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Elimination Rate Constant (elimination + rate_constant)
Selected AbstractsEffects of altered plasma ,-1-acid glycoprotein levels on pharmacokinetics of some basic antibiotics in pigs: simulation analysisJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2001M. Kuroha Effects of altered plasma , -1-acid glycoprotein (AGP) levels on pharmacokinetic parameters of basic antimicrobials, erythromycin (EM), lincomycin (LM) and clindamycin (CM) were evaluated in pigs by simulation analysis. Intravenous (i.v.) injections of EM, LM and CM were performed to obtain pharmacokinetic parameters in healthy conditions. Binding parameters were obtained from an in vitro study using ultrafiltration. Simulation studies indicated that an increase of plasma AGP levels resulted in a decrease of both volume of distribution at steady state (Vdss) and total body clearance (Cltot) for all the drugs. Elimination rate constant for LM was almost unchanged by an increase of plasma AGP levels, whereas those for EM and CM were increased. Plasma concentration,time profiles at a high AGP level (often observed in pathophysiological conditions) were also simulated. All of the total plasma concentration,time profiles were different from those at normal AGP level. The differences were characterized by a higher initial concentration with faster or similar elimination. Unbound plasma concentration,time profile of LM was unaffected by AGP levels, whereas EM and CM were eliminated from plasma more rapidly at high AGP level. These results suggested that adjustment of dosage regimen of EM and CM is required in pathophysiological conditions, but that of LM is not required. [source] Estimating metabolic biotransformation rates in fish from laboratory dataENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2008Jon A. Arnot Abstract A method is proposed for estimating metabolic biotransformation rate constants for nonionic organic chemicals from measured laboratory bioconcentration and dietary bioaccumulation data in fish. Data have been selected based on a quality review to reduce uncertainty in the measured values. A kinetic mass balance model is used to estimate rates of chemical uptake and elimination. Biotransformation rate constants are essentially calculated as the difference between two quantities, a measured bio-concentration factor or elimination rate constant, and a model-derived bioconcentration factor or elimination rate constant estimated assuming no biotransformation. Model parameterization exploits key empirical data when they are available and assumes default values when study specific data are unavailable. Uncertainty analyses provide screening level assessments for confidence in the biotransformation rate constant estimates. The uncertainty analyses include the range for 95% of the predicted values and 95% confidence intervals for the calculated biotransformation values. Case studies are provided to illustrate the calculation and uncertainty methods. Biotransformation rate constants calculated by the proposed method are compared with other published estimates for 31 chemicals that range in octanol,water partition coefficients from approximately 101 to 108 and represent over four orders of magnitude in biotransformation potential. The comparison of previously published values with those calculated by the proposed method shows general agreement with 82% of the estimated values falling within a factor of three. [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] 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] 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] Pharmacokinetic characterization of 14C-vascular endothelial growth factor controlled release microspheres using a rat modelJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2002Tae-Kyoung Kim The objectives of this study were to characterize the pharmacokinetics of vascular endothelial growth factor (VEGF) in poly(lactic-co-glycolic) acid (PLGA) microspheres using a rat model, and to develop a pharmacokinetic model for this controlled release formulation. 14C-VEGF was encapsulated using a solid-in-oil-in-water emulsification method. The microspheres were administered subcutaneously to rats and the pharmacokinetic parameters were compared with those of protein solutions. Intravenous administration of protein solutions resulted in short half-lives and subcutaneous administration resulted in rapid clearance from the subcutaneous tissue, with high plasma concentrations as expressed by rapid absorption and elimination. The subcutaneous administration of the VEGF microspheres produced low plasma concentrations and high subcutaneous concentrations over a period of 7 weeks. The area under the curve (AUC), the time required to achieve the maximum concentration (tmax), the maximum concentration (Cmax) in blood samples and the elimination rate constant (kel) values at the subcutaneous tissue site were selected to compare the pharmacokinetic characterization of VEGF microspheres with that of protein solutions. The in-vivo release profiles of the proteins were slower than the in-vitro release profiles and they followed the same trend as the in-vitro and in-vivo PLGA degradation rates. The PLGA microsphere degradation was the determinant step for VEGF release from the microspheres and its absorption at the subcutaneous site. Microspheres appear to be an attractive system for the localized rate-controlled delivery of VEGF. 14C-Methylation via reductive alkylation of VEGF did not affect its mitogenic activity, however approximately 25% activity was lost following release from PLGA microspheres. This loss of activity may be due to degradation in an acidic environment as a result of PLGA degradation. [source] Controlled Transdermal Delivery of Propranolol Using HPMC Matrices: Design and In-vitro and In-vivo EvaluationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2000P. R. P. VERMA To improve bioavailability and achieve a smoother plasma-concentration profile as compared with oral administration, a matrix-dispersion-type transdermal delivery system was designed and developed for propranolol using different ratios of hydroxypropyl-methylcellulose (HPMC) K4M, K15M and K100M. Formulations were evaluated for in-vitro dissolution characteristics using a Cygnus' sandwich-patch holder. Drug release followed Higuchi rather than zero-order or first-order kinetics. In-vivo evaluation was carried out on healthy volunteers (21 ± 1.41 years; 60.89 ± 5.35 kg) following the balanced incomplete block design. The dissolution rate constant (k) and data generated from plasma and urine (Cmax, maximum plasma concentration; tmax, time to reach peak plasma concentration; AUC, area under the curve; ke, elimination rate constant; t½e, elimination half-life; ka, absorption rate constant; t½a, absorption half-life) were evaluated statistically by two-way analysis of variance. Statistically excellent correlation was found between the percentage of drug absorbed and Cmax, AUC0,24 and AUC0-,. A highly significant difference (P < 0.001) was observed when Cmax and AUC0-, generated from plasma and urine were compared, but ke, t½e, ka and t½a did not differ significantly (P > 0.1). We conclude that urinary excretion data may be used as a simpler alternative to blood level data in studying the kinetics of absorption and deriving the absorption parameters. [source] KICG value, a reliable real-time estimator of graft function, accurately predicts outcomes in adult living-donor liver transplantation,LIVER TRANSPLANTATION, Issue 4 2006Tomohide Hori Reliable monitoring enabling evaluation of graft function is crucial after living-donor liver transplantation (LDLT). A method to identify poor graft function at an early postoperative period would allow opportune intensive clinical management to bring about further improvements in LDLT outcomes. This study assessed the reliability of the indocyanine green (ICG) elimination rate constant (KICG) value as an estimator of graft function and determined the actual temporal changes of KICG after LDLT. KICG values were measured using a noninvasive method in 30 adult recipients up to 28 days after LDLT. The receptor index (LHL15) based on liver scintigraphy, and graft parenchymal damage score based on histopathological findings were evaluated after LDLT and correlated well with simultaneous KICG. Thus, KICG measured by noninvasive method was confirmed as accurately evaluating graft function. Changes of KICG after LDLT in recipients with good graft function were maintained, after some falls in the early periods, and had a significant difference compared with those for recipients without good graft function; moreover, there were already significant differences in KICG 24 hours after LDLT. Mean transit time reflecting systemic hemodynamics revealed that recipients without good outcomes fell into an unstable systemic hemodynamic state, and effective hepatic blood flow has a large influence on liver regeneration after LDLT. In conclusion, we suggested that KICG values can predict clinical outcomes at the early postoperative period after LDLT by sharply reflecting the influence of systemic dynamics on splanchnic circulation. Liver Transpl 12:605,613, 2006. © 2006 AASLD. [source] Liquid chromatographic/mass spectrometric assay of rabprazole in dog plasma for a pharmacokinetic studyBIOMEDICAL CHROMATOGRAPHY, Issue 11 2006Shao Feng Abstract In order to evaluate the pharmacokinetic (PK) profile of rabeprazole (RA) sterile powder for injection, a rapid, sensitive and specific assay for quantitative determination of RA in dog plasma was developed and validated. After a liquid,liquid extraction procedure, samples were analyzed by liquid chromatography,electrospray ionization mass spectrometry (LC-ESI-MS) using omepazole as the internal standard (IS). The analyte and IS was chromatographed on a ZORBAX Extend-C18 analytical column (50 × 2 mm i.d, 5 µm, Agilent Technologies, USA). The assay was linear in the range 1,2000 ng/mL. The lower limit of quantification of RA was 1 ng/mL. The recovery of RA was greater than 70%. The within- and between-batch accuracy was 102.7,107.4% and 103.5,105.7%, respectively. The plasma samples for the PK study were collected at defined time points during and after an intravenous injection (1 mg/kg) to beagle dogs and analyzed by LC-ESI-MS method. The PK parameters, such as half-life, volume of distribution, total clearance and elimination rate constant, were determined. The PK profile of RA gave insights into the application in the clinics. Copyright © 2006 John Wiley & Sons, Ltd. [source] Bioequivalence evaluation of two brands of furosemide 40mg tablets (Salurin and Lasix) in healthy human volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2003Naji Najib Abstract A randomized, two-way, crossover, bioequivalence study was conducted in 24 fasting, healthy, male volunteers to compare two brands of furosemide 40 mg tablets, Salurin (Julphar, UAE) as test and Lasix (Hoechst AG, Germany) as reference product. The study was performed at the International Pharmaceutical Research Centre (IPRC), in a joint venture with Al-Mowasah Hospital, Amman, Jordan. One tablet of either formulation was administered with 240 ml of water after a 10 h overnight fast. After dosing, serial blood samples were collected for a period of 12 h. Plasma harvested from blood was analysed for furosemide by a validated HPLC method. Various pharmacokinetic parameters including AUC0,t, AUC0,,, Cmax, Tmax, T1/2, and elimination rate constant were determined from plasma concentrations of both formulations. Statistical modules (ANOVA and 90% confidence intervals) were applied to AUC0,t, AUC0,,, and Cmax to assess the bioequivalence of the two brands which revealed no significant difference between them, and 90% CI fell within the US FDA accepted bioequivalence range of 80%,125%. Based on these statistical inferences, Salurin was found to be bioequivalent to Lasix. Copyright © 2003 John Wiley & Sons, Ltd. [source] Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1,2 studyBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2010Bertrand Coiffier Summary The purpose of this phase 1,2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumumab concentration profiles were fitted well by a two-compartment model with different elimination rate constant at first infusion compared to the remaining infusions in line with the observed rapid and sustained B-cell depletion. Exposure to ofatumumab was linked to clinical outcomes: high exposure was associated with higher probability of overall clinical response and longer progression-free survival. This association still remained statistically significant even when adjusting for relevant baseline covariates including tumour burden. The trial was registered at http://www.clinicaltrials.gov (NCT00093314). [source] Lornoxicam pharmacokinetics in the vitreous humor of albino rabbitsACTA OPHTHALMOLOGICA, Issue 2009C TSIKA Purpose To assess the elimination half-life of intravitreal lornoxicam, a non-steroidal anti-inflammatory drug (NSAID). Methods Both eyes of 15 rabbits were intravitreally injected with 250 ,g of commercially available lornoxicam (for intravenous/intramuscular use, Xefo® 8 IV/IM Injection, Nycomed Hellas S.A.). Six eyes were enucleated at time points 0, 1, 2, 6 and 24 hours after the injection was performed. The eyes were immediately frozen at -80°C. The vitreous was eviscerated from the eye and the drug was liquid-liquid extracted from a 0.4 ml sample. Lornoxicam was isolated by a reversed-phase High Performance Liquid Chromatography (HPLC) method at retention time 10.7 min and detected at 372 nm. The data were statistically analyzed in order to evaluate the pharmacokinetic parameters of the drug. Results The recovery of lornoxicam after liquid-liquid extraction was calculated at 69.6% and the limit of determination was 0.1 ,g/ml. Statistical analysis revealed that lornoxicam concentrations followed first-order kinetics with an elimination rate constant of 0.235h-1 and a half-life of 3.0 h. Conclusion The determination of the pharmacokinetic characteristics of intravitreal lornoxicam allows the possibility for further investigation of the drug's intraocular behaviour and therapeutic potential. [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] Accumulation of 137Cs by larvae of the midge Chironomus riparius from sediment: Effect of potassiumENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2003Lieven Bervoets Abstract We studied the effect of potassium on the uptake of radiocesium from sediment by larvae of the midge Chironomus riparius. Sediment ingestion rate was determined for one week. After 24 h the gut content remained constant, indicating that equilibrium was reached between sediment ingestion and sediment elimination. These data were used to account for radiocesium present in the gut in subsequent uptake experiments. Reference sediment was equilibrated with solutions containing different concentrations of potassium: 1, 10, 100, and 1,000 ,M. Adsorption of 137Cs to the sediment was investigated. Three different radiocesium levels (0.3, 0.6, and 1.2 KBq/ml) were applied at the four different potassium levels. In all cases more than 94% of all radiocesium was adsorbed to the sediment within 48 h. The sediment, equilibrated with the four different potassium levels, was spiked with a constant amount of 296 Bq/ml 137Cs. Accumulation by midge larvae was followed for one week, and subsequently elimination was followed for another week. No significant differences in radiocesium levels in midge larvae among the treatments were found after one week of exposure. However, using a one-compartment accumulation model, a small but significant effect of potassium in water and sediment on the uptake and elimination rate constants (ka and ke) was found. These results indicate that although differences were rather small, radiocesium accumulation decreased with increasing potassium level in the sediment. [source] Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17,-glucuronide and 2,4-dinitrophenyl- S -glutathione across the blood,cerebrospinal fluid barrier?JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2004Young-Joo Lee Abstract The purpose of this study was to examine the role of multidrug resistance-associated protein-1 and -2 (Mrp1 and Mrp2) in the efflux transport of organic anions across the blood,cerebrospinal fluid (CSF) barrier. The CSF concentration of estradiol-17,-glucuronide (E217,G) and 2,4-dinitrophenyl- S -glutathione (DNP-SG) in the CSF after intracerebroventricular and intravenous injection were compared between wild-type and Mrp1 gene knockout mice. There was no significant difference in the apparent CSF elimination rate constants of E217,G (0.158 and 0.145 min,1) and DNP-SG (0.116 and 0.0779 min,1) between wild-type and Mrp1 knockout mice, respectively. After intravenous administration of E217,G, its brain-to-serum and CSF-to-serum concentration ratios in Mrp1 knockout mice were not significantly different from those in the wild-type. Results from in vivo and in vitro studies using Eisai hyperbilirubinemic rats, in which Mrp2 is hereditarily deficient, were similar to those using normal rats. Quantitative polymerase chain reaction (PCR) showed that the expression level of Mrp4 and Mrp5 was several times higher than that of Mrp1, whereas the expression levels of Mrp2, Mrp3, and Mrp6 were negligible or low. Therefore, Mrp4 and Mrp5 may contribute to the efflux transport of E217,G and DNP- SG from the CSF. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:99,107, 2004 [source] | |||||||||||||