Elimination Rate Constant Research Articles

Long-Chain Perfluoroalkyl acids (PFAAs) Affect the Bioconcentration and Tissue Distribution of Short-Chain PFAAs in Zebrafish (Danio rerio).

Short- and long-chain perfluoroalkyl acids (PFAAs), ubiquitously coexisting in the environment, can be accumulated in organisms by binding with proteins and their binding affinities generally increase with their chain length. Therefore, we hypothesized that long-chain PFAAs will affect the bioconcentration of short-chain PFAAs in organisms. To testify this hypothesis, the bioconcentration and tissue distribution of five short-chain PFAAs (linear C-F = 3-6) were investigated in zebrafish in the absence and presence of six long-chain PFAAs (linear C-F = 7-11). The results showed that the concentrations of the short-chain PFAAs in zebrafish tissues increased with exposure time until steady states reached in the absence of long-chain PFAAs. However, in the presence of long-chain PFAAs, these short-chain PFAAs in tissues increased until peak values reached and then decreased until steady states, and the uptake and elimination rate constants of short-chain PFAAs declined in all tissues and their BCFss decreased by 24-89%. The inhibitive effect of long-chain PFAAs may be attributed to their competition for transporters and binding sites of proteins in zebrafish with short-chain PFAAs. These results suggest that the effect of long-chain PFAAs on the bioconcentration of short-chain PFAAs should be taken into account in assessing the ecological and environmental effects of short-chain PFAAs.

A method to determine pharmacokinetic parameters based on andante constant-rate intravenous infusion

On account of the disturbance from the distribution phase, the concentration-time curve of drugs cannot fully reflect the characteristics of elimination, and thus, it is difficult for present methods to obtain ideal pharmacokinetic parameters. This paper presents a method to determine pharmacokinetic parameters based on an andante constant-rate intravenous infusion. A mathematical model of the constant-rate intravenous infusion combined with the elimination of first-order kinetics was established. During infusion, the accumulation tendency of drugs was deduced as {C}_{t}={C}_{{0}}+({C}_{ss}-{C}_{{0}})cdot (1-{e}^{-Kt}) using the principle of calculus. Then, the method to determine the pharmacokinetic parameters was summed up. After collecting the blood drug concentration (Ct) -time (t) data from a constant-rate (v) infusion period, an exponential regression analysis was conducted to obtain the elimination rate constant (K) and plateau concentration (Css). Then, the half-life (t1/2), apparent volume of distribution (Vd) and clearance rate (CL) were calculated based on the equations, t1/2 = 0.693/K, Vd = (v/K)/Css and CL = v/Css, respectively. In addition, an application example of cimetidine in a beagle dog was used to demonstrate the implementation process of the method.

The effect of quercetin on the pharmacokinetics of chlorzoxazone, a CYP2E1 substrate, in healthy subjects.

Previous in vitro studies have demonstrated that quercetin inhibits CYP2E1 enzyme, but there are no available data to indicate that quercetin inhibits CYP2E1 enzyme in humans. The purpose of the present study was to assess the effect of quercetin on CYP2E1 enzyme activity in healthy subjects using chlorzoxazone (CHZ) as a CYP2E1 substrate. An open-label, two-period, sequential study was conducted in 12 healthy subjects. A single dose of CHZ 250mg was given to subjects during control phase and after treatment phases. Quercetin at a dose of 500mg was given to subjects twice daily for a period of 10days. The blood samples were collected at predetermined time intervals after CHZ dosing and analyzed to determine the concentrations of CHZ and 6-hydroxychlorzoxazone (6-OHCHZ). Treatment with quercetin significantly enhanced the maximum plasma concentration (C max), area under the curve (AUC), and half-life (t 1/2) by 47.8, 69.3, and 36.4%, respectively, while significantly decreased the elimination rate constant (k el) and apparent oral clearance (CL/F) of CHZ by 25.1 and 41.6%, respectively, in comparison with the control. On the other hand, C max and AUC of 6-OHCHZ were decreased by 30.1 and 32.6%, respectively, after quercetin treatment when compared to control. In addition, geometric mean ratios and 90% confidence intervals for C max and AUC of CHZ and 6-OHCHZ were both out of the no-effect boundaries of 0.80-1.25, which indicates a significant pharmacokinetic interaction present between CHZ and quercetin. Furthermore, treatment with quercetin significantly decreased the metabolic ratios of C max and AUC by 57.1 and 60.1%, respectively, as compared to control suggesting that reduced formation of CHZ to 6-OHCHZ. The results suggest that altered pharmacokinetics of CHZ might be attributed to quercetin-mediated inhibition of CYP2E1 enzyme. Further, the inhibition of CYP2E1 by quercetin may represent a novel therapeutic approach for minimizing the ethanol-induced CYP2E1 enzyme activity and results in reduced hepatotoxicity of ethanol.

Tools for the Individualized Therapy of Teicoplanin for Neonates and Children.

ABSTRACTThe aim of this study was to develop a population pharmacokinetic (PK) model for teicoplanin across childhood age ranges to be used as Bayesian prior information in the software constructed for individualized therapy. We developed a nonparametric population model fitted to PK data from neonates, infants, and older children. We then implemented this model in the BestDose multiple-model Bayesian adaptive control algorithm to show its clinical utility. It was used to predict the dosages required to achieve optimal teicoplanin predose targets (15 mg/liter) from day 3 of therapy. We performed individual simulations for an infant and a child from the original population, who provided early first dosing interval concentration-time data. An allometric model that used weight as a measure of size and that also incorporated renal function using the estimated glomerular filtration rate (eGFR), or the ratio of postnatal age (PNA) to serum creatinine concentration (SCr) for infants <3 months old, best described the data. The median population PK parameters were as follows: elimination rate constant (Ke) = 0.03 · (wt/70)−0.25 · Renal (h−1); V = 19.5 · (wt/70) (liters); Renal = eGFR0.07 (ml/min/1.73 m2), or Renal = PNA/SCr (μmol/liter). Increased teicoplanin dosages and alternative administration techniques (extended infusions and fractionated multiple dosing) were required in order to achieve the targets safely by day 3 in simulated cases. The software was able to predict individual measured concentrations and the dosages and administration techniques required to achieve the desired target concentrations early in therapy. Prospective evaluation is now needed in order to ensure that this individualized teicoplanin therapy approach is applicable in the clinical setting. (This study has been registered in the European Union Clinical Trials Register under EudraCT no. 2012-005738-12.)

Effect of fever on pharmacokinetics and disposition in biological fluids of minocycline in goats

Effect of fever on distribution, kinetic parameters and dosage regimen of minocycline in goats was studied. Concentrations of minocycline (5 mg.kg-1, i.v.) in plasma, milk, urine and interstitial fluid (ISF) were estimated in six afebrile and febrile goats by microbiological assay. Fever was induced by i.m. injection of lipopolysccharide of Eschreichia coli @ 0.20 mg.kg-1 i.m. which induced an in temperature of 1. 5 – 2.00F after 1 h of injection which was maintained for 8 h. Three injections of endotoxin were given during the period of study. Minocycline attained its mean peak concentration in milk, urine and interstitial fluid (ISF) earlier in febrile goats (0.75 h) than in afebrile goats (1 h). Kinetic parameters like absorption rate constant (a), elimination rate constant (b), elimination rate constant from central to peripheral compartment (K12), elimination rate constant from peripheral to central constant (K21) and elimination rate constant from central compartment (Kel) were higher in febrile goats as compared to afebrile goats. Dosage regimen in goat, particularly in febrile condition was calculated so that it may be a guideline for physicians to treat the animals. Loading dose and maintenance doses were dependent on â and hence, for maintaining mean therapeutic level of 0.5ìg/ml in plasma, a loading dose (D*) of 6.9 mg/kg and maintenance dose (D0) of 4.7 mg/kg at dosage interval (g) of 12 h may be used in afebrile goats whereas higher doses of D* of 7.8 mg/kg followed by D0 of 6.1 mg/kg at g of 12 h may be administered in febrile goats.

A pharmacokinetic study of diclofenac sodium in rats.

The aim of the present study was to examine the pharmacokinetics of a single intravenous injection (i.v.) and oral administration (p.o.) of diclofenac sodium (DIC) in Sprague-Dawley (SD) rats. Twelve male SD rats were divided into 2 groups (n=6 per group); one group was injected intravenously with 2 mg/kg DIC, whereas the other group was lavaged with 2 mg/kg DIC. Blood samples were collected prior to DIC delivery (0 h) and 0.033, 0.083, 0.167, 0.25, 0.5, 1, 2, 4, 6, and 8 h post-administration. Blood plasma samples were analyzed using liquid chromatography-mass spectrometry (LC-MS/MS) following pretreatment to induce protein precipitation. Pharmacokinetics software was applied to calculate relevant pharmacokinetic parameters using a non-compartmental model. Following i.v. administration of DIC, the terminal elimination rate constant (λz), apparent terminal elimination half-life (t½), area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞), clearance (CL), apparent volume of distribution (Vz), mean residence time (MRT), and apparent volume of distribution at steady state (Vss) were 0.57±0.05 l/h, 1.22±0.11 h, 3356±238 h × ng/ml, 0.60±0.04 l/h, 1.05±0.10 l, 1.05±0.07 h and 0.63±0.07 l, respectively. Following p.o. administration of DIC, the λz, t½, Cmax, tmax, AUC0-∞, CL, Vz, MRT were: 0.63±0.12 l/h, 1.12±0.18 h, 1272±112 ng/ml, 0.19±0.04 h, 2501±303 h × ng/ml, 0.81±0.10 l/h, 1.29±0.12 l, and 2.70±0.18 h, respectively. The pharmacokinetic parameters of i.v. and p.o. DIC in rats show that the drug is rapidly absorbed, distributed, and eliminated.

Numerical investigation of flow pattern and hydrodynamic forces of submerged marine propellers using unsteady boundary element method

In this study, a numerical model of unsteady potential flow around submerged marine propellers has been developed. The boundary element approach in combination with time stepping method to model free wake dynamics has been implemented. An important feature of this method in the simulation of pressure-dominant problems is a proper balance between time and accuracy in the numerical process. Another advantage of time stepping method is that there is no need to define wake geometry before modeling. Due to inherent instability of boundary integral equations, a smoothing function to damp the effect of singularities is imposed to the solution. The main innovative idea of this work is that the effect of this mollifier function with different constants for elimination of singularity in mean induced velocity equation has been investigated. The mathematical formulation and implementation of numerical algorithm followed by a number of test cases to verify the model are presented. The results indicate good agreements between model and experiments.

Abstract 5052: Mechanistic pharmacodynamic analysis on safety profiles of eribulin in patients with breast cancer using data obtained by post-marketing observational study

Abstract Background: Japanese regulation imposes a mandatory post-marketing observational cohort study for new chemical entities and biological products. The primary purpose is collection of safety data in actual clinical settings by an active surveillance approach. In this study, we utilized the observational safety data of eribulin for model-based pharmacodynamic analysis to investigate more detailed safety profile of eribulin in patients with recurrent or metastatic breast cancer (RBC/MBC). Methods: The demographics and safety data were collected from RBC/MBC patients who were treated with eribulin by an active surveillance method. Since dose-limiting toxicity of eribulin is neutropenia, we analyzed the time course of neutrophil counts using a mechanistic pharmacodynamic model. Plasma concentrations of eribulin were simulated by a population pharmacokinetic model developed by Majid et al. (J. Clin. Pharmacol. 2014). All analyses were performed by Phoenix64 NLME1.3 (Certara). Estimated pharmacodynamic parameters were mean transit time (MTT [h]), proliferation rate constant of neutrophils (Kprol [1/h]), elimination rate constant of neutrophils (Kout [1/h]), feedback constant (Gamma) and linear coefficient of drug effect (Slope [mL/ng]). Results: Clinical and laboratory data of 607 patients who were not given granulocyte colony stimulating factor were collected from July through December 2011. Among them, 406 patients with a total of 5204 neutrophil count measurements were eligible for mechanistic pharmacodynamic analysis. The estimated mean parameters for eribulin were: MTT=45.4 [h], Kprol=0.1111 [1/h], Kout=0.2074 [1/h], Gamma=0.317 and Slope=0.0254 [mL/ng]. Pathophysiological factors (age, ECOG performance status, serum albumin level, and previous treatment history of cytotoxic agents) that can affect severity of neutropenia were investigated by Chi-squared test, and albumin level was supposed to influence the proliferation of progenitor cells. Conclusions: The present study reports the first example that observational data collected by a post-marketing cohort study can be successfully applied to a model-based safety analysis. Different from pre-marketing clinical trials which strictly limit the eligible population, the use of post-marketing data is useful to investigate extensive safety profiles of eribulin in patients with broader backgrounds. The obtained safety profile of real-world clinical settings will provide clinically useful information for the treatment of breast cancer using eribulin. Citation Format: Takahisa Kawamura, Valentina Fermanelli, Toshiaki Takahashi, Yukinori Sakata, Toshiyuki Matsuoka, Mika Ishii, Yusuke Tanigawara. Mechanistic pharmacodynamic analysis on safety profiles of eribulin in patients with breast cancer using data obtained by post-marketing observational study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5052. doi:10.1158/1538-7445.AM2017-5052

A Mechanism-Based PK/PD Model for Hematological Toxicities Induced by Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia. Murine xenograft experiments and data from literature were combined, and the PK of both ADCs and their analytes were described with two-compartment models, with linear elimination and first-order payload release rate constants (k rel). ADC-associated hematotoxicities were captured with a previously published PD model for myelosuppression driven by various analytes. ADC half-lives were about 5days, and k rel values were 0.46 (T-DM1) and 0.12h-1 (SGN-35). The lifespans of platelets following T-DM1 and neutrophils following SGN-35 were 3.73 and 4.72days. Comparison of alternate model structures suggested that mechanisms of myelosuppression are payload-driven for SGN-35 and ADC pinocytosis-dependent for T-DM1. Model simulations suggested that a 4-fold increase (T-DM1) and 70% decrease (SGN-35) in k rel would improve hematotoxicity to grade 1. The proposed model successfully captured the PK and associated myelosuppression of both ADCs and might serve as a general PK/PD platform for assessing hematological toxicities to ADCs.

Theranostic carbon dots ‘clathrate-like’ nanostructures for targeted photo-chemotherapy and bioimaging of cancer

Abstract The drug delivery application of carbon-based quantum dots is a new platform in the medical field. We report a unique morphological structure called carbon-dots clathrates (C-dots CL ) conjugated with folic acid (FA) for targeted delivery of methotrexate (MTX), an anti-cancer drug under physiological conditions followed by photothermal (PTT) and photodynamic (PDT) treatment on cancer cells. Under physiological milieu, the C-dots CL –MTX–FA complex are pH-dependent and it can control release the anti-cancer drug in vitro . Furthermore, in vivo studies were also performed by using genetically-induced pancreatic cancer model to comprehend the in vivo pharmacokinetics and tissue distribution pattern of C-dots CL –MTX–FA complex. The results demonstrated that the CQD was able to deliver high concentration of MTX in tumour tissues in contrast to the non-tumour tissues. The impact of near-infrared (NIR) laser (1064 nm; Nd-YAG) on the CQDs system was found to be extremely effective for the rapid release of MTX in tumour tissues. The generation of reactive oxygen species (ROS) by C-dots CL upon irradiation of NIR laser was evaluated using flow cytometry. After conjugation with the C-dots CL , the half-life of the MTX drug (t 1/2 ), elimination constant (K el ), area under the curve (AUC) was drastically improved to prove the efficacy of C-dot CL as a powerful drug vehicle. This study has significantly improved the cancer theranostics research using C-dots CL to act as a multi-functional nanomaterial for imaging and as a drug delivery agent.

Bioaccumulation of pharmaceutically active compounds and endocrine disrupting chemicals in aquatic macrophytes: Results of hydroponic experiments with Echinodorus horemanii and Eichhornia crassipes

Information regarding the bioaccumulation behaviour of pharmaceutically active compounds (PhACs) and endocrine disrupting chemicals (EDCs) in aquatic plants is limited. The present study involved controlled hydroponic experiments to assess uptake and elimination rate constants (ku, ke), bioconcentration factors (BCFs) and translocation factors (TFs) of several PhACs and EDCs in two aquatic macrophyte species, including one submerged species (Echinodorus horemanii) and one free-floating species (Eichhornia crassipes). The results revealed that the studied compounds are readily taken up in these aquatic plants. While bioconcentration factors (BCFs) and translocation factors (TFs) of the test compounds varied substantially, no discernible relationship with physicochemical properties such as octanol-water distribution coefficient (Dow), membrane-water distribution coefficient (Dmw) and organic carbon-water partition coefficient (Koc). Diphenhydramine and triclosan exhibited the highest degree of uptake and bioaccumulation potential. For example, the whole-plant BCF of triclosan in E. horemanii was 4390L/kg, while the whole-plant BCF of diphenhydramine in E. crassipes was 6130L/kg. BCFs of 17β-estradiol (E2), 17α-ethinylestradiol (EE2), estrone (E1) and bisphenol A (BPA) were relatively low (2–150L/kg). BCFs were generally higher in free-floating aquatic macrophyte species compared to the submerged species. For the free-floating species, E. crassipes, the majority of PhACs and EDCs were more allocated in roots compared to leaves, with TFs<1. However, some compounds such as caffeine, atrazine, diphenhydramine, E2 and carbamazepine were more allocated in leaf tissue (TFs>1). The study findings may be useful for design and implementation of phytoremediation systems, as well as aid future modeling and risk assessment initiatives for these emerging organic contaminants.

Arterial Pressure and the Rate of Elimination of Crystalloid Fluid.

Excretion of crystalloid fluid is slow during general anesthesia. The distribution and elimination of buffered Ringer's solution were analyzed to determine whether the rate of elimination correlates with a hemodynamic factor, consciousness, patient posture, or the type of general anesthesia. Data were derived from 4 separately published studies in which 30 volunteers and 48 anesthetized patients had received 0.833 (1 series 0.667) mL/kg/min of lactated or acetated Ringer's solution over 30 minutes. Frequent measurements of the blood hemoglobin and mean urinary excretion were used as input in a kinetic analysis according to a 2-volume model and covariates, using microconstants and mixed-effects modeling software.The results show that rate of elimination of crystalloid fluid decreased with the mean arterial pressure (MAP) and patient age, but was unaffected by consciousness and inhalational or intravenous anesthesia. The elimination rate constant was 6.5 (95% confidence interval, 5.2-7.9) × 10 × (MAP/mean MAP) × (Age/mean Age). The mean MAP for the 2108 data points was 81.3 mm Hg and the mean age was 40 years. The central fluid space that was expanded by infused fluid (Vc, plasma volume) increased with body weight but decreased with general anesthesia and with reductions of MAP.Simulations revealed a more than 10-fold difference in the excreted fluid volume after a theoretical 30-minute infusion, depending on whether the MAP was 50 or 100 mm Hg.In conclusion, the rate of elimination of crystalloid fluid decreased in proportion to MAP but was independent of general anesthesia and moderate-sized surgery.

Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations

The present study considered the pharmacokinetic evaluation of empagliflozin after administration to Egyptian volunteers, and the results were compared with other ethnic populations. The FDA recognizes that standard methods of defining racial subgroups are necessary to compare results across pharmacokinetic studies and to assess potential subgroup differences. The design of the study was as an open labeled, randomized, one treatment, one period, single dose pharmacokinetic study. The main pharmacokinetic parameters estimated were Cmax, Tmax, t1/2, elimination rate constant, AUC0-t and AUC0-inf. The insignificant difference in pharmacokinetic parameters between Egyptians and white German subjects suggests that no dose adjustment should be considered with administration of 25 mg empagliflozin to Egyptian population. A new LC-MS/MS method was developed and validated, allowing sensitive estimation of empagliflozin (25–600 ng mL−1) in human plasma using dapagliflozin as an internal standard (IS). The method was applied successfully on the underlying pharmacokinetic study with enhanced sample preparation that involved liquid-liquid extraction. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 449.01 to 371.21 for empagliflozin and m/z 407.00 to 328.81 for dapagliflozin (IS) was employed utilizing negative mode Electro Spray Ionization (ESI). The validated LC-MS/MS method is suitable for further toxicodynamic and bioequivalence studies.

Kinetic simulation method of C-reactive protein in beagle dogs during acute inflammation

The half-life ( t1/2) of C-reactive protein (CRP) and its ability to stimulate weak inflammatory responses were investigated in beagle dogs. Four beagle dogs were administered 20 mg/kg indomethacin and blood was collected from the cephalic vein pre-dosing and at 24, 48, 72, 96, 144, 192, 240, 312, and 360 h post-administration. The serum concentrations of CRP were measured by enzyme-linked immunosorbent assay. The serum t1/2 was calculated using the equation 0.693/elimination rate constant. The serum concentration of CRP beyond 192 h post-administration declined to levels in the normal range. The t1/2 was 148.3 h, which is considered to be the essential t1/2 of CRP. The simulation of CRP serum concentrations at arbitrary times using the elimination rate constant obtained in this study became possible.

A new TK model approach to assess the effect of migration on copper toxicokinetics in inbred populations of the flour beetle, Tribolium castaneum

The aim of the study was to determine the influence of migration on copper (Cu) kinetics of male Tribolium castaneum after 25 generations of exposure for Cu-adapted and non-Cu-adapted inbred lines. Adapted lines were kept on a flour medium contaminated with 1000 mg Cu kg−1. A medium contaminated with 2000 mg Cu kg−1 of copper was used during the intoxication phase. Based on our data and literature reports, we introduced a new two-phase four-stage toxicokinetics (TK) model. The intoxication phase was successfully divided into three stages with separate assimilation rate constant (ka) and elimination rate constant (ke) values. The influence of migration was examined by comparing ka and ke parameters confidence intervals. In non-contaminated environments, migrants significantly increased ka and ke values in the second stage. Migrants decreased the maximum Cu accumulation observed in the experiment. The results indicated that the TK model must show high goodness-of-fit to be a useful tool for comparing treatments.

Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients.

Rituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients. In a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis. A two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7l and 0.56lday-1 , respectively. Distribution and elimination half-lives were 0.9days and 17.3days, respectively. As expected, the central volume of distribution increased with body surface area (P=0.012) and was higher in male than in female (P=0.004). We found that the elimination rate constant (k10 ) increased with CD19+ count (P=0.00022) and IgG concentration (P=7.4 × 10-8 ), and that k10 decreased with time (P=0.00015), partly explained by a change in target-antigen amount. The association between CD19+ count and k10 may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k10 may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab.

Relationship between metabolic enzyme activities and bioaccumulation kinetics of PAHs in zebrafish (Danio rerio)

Many studies have investigated bioaccumulation and metabolism of polycyclic aromatic hydrocarbons (PAHs) in aquatic organisms. However, lack of studies investigated both processes simultaneously, and the interaction between these two processes is less understood so far. This study investigated the bioaccumulation kinetics of PAHs and metabolic enzyme activities, including total cytochrome P450 (CYPs) and total superoxide dismutase (T-SOD), in zebrafish. Mature zebrafish were exposed to the mixture of phenanthrene and anthracene under constant concentration maintained by passive dosing systems for 16days. The results showed that PAH concentrations in zebrafish experienced a peak value after exposure for 1.5days, and then decreased gradually. The bioaccumulation equilibrium was achieved after exposure for 12days. Both of the uptake rate constants (ku) and the elimination rate constants (ke) decreased after the peak value. The variation of PAH concentrations and metabolic enzyme activities in zebrafish had an interactive relationship. The activities of CYPs and T-SOD increased initially with the increase of PAH concentrations, but decreased to the lowest state when PAH concentrations reached the peak value. When the bioaccumulation equilibrium of PAHs was achieved, CYPs and T-SOD activities also reached the steady state. In general, CYPs and T-SOD activities were activated after exposure to PAHs. The decrease of PAH concentrations in zebrafish after the peak value may be attributed to the great drop of ku and the variation of CYPs activities. This study suggests that an interactive relationship exists between bioaccumulation kinetics of PAHs and metabolic enzyme activities in aquatic organisms.

Uptake and elimination kinetics of perfluoroalkyl substances in submerged and free-floating aquatic macrophytes: Results of mesocosm experiments with Echinodorus horemanii and Eichhornia crassipes

Studies investigating the bioaccumulation behavior of perfluoroalkyl substances (PFASs) in aquatic macrophytes are limited. The present study involved controlled mesocosm experiments to assess uptake and elimination rate constants (ku,ke), bioconcentration factors (BCFs) and translocation factors (TFs) of several perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkane sulfonic acids (PFSAs) in two aquatic plant species, including one submerged species (Echinodorus horemanii) and one free-floating species (Eichhornia crassipes). The results indicated all PFASs were readily accumulated in these aquatic macrophytes. ku and BCFs increased with increasing perfluoroalkyl chain length. For PFCAs and PFSAs with identical perfluoroalkyl chain length, the corresponding PFSA exhibited higher bioaccumulation potential. On a whole-plant basis, the bioaccumulation potential of PFASs in submerged and free-floating macrophytes were comparable, indicating sorption to plant biomass is similar in the different species. Conversely, when considering accumulation in foliage, BCFs in the free-floating macrophyte were substantially lower compared to submerged species, especially for longer-chain PFASs. Compounds with shorter perfluoroalkyl chain length (PFBS, PFPeA and PFHxA) exhibited preferential translocation to leaf tissue (TFs >1). BCFs exhibited a sigmoidal relationship with pefluoroalkyl chain length, membrane-water distribution coefficients (Dmw), protein-water distribution coefficients (Dpw) and organic-water partition coefficients (Koc). For these trends, maximum BCF values were exhibited by long-chain PFCAs, with a log Dmw, log Dpw and log Koc of 6.47, 5.72 and 5.04, respectively. These findings are useful for future design and implementation of phytoremediation systems, as well for future develop of mechanistic models for predicting the environmental fate and distribution of these contaminants of concern.

Quantification of Etodolac in Human Plasma for Pharmacokinetics and Bioequivalence Studies in 27 Korean Subjects.

We developed a simple and validated liquid chromatography tandem mass spectrometry( LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects. Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288.2→ 172.3 and m/z 357.1→ 134.2 for quantification of etodolac and IS each. The standard calibration curves displayed significant linearity within the range of 0.2-30.0 μ g/mL (r2=0.9956, 1/x2 weighting) with LLOQ of 0.1 μg/mL. The retention times of etodolac and the IS were 0.77 min and 0.57 min each, indicating the high-throughput potential of the proposed method. The pharmacokinetic parameters were calculated from the plasma samples and data form the reference and test drugs were represented as follows; Area under plasma concentration-time curve (AUCt) (78.03 vs. 84.00 μgxh/mL), AUC∞ (86.67 vs. 93.92 μgxh/mL), maximal plasma concentration (Cmax) (19.49 vs. 18.94 μg/mL), time for maximal concentrations (Tmax) (2.13 vs. 2.26 h), Plasma elimination half-life (T1/2) (8.12 vs. 8.47 h), elimination rate constant (λz) (0.0853 vs. 0.0818 h-1). Pharmacokinetic parameters with 90% confidence interval fall within the bioequivalence range of 80-125%. Thus, the new testified method was successfully applied for the pharmacokinetic and bioequivalence studies for two etodolac formulations.

Individual peculiarities in pharmacokinetics of antiblastomic drugs in healthy volunteers

The data of inter-individual variations in pharmacokinetics of antiblastomic drugs from the group of tyrosine proteinkinase inhibitors (imatinib, gefitinib and nilotinib) and antiblastomic immune modulator lenalidomide in healthy volunteers by meams of HPLC-MS/MS were represented in the article. The concentrations of the drugs studied were measured in the volunteer blood serum. The indeces Cmax (maximal concentration and time reaching), Tmax (time covering maximal concentration measure), AUC0-t (squire under pharmaceutical curve) were processed by trapetias method, Cmax/AUC0-t as well as Kel (elimination constant) and T1/2 (period of semielimination) according to individual signs. The significant individual variability revealed for imatinib, gefitinib and nilotinib in healthy volunteers indicates on necessity of therapeutic drug monitoring in patients treated with them to aim optimal dosing.