the intestine serves as an organ of DPC 333 excretion, mediated in part by the transporter P-gp.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Mucosa Intestinal/metabolismo , Quinolinas/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Animales , Células CACO-2 , Línea Celular , Perros , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Quinolinas/sangre , Ratas , Ratas Sprague-Dawley , TransfecciónRESUMEN
DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a V(ss) of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC(50) for the suppression of TNF-alpha production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC(50) for suppressing TNF-alpha production was 113 nM. Measurement of the suppression of TNF-alpha production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-alpha with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-alpha production.