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Elimination Rate (elimination + rate)
Terms modified by Elimination Rate Selected AbstractsDisposition of perfluorinated acid isomers in sprague-dawley rats; Part 2: Subchronic doseENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2009Amila O. De Silva Abstract Two major industrial synthetic pathways have been used to produce perfluorinated acids (PFAs) or their precursors: Telomerization and electrochemical fluorination (ECF). Products of telomer and ECF origin can be distinguished by structural isomer profiles. A mixture of linear and branched perfluoroalkyl isomers is associated with ECF. Telomer products characteristically consist of a single perfluoroalkyl geometry, typically linear. In biota, it is unclear if the isomer profile is conserved relative to the exposure medium and hence whether PFA isomer profiles in organisms are useful for distinguishing environmental PFA sources. A companion study suggested isomer-specific disposition following a single oral gavage exposure to rats. To confirm these findings under a more realistic subchronic feeding scenario, male and female rats were administered PFA isomers by diet for 12 weeks, followed by a 12-week depuration period. The diet contained 500 ng/g each of ECF perfluorooctanoate (PFOA, ,80% n -PFOA), ECF perfluorooctane sulfonate (PFOS, ,70% n -PFOS), and linear and isopropyl perfluorononanoate (n - and iso -PFNA). Blood sampling during the exposure phase revealed preferential accumulation of n -PFOA and n -PFNA compared to most branched isomers. Female rats depurated all isomers faster than males. Both sexes eliminated most branched perfluorocarboxylate isomers more rapidly than the n -isomer. Elimination rates of the major branched PFOS isomers were not statistically different from n -PFOS. Two minor isomers of ECF PFOA and one branched PFOS isomer had longer elimination half-lives than the n-isomers. Although extrapolation of these pharmacokinetics trends in rats to humans and wildlife requires careful consideration of dosage level and species-specific physiology, cumulative evidence suggests that perfluorocarboxylate isomer profiles in biota may not be suitable for quantifying the relative contributions of telomer and ECF sources. [source] Predicting world health organization toxic equivalency factor dioxin and dioxin-like polychlorinated biphenyl levels in farmed atlantic salmon (Salmo salar) based on known levels in feedENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2007Marc H. G. Berntssen Abstract Assimilation and elimination rate constant of dietary polychlorinated dibenzo- p -dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DLPCBs) with a World Health Organization toxic equivalency factor (WHO-TEF) were estimated in market-size Atlantic salmon (Salmo salar) using fish that were previously fed vegetable oil,based (low in PCDD/Fs and DLPCBs) or fish oil,based (high in PCDD/Fs and PCBs) diets. At the start of the kinetic trial, half the fish that were fed fish oils were fed vegetable oil feeds and inverted (cross-over design) for five months. The assimilation efficiencies of the PCDD/F congeners were more variable (3,89%) and, generally, were lower than those of the DLPCBs (70,80%). Among the PCDD/F congeners, the assimilation efficiency of the most toxic tetra- and pentachlorinated PCDD/Fs was greater than that of higher-chlorinated PCDD/Fs. Elimination rates for DLPCBs were higher than those for PCDD/Fs. Lower-chlorinated PCDDs had a lower elimination rate than the higher-chlorinated PCDDs, but no differences were observed among PCDF congeners or DLPCB congeners. Kinetic parameters were used to predict the level of WHO-TEF dioxins and DLPCBs in Atlantic salmon reared in a large-scale facility under commercial conditions. Predictions were based on preanalyzed levels of these organochlorines in feeds with three different replacement levels (0, 30, and 60%) of vegetable oil. A simple one-compartmental, first-order kinetic model was used to predict the level of sum WHO toxic equivalents for PCDD/Fs and DL-PCBs. The predicted values varied by 0 to 11% from the measured values in the commercially reared salmon. [source] Soil and plant diet exposure routes and toxicokinetics of lindane in a terrestrial isopodENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2000José Paulo Sousa Abstract In most studies dealing with effects of toxic substances in saprotrophic isopods, animals are exposed to the test substance through contaminated food. Because these animals can be in a close contact with the soil surface, the substrate, as an exposure pathway, should not be neglected. Here the authors analyze the toxicokinetic behavior of lindane (,-hexachlorocyclohexane [,-HCH]) in the isopod species Porcellionides pruinosus, comparing two exposure routes: food and two soil types (artificial Organisation for Economic Cooperation and Development [OECD] soil and a natural agricultural soil). In the feeding experiment, a strong decrease of ,-HCH concentration over time was observed on the food material, with the animals showing a broader range in chemical assimilation efficiency values (averaging 17.7% and ranging from 10 to 40%). The ,-HCH bioaccumulation results indicate that when animals incubated under both soil types reached a steady state, they displayed much higher body burdens (1,359.60 pg/animal on OECD soil and 1,085.30 pg/animal on natural soil) than those exposed to contaminated food (43.75 pg/animal). Kinetic models also revealed much lower assimilation and elimination rates in the food experiment (20.66 pg/d and 0.10 pg/d) than in both soil experiments (238.60 pg/d and 350.54 pg/d for the assimilation rate and 0.19 pg/d and 0.32 pg/d for the elimination rate). Differences in results between exposure routes are discussed according to equilibrium-partitioning theory and the enhanced relevance of the substrate exposure route is analyzed under future prospects on chemical toxicity testing using isopods. [source] Oral bioavailability and toxicokinetics of 3,3,,4,4,,5-pentachlorobiphenyl in northern leopard frogs, Rana pipiensENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2000Yue-wern Huang Abstract This study is the first report on oral bioavailability, whole-body elimination, and distribution of a specific polychlorinated biphenyl (PCB) congener on an amphibian species, northern leopard frogs. Each frog was orally dosed once with either 0.35 or 5.0 mg/kg PCB 126 (based on frog wet wt), including tracer 14C-PCB 126 (3,,4,,5,-phenyl-ring- 14C) by force feeding it a cricket injected with the PCB. We found no statistical difference (t = 0.917, df = 5, p = 0.401) in the average 48-h oral bioavailabilities of 0.35- and 5.0-mg/kg dosage groups, which were 84.6 ± 5.8% (mean ± SE, n = 4) and 90.9 ± 1.5% (n = 3), respectively. Statistical analysis indicated that time was the only independent variable affecting the retention of whole-body 14C content. Kinetics were apparently first order because elimination rate was independent of dose. Assuming a single pool and one elimination rate, the t1/2 value for whole-body elimination of PCB-derived 14C was 763 d. Liver, fat bodies (corpora adiposa), carcass (head, bone, cartilage materials, and residues of other tissues), skin, and muscle were the major organs for PCB 126 retention in both dosage groups. The concentrations of 14C residue in fat bodies were relatively constant throughout the experiment. However, total residues in fat bodies declined throughout the experiment in both dosage groups in correlation with declining masses of fat bodies. Gonad, kidney, stomach, intestine, and a tissue pool including esophagus, lung, spleen, heart, and cloacal materials each accumulated <1% of the initial total 14C residue. The egg follicles in 19 females contained 1 to 23% of the initial total 14C residue, with an average of 10.0 ± 9.2% (mean ± SE, n = 19). [source] Toxicokinetics of polycyclic aromatic hydrocarbons in Eisenia andrei (Oligochaeta) using spiked soilENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 4 2000Tjalling Jager Abstract The accumulation of four polycyclic aromatic hydrocarbons ([PAHs]; phenanthrene, pyrene, fluoranthene, and ben-zo[a]pyrene) was tested in the earthworm Eisenia andrei in a spiked artificial soil medium. A typical peak in the body residues was observed for all PAHs around day 7, which could not be explained from changes in the total soil concentration. It is argued that the most likely cause of this peak is a decrease in the concentration in pore water, the main bioavailable phase for earthworms. This decrease is caused by biodegradation while the low rate of mass transfer from the solid state precludes replenishment. To describe the data, bioavailability was assumed to decline exponentially in time, but the shape of the accumulation curves suggests a more abrupt change. Estimates of the uptake rate (k1) are similar for all PAHs when expressed on soil solution basis (approximately 2,000 L/kg/d); the elimination rate (k2) shows a decrease with Kow as expected, but the values tend to be slightly lower than literature data. The dynamic bioconcentration factors (k1/k2) agree well with an equilibrium partitioning between soil water and the phases inside the organism. [source] The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] Advanced oxidation of cork-processing wastewater using Fenton's reagent: kinetics and stoichiometryJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 4 2004Jesús Beltrán de Heredia Abstract This work evaluates Fenton oxidation for the removal of organic matter (COD) from cork-processing wastewater. The experimental variables studied were the dosages of iron salts and hydrogen peroxide. The COD removal ranged from 17% to 79%, depending on the reagent dose, and the stoichiometric reaction coefficient varied from 0.08 to 0.43 g COD (g H2O2),1 (which implies an efficiency in the use of hydrogen peroxide varying from 17% to 92%). In a study of the process kinetics, based on the initial rates method, the COD elimination rate was maximum when the molar ratio [H2O2]o:[Fe2+]o was equal to 10. Under these experimental conditions, the initial oxidation rate was 50.5 mg COD dm,3 s,1 with a rate of consumption of hydrogen peroxide of 140 mg H2O2 dm,3 s,1, implying an efficiency in the use of the hydrogen peroxide at the initial time of 77%. The total amount of organic matter removed by Fenton oxidation was increased by spreading the H2O2 and ferrous salt reagent over several fractions by 15% for two-fractions and by 21% for three-fractions. Copyright © 2004 Society of Chemical Industry [source] Reduction of Acrylamide and Its Kinetics by Addition of Antioxidant of Bamboo Leaves (AOB) and Extract of Green Tea (EGT) in Asparagine,Glucose Microwave Heating SystemJOURNAL OF FOOD SCIENCE, Issue 2 2008Yu Zhang ABSTRACT:, This study investigated the effect of antioxidant of bamboo leaves (AOB) and extract of green tea (EGT) on the formation and kinetics of acrylamide in an equimolar asparagine,glucose model system. The substrates spiked with AOB and EGT were microwave-heated at 180 °C and the acrylamide content in final reaction products was quantified by ultra-performance liquid chromatography,tandem mass spectrometry (UPLC-MS/MS). The results showed that both AOB and EGT could effectively reduce the formation of acrylamide in an asparagine,glucose microwave heating model system and achieved a maximum reduction rate when the addition levels of AOB and EGT were both 10,6 mg/mL reaction solution. To describe the kinetic behavior of acrylamide, a simplified kinetic model was optimized and relative kinetic rate constants were evaluated under isothermal conditions. The results indicated that the reduction effect of AOB and EGT on the acrylamide formation may partly be ascribed to the decrease of the formation rate constant (kF) in both AOB and EGT-spiked systems (43.4% and 32.3% of decrease, respectively, P < 0.05). The kinetic parameter kE, which represents the elimination rate of acrylamide in both AOB and EGT-spiked systems, was not significantly different (6.9% of increase and 10.9% of decrease, respectively, P > 0.05). The results of the kinetic study indicated that addition of AOB and EGT could significantly reduce the formation rate constant (kF) of acrylamide, but could not significantly affect the elimination rate constant (kE) of acrylamide. [source] Pharmacokinetics of roxatidine acetate in patients with chronic liver diseaseJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2001Mikihiro Tsutsumi Abstract Background and Aim: Patients with liver disease are prone to develop peptic ulceration and often receive H2 -receptor antagonists. Therefore, it is important to clarify whether the pharmacokinetics of H2 -receptor antagonists is affected by hepatic function. However, pharmacokinetics of a new H2 -receptor antagonist, roxatidine acetate, in chronic liver disease has not been well known. In this study, we analyzed the pharmacokinetics of roxatidine in patients with liver disease. Methods: Blood samples were obtained from 11 patients with chronic hepatitis, 11 patients with cirrhosis and six healthy subjects. Under fasting conditions, 75 mg of roxatidine acetate was administered orally, and plasma roxatidine levels were determined sequentially from 3 to 12 h. Relationships between pharmacokinetic variables and each parameter related to hepatic functions were also investigated. Results: There was no difference in the pharmacokinetic variables and serum levels of roxatidine between chronic hepatitis and healthy controls. In contrast, in cirrhosis, serum roxatidine levels were significantly higher than those in chronic hepatitis and normal control. Half-life, the area under the plasma concentration,time curve and clearance in cirrhosis were also significantly longer, bigger and smaller than those in chronic hepatitis and healthy controls, respectively. The half-life became longer and the clearance became smaller in parallel with the progression of liver disease. Serum levels of hyaluronate and ,-glutamyl transpeptidase showed a good correlation with half-life, clearance and elimination rate. A good correlation between creatinine clearance and elimination rate was found. Conclusion: Pharmacokinetics of roxatidine acetate is affected by hepatic function, and the dosage of roxatidine acetate for patients with liver disease, especially cirrhosis, should be modified. [source] SIAM-Like Phenomenon Caused by Low Doses of AlcoholALCOHOLISM, Issue 2010Akiko Shimamoto Background:, Swift increase in alcohol metabolism (SIAM) is usually evoked by a large dose of ethanol, which is often demonstrated by an abrupt increase in oxygen uptake. SIAM was induced by low doses of ethanol and evaluated by pharmacokinetic analyses of ethanol and its metabolites. Methods:, Rabbits were initially administered 1.0 g/kg of ethanol solution and the same dose was given to the bolus group 6 hours after the first injection. The infusion group was administered 0.25 g/kg/h of ethanol 2 hours after the first injection. Blood concentrations of ethanol, acetaldehyde, and acetate were then determined and comparisons were made using pharmacokinetic parameters. Results:, A significantly higher ethanol elimination rate was observed after re-administration of ethanol to the bolus group. Other pharmacokinetic parameters were unaffected. The concentration at steady state (Css) for the infusion group was stable. A significantly higher level of mean residence time (MRT) in blood acetaldehyde was observed for the bolus group, whereas no MRT changes were observed for the infusion group. A significantly higher level of blood acetate Css was observed after re-administration of ethanol to the bolus group, following the changes in area under concentration and MRT. No Css changes were observed for the infusion group. The Css of acetate at stage 2 was significantly higher for the bolus group, compared to the infusion group. Conclusion:, Low doses of ethanol enhanced alcohol metabolism in rabbits, according to a pharmacokinetic analysis of circulating ethanol concentrations. Simultaneous analyses of its metabolites followed the kinetic of ethanol. [source] Possible Pleiotropic Effects of Genes Specifying Sedative/Hypnotic Sensitivity to Ethanol on Other Alcohol-Related TraitsALCOHOLISM, Issue 10 2002Jeremy C. Owens Background Initial sensitivity to ethanol is a predictor of alcohol abuse that has been studied extensively in both human and animal populations. Selection for initial sensitivity to the sedative/hypnotic effects of ethanol resulted in the long-sleep and short-sleep lines of mice. Some of the genes selected in these lines could also specify differential responses in other ethanol-related phenotypes and, perhaps, for other drugs of abuse. We assessed congenic mice carrying a single quantitative trait locus (QTL) from the inbred long-sleep (ILS) or inbred short-sleep (ISS) strain on the reciprocal background for a number of ethanol- and pentobarbital-related phenotypes. Methods Each congenic strain was tested for ethanol elimination rates at 4.1 g/kg, ethanol-induced ataxia at 2.0 g/kg, ethanol-induced hypothermia at 4.1 g/kg, and pentobarbital-induced loss of righting reflex (LORR) at 60 mg/kg. Additionally, the ILS.ISS congenics were tested for low-dose ethanol-induced activation (LDA) at five doses ranging from 0.6 to 1.2 g/kg ethanol, and the ISS.ILS congenics were tested for LDA at 1.8 g/kg of ethanol. Results There was little difference in the ethanol elimination rate between congenics and background strains, although a modest sex effect was found, with the females eliminating ethanol more rapidly than the males. We were unable to replicate previous differences found in LDA for the Lore1 congenic on the ISS background, because none of the congenics differed from controls for LDA. Lore5 congenics showed a differential effect of pentobarbital-induced LORR in the expected directions. The Lore1 congenics on the ISS background showed more ethanol-induced ataxia than the ISS controls. Additionally, the hypothermic response seems affected by Lore4 and Lore5 and maybe others. Conclusions At least two regions carrying a QTL specifying sensitivity to high doses of ethanol cospecify altered sensitivity in other measures of alcohol action. Specifically, these QTLs clearly affect ethanol-induced hypothermia and pentobarbital-induced LORR and possibly ethanol-induced ataxia. [source] The effect of gender on the pharmacokinetics of verapamil and norverapamil in humanBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2006S. Dadashzadeh Abstract The effects of gender on the pharmacokinetics of verapamil and its active metabolite, norverapamil, following single oral dose (80mg, Isoptin) to 12 healthy male (mean age: 25.75±2.42 years, mean body weight: 70.59±9.94kg) and 12 healthy female subjects (mean age: 24.08±2.84 years, mean body weight: 56.67±5.23kg) were investigated in the present study. Plasma concentrations of verapamil and norverapamil were analysed using a modified high-pressure liquid chromatography method. Pharmacokinetic parameters were calculated by non-compartmental analysis for each subject. For verapamil the half-life (t1/2) and mean residence time (MRT) were significantly shorter in women than men (p<0.01 and p<0.05, respectively). For other pharmacokinetic parameters of verapamil there were no significant differences between males and females. For norverapamil, t1/2, MRT and time to reach to the maximum plasma concentration (Tmax) showed statistically significant differences between the two genders. The AUC0,24 and AUC0,, ratios of norverapamil to verapamil were also calculated. The ratios were significantly higher in women compared with men. These observations indicate that the elimination rate of verapamil is faster in women than men which may be attributed to the higher activity of CYP3A4 or lower activity of P-glycoprotein in women compared with men. A contribution of both factors in the appearance of gender differences in verapamil pharmacokinetics is also possible. Copyright © 2006 John Wiley & Sons, Ltd. [source] Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancerBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2010Stijn L. W. Koolen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Docetaxel is an approved drug for the treatment of cancer of various primary origins. , An oral docetaxel regimen is warranted because of patient convenience and the opportunity to investigate more schedule intensive treatment regimens. , Co-administration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. WHAT THIS STUDY ADDS , This study demonstrates that ritonavir increased the absorption of docetaxel after oral administration. , Furthermore, we showed that the clearance of docetaxel was inhibited in a concentration dependent manner. , The developed model will be used for further development of an oral docetaxel regimen. AIM Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel. METHODS Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m,2 or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co-administration of oral ritonavir (100 mg). Population modelling was performed using non-linear mixed effects modelling. A three-compartment model was used to describe the i.v. data. PK data after oral administration, with or without co-administration of ritonavir, were incorporated into the model. RESULTS Gut bioavailability of docetaxel increased approximately two-fold from 19 to 39% (CV 13%) with ritonavir co-administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 µg ml,1 (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached. CONCLUSIONS A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co-administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel. [source] Performance of a full-scale biotrickling filter treating H2S at a gas contact time of 1.6 to 2.2 secondsENVIRONMENTAL PROGRESS & SUSTAINABLE ENERGY, Issue 2 2003David Gabriel Emission of objectionable odors is a major problem for wastewater treatment and other processing facilities. Biological treatment is a promising alternative to conventional control methods, such as chemical scrubbing, but historically, biotreatment has always required significantly larger reactor volumes than chemical scrubbers. In this paper, we present several aspects of the operation and performance of a chemical scrubber, retrofitted to operate as a biotrickling filter treating 16,000 m3 h,1 of foul air with the original gas contact time of 1.6 to 2.2 seconds. In continuous operation for more than a year, the biotrickling filter has shown stable performance and robust behavior for H2S treatment, with pollutant removal performance comparable to using a chemical scrubber. Reclaimed water was used as a nutrient source for the process, and to maintain the pH in the biotrickling filter between 1.5 and 2.2. At a gas contact time of 1.6 seconds, H2S removal was in excess of 95% for sustained inlet H2S concentrations as high as 30 ppmv. This corresponds to volumetric elimination rates of 95 to 105 g H2S m,3 h,1. Efficiencies of about 90% were observed under transient conditions at 2.2 seconds gas contact time for inlet concentration peaks up to 60 ppmv. The biotrickling filter also removed significant amounts of reduced sulfur compounds, ammonia, and volatile organic compounds present in traces in the air, which is important in practical applications. Selected experiments, such as intermittent trickling operation and a one-month operation period at neutral pH, are also presented. Results indicate that the intermittent trickling operation does not have a significant effect on H2S removal. However, when operated at neutral pH, biotrickling filter performance clearly decreased, probably due to an excessive chlorine supply to the reactor through the make-up water. The study demonstrates that biotrickling filters can replace chemical scrubbers as a safer, more economical technique for odor control. [source] Determination of polychlorinated biphenyl and polycyclic aromatic hydrocarbon elimination rates in adult green and leopard frogsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2006Jocelyn L. Leney Abstract The purpose of the present study was to quantify elimination kinetics of polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) in adult green frogs (Rana clamitans) and leopard frogs (Rana pipiens). Three experiments were conducted: PCB elimination rate constants were determined for both frog species, and PAH elimination rate constants were determined for leopard frogs only. In green frogs, significant PCB elimination rate constants ranged from 0.013 to 0.04 d,1 (time for frogs to achieve 90% steady state with water [t90] = 57.8-178.2 d). In leopard frogs, significant PCB elimination rate constants ranged from 0.004 to 0.047 d,1 (t90 = 48.8-657.9 d). Polycyclic aromatic hydrocarbon elimination in leopard frogs was faster than PCB elimination in either frog species: Significant PAH rate constants ranged from 0.069 to 0.188 d,1 (t90 = 12.2-33.5 d). In both species, and for both PCBs and PAHs, a significant inverse relationship was found between the chemical elimination rate constant and Kow. These results show that adult anurans have relatively low elimination rates of PCBs but exhibit a small capacity for metabolic biotransformation of PAHs that is comparable to that of invertebrates but lower than that of fish. These findings suggest that adult amphibians have the potential to be used as biomonitors for persistent organic chemicals. [source] A simulation study comparing different experimental designs for estimating uptake and elimination ratesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2006Bryan R. Bell Abstract The design of ecotoxicological studies requires decisions about the number and spacing of exposure groups tested, the number of replications, the spacing of sampling times, the duration of the study, and other considerations. For example, geometric spacing of sampling times or toxicant concentrations is often used as a default design. Optimal design methods in statistics can suggest alternative spacing of sampling times that yield more precise estimates of regression coefficients. In this study, we use a computer simulation to explore the impact of the spacing of sampling times and other factors on the estimation of uptake and elimination rate constants in an experiment addressing the bioaccumulation of a contaminant. Careful selection of sampling times can result in smaller standard errors for the parameter estimates, thereby allowing the construction of smaller, more precise confidence intervals. Thus, the effort invested in constructing an optimal experimental design may result in more precise inference or in a reduction of replications in an experimental design. [source] Soil and plant diet exposure routes and toxicokinetics of lindane in a terrestrial isopodENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2000José Paulo Sousa Abstract In most studies dealing with effects of toxic substances in saprotrophic isopods, animals are exposed to the test substance through contaminated food. Because these animals can be in a close contact with the soil surface, the substrate, as an exposure pathway, should not be neglected. Here the authors analyze the toxicokinetic behavior of lindane (,-hexachlorocyclohexane [,-HCH]) in the isopod species Porcellionides pruinosus, comparing two exposure routes: food and two soil types (artificial Organisation for Economic Cooperation and Development [OECD] soil and a natural agricultural soil). In the feeding experiment, a strong decrease of ,-HCH concentration over time was observed on the food material, with the animals showing a broader range in chemical assimilation efficiency values (averaging 17.7% and ranging from 10 to 40%). The ,-HCH bioaccumulation results indicate that when animals incubated under both soil types reached a steady state, they displayed much higher body burdens (1,359.60 pg/animal on OECD soil and 1,085.30 pg/animal on natural soil) than those exposed to contaminated food (43.75 pg/animal). Kinetic models also revealed much lower assimilation and elimination rates in the food experiment (20.66 pg/d and 0.10 pg/d) than in both soil experiments (238.60 pg/d and 350.54 pg/d for the assimilation rate and 0.19 pg/d and 0.32 pg/d for the elimination rate). Differences in results between exposure routes are discussed according to equilibrium-partitioning theory and the enhanced relevance of the substrate exposure route is analyzed under future prospects on chemical toxicity testing using isopods. [source] The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] PRECLINICAL STUDY: Circadian regulation of central ethanol sensitivity by the mPer2 geneADDICTION BIOLOGY, Issue 3 2009Stéphanie Perreau-Lenz ABSTRACT The effect of alcohol is known to vary with the time of the day. Although initially it was suggested that this phenomenon may be due to diurnal differences in ethanol metabolism, more recent studies were contradicting. In the present study, we therefore first set out in assessing the diurnal variations in ethanol sensitivity in mice analysing, concurrently, ethanol elimination rates. Ethanol-induced (3.5 g/kg; intraperitoneal) loss of righting reflex (LORR) duration was thus determined at several Zeitgeber time (ZT) points (ZT5, 11, 17 and 23) in C57BL/6N mice. In parallel, the corresponding ethanol elimination rates were also assessed. The results display the existence of a distinct diurnal rhythm in LORR duration peaking at ZT11, whereas no differences could be observed regarding the elimination rates of alcohol. Successively, we checked the involvement of the clock genes mPer1 and mPer2 in conveying this rhythm in sensitivity, testing LORR and hypothermia at the peak and trough previously observed (ZT5 and ZT11). Per1Brdm1 mice demonstrate a similar diurnal pattern as control mice, with enhanced LORR durations at ZT11. In contrast, Per2Brdm1 mice did not exhibit a temporal variation to the depressant effects of ethanol with respect to LORR, revealing a constant high sensitivity to ethanol. The present study reveals a central role of the mPer2 gene in inhibiting alcohol sensitivity at the beginning of the inactive phase. [source] Deletion of the ,7 Nicotinic Receptor Subunit Gene Results in Increased Sensitivity to Several Behavioral Effects Produced by AlcoholALCOHOLISM, Issue 3 2005Barbara J. Bowers Background: The finding that most people with alcoholism are also heavy smokers prompted several research groups to evaluate the effects of ethanol on neuronal nicotinic acetylcholine receptor (nAChR) function. Data collected in vitro indicate that physiologically relevant concentrations of ethanol inhibit the functional activation of homomeric ,7 nAChRs, which are one of the most abundant nAChR subtypes expressed in the mammalian brain. The studies outlined here used ,7 gene knockout (null mutant) mice to evaluate the potential role of ,7 nAChRs in modulating selected behavioral and physiological effects produced by ethanol. Methods: Current evidence indicates that many responses to ethanol are not genetically correlated. Therefore, the authors measured the effects of acute administration of ethanol on several behaviors that are altered by both ethanol and nicotine: two tests of locomotor activity, acoustic startle, prepulse inhibition of acoustic startle, and body temperature. Ethanol-induced durations of loss of righting reflex and ethanol elimination rates were also determined. These studies used null mutant (,7,/,) and wild-type (,7+/+) mice. Results: Relative to ,7+/+ mice, ,7,/, mice were more sensitive to the activating effects of ethanol on open-field activity, ethanol-induced hypothermia, and duration of loss of the righting response. Deletion of the ,7 gene did not influence the effects of ethanol on Y-maze crossing or rearing activities, acoustic startle, or prepulse inhibition of startle. Gene deletion did not alter ethanol metabolism. Conclusions: These results indicate that some but not all of the behavioral effects of ethanol are mediated in part by effects on nAChRs that include the ,7 subunit and may help to explain the robust association between alcohol consumption and the use of tobacco. [source] Chronic Intermittent Injections of High-Dose Ethanol During Adolescence Produce Metabolic, Hypnotic, and Cognitive Tolerance in RatsALCOHOLISM, Issue 10 2003Janelle M. Silvers Background: Many humans are first exposed to ethanol during adolescence, the time at which they are most likely to binge drink ethanol. Chronic intermittent ethanol (CIE) exposure produces ethanol tolerance in adolescent rodents. Recent studies suggested that adolescent animals administered CIE experienced increased cognitive impairment following an ethanol challenge. These studies further explore development of ethanol tolerance caused by CIE in adolescence, and whether CIE during adolescence leads to altered ethanol response in adulthood. Methods: Beginning postnatal day (P) 30, adolescent rats were administered 5.0 g/kg ethanol or saline every 48 hours for 20 days. In experiment I, animals were tested for differential weight gain. In experiment II, loss of righting reflex (LORR) was observed after each injection, then at completion of pretreatment all animals were tested with 5.0 g/kg ethanol and LORR was observed. In experiment III, blood ethanol levels were observed and elimination rates calculated after the first and fifth pretreatments. All animals were tested with 5.0 g/kg at completion of pretreatment and elimination rates were recalculated. In experiment IV, animals were trained on the spatial version of the Morris Water Maze Task (MWMT) on non-treatment days. Following completion of pretreatment and training, animals were tested after receiving an ethanol (1.0, 1.5, or 2.0 g/kg), or saline. Tests for experiments II, III, and IV were repeated in the same animals following 12 ethanol-free days. Results: Chronic intermittent ethanol exposure during adolescence caused differential weight gain (experiment I). Adolescent rats developed tolerance to ethanol-induced LORR (experiment II) and metabolic tolerance to ethanol (experiment III). This tolerance was seen after 12 ethanol-free days. CIE also attenuated ethanol-induced spatial memory deficits in the MWMT (experiment IV). This effect was not long-lasting. Conclusions: Following CIE pretreatment during adolescence, tolerance developed to the hypnotic and cognitive impairing effects of ethanol, along with increased metabolic rate and decreased weight gain. These results further emphasize the ability of CIE to produce a variety of effects during adolescence, some having long-lasting consequences. [source] Possible Pleiotropic Effects of Genes Specifying Sedative/Hypnotic Sensitivity to Ethanol on Other Alcohol-Related TraitsALCOHOLISM, Issue 10 2002Jeremy C. Owens Background Initial sensitivity to ethanol is a predictor of alcohol abuse that has been studied extensively in both human and animal populations. Selection for initial sensitivity to the sedative/hypnotic effects of ethanol resulted in the long-sleep and short-sleep lines of mice. Some of the genes selected in these lines could also specify differential responses in other ethanol-related phenotypes and, perhaps, for other drugs of abuse. We assessed congenic mice carrying a single quantitative trait locus (QTL) from the inbred long-sleep (ILS) or inbred short-sleep (ISS) strain on the reciprocal background for a number of ethanol- and pentobarbital-related phenotypes. Methods Each congenic strain was tested for ethanol elimination rates at 4.1 g/kg, ethanol-induced ataxia at 2.0 g/kg, ethanol-induced hypothermia at 4.1 g/kg, and pentobarbital-induced loss of righting reflex (LORR) at 60 mg/kg. Additionally, the ILS.ISS congenics were tested for low-dose ethanol-induced activation (LDA) at five doses ranging from 0.6 to 1.2 g/kg ethanol, and the ISS.ILS congenics were tested for LDA at 1.8 g/kg of ethanol. Results There was little difference in the ethanol elimination rate between congenics and background strains, although a modest sex effect was found, with the females eliminating ethanol more rapidly than the males. We were unable to replicate previous differences found in LDA for the Lore1 congenic on the ISS background, because none of the congenics differed from controls for LDA. Lore5 congenics showed a differential effect of pentobarbital-induced LORR in the expected directions. The Lore1 congenics on the ISS background showed more ethanol-induced ataxia than the ISS controls. Additionally, the hypothermic response seems affected by Lore4 and Lore5 and maybe others. Conclusions At least two regions carrying a QTL specifying sensitivity to high doses of ethanol cospecify altered sensitivity in other measures of alcohol action. Specifically, these QTLs clearly affect ethanol-induced hypothermia and pentobarbital-induced LORR and possibly ethanol-induced ataxia. [source] | ||||||||||||||||