Elimination Rate Constant Research Articles

607. Establishing Pharmacokinetic Profile of β -lactams in Critically Ill Patients on Continuous Sustained Low-efficiency Dialysis (C-SLED)

Abstract Background Critically ill patients have altered pharmacokinetic (PK) due to severity of illness and multi-organ failure. The lack of pharmacokinetic and pharmacodynamic data in Continuous Sustained Low-efficiency Dialysis (C-SLED) further perpetuates the uncertainty of efficacy with current antimicrobial dosing strategies. The objective of this study is to evaluate patient-specific PK of various β-lactams antibiotics in critically ill patients on C-SLED to assess if the current dosing strategy leads to therapeutic drug levels. Methods This prospective observational cohort study was performed at an academic medical center from November 2021 to June 2022. It included patients age > 18 years and on β-lactam antibiotics while on C-SLED. Therapeutic drug monitoring (TDM) was performed by checking two levels (peak and trough). These levels were used to calculate patient-specific elimination rate constant (k), half-life, and the fraction of time above MIC (fT>MIC). Other data collected included demographics, β-lactam regimens, source of infection, microbiology data, mortality on days 7 and 30, and length of stay. Descriptive statistics were used for data analysis. Results There were 11 patients included in the study with a median age of 55 and 82% (n = 9) of patients were male. β-lactam daily regimen was dosed as creatinine clearance (CrCl) > 50mL/min in 71.4% of patients (n = 10), CrCl 30-50 mL/min in 28.5% (n = 4), and < 30mL/min in 0% of patients. An extended infusion dosing strategy was used in 35.6% of patients (n = 5). The therapeutic drug target (50%fT > MIC for penicillins, 60%fT > MIC for cephalosporins, 40%fT > MIC for carbapenems) was achieved in 100% (n=14) of patients. Dose adjustment was not needed in all 14 cases. However, 100%fT > MIC was only achieved in 64% (n=9) patients. The median hospital length of stay was 60 days. Mortality on days 7 and 30 was 9% (n=1) and 27% (n=3), respectively. Conclusion Preliminary analysis shows that β-lactam daily dose based on CrCl of >30mL/min leads to therapeutic drug levels in patients on C-SLED. Disclosures All Authors: No reported disclosures.

Hemodialysis as emergency treatment of a severe baclofen intoxication in a 3 kg dog

To describe the clinical efficacy and drug removal kinetics of hemodialysis (HD) as emergency treatment in a small size dog with severe baclofen intoxication. A 2-year-old dog was presented in stupor to the emergency service a few hours after ingestion of up to 25 mg of baclofen. Medical stabilisation was attempted but was unsuccessful in improving the neurological condition and the patient rapidly progressed to coma. A 4-h session of HD was performed in emergency with near complete resolution of neurological signs and only mild disorientation by the end of the treatment. No adverse side effects occurred during HD. Baclofen concentration was measured serially during the session. Drug extraction ratio, clearance and mass removal by the dialyser were calculated. Dialytic elimination rate constant (Kd ) was seven times higher than the intrinsic elimination rate constant (Kintr ) and the half-life (t½) during HD was nearly nine times shorter than the endogenous one. This is the first case report providing pharmacokinetic data associated with HD treatment of severe baclofen intoxication in a dog.

Pharmacokinetic-pharmacodynamic model to predict drug concentrations and intraocular pressure lowering effect for a bimatoprost six-month slow-release system.

Ophthalmic drug product development and dosing regimen selection depend on animal eye drug concentration-effect relationships since human eye tissues cannot be sampled for drug quantification. This study hypothesized that a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model developed based on dog studies can be applied to the human eye of different ages, based on physiological parameter adjustment, to predict drug concentrations and effects in response to a new 6-month slow-release, intracameral, intraocular pressure (IOP) lowering, anti-glaucoma bimatoprost implant. Using previously reported dog concentration-effect relationship data at various doses, and the physiological parameters of dog eye, a PK-PD model was designed to predict dog aqueous humor drug concentrations and IOP lowering effects simultaneously for a given dose. After validating the model using the dog IOP data, it was applied to the human eye. Using a drug release rate constant of 0.0002 h-1, the model predicted the dog IOP lowering effect with an error less than 6% or less at various doses (Observed = 0.91*Predicted + 2.35; R2 = 0.98). Considering literature reported aqueous humor volumes and flow rates in old (over 60 years) and young (20 to 30 years) humans, aqueous humor elimination rate constant was estimated to be 0.9 and 0.68 h-1, respectively. The model when modified using the older human eye parameters, predicted the IOP lowering effects reported in a clinical trial with 63-year-old adults, with an error of 6.2% or less. The model, when used for young adult eye not previously tested in clinical trials, predicted lower drug concentrations and effects, possibly due to 54% higher aqueous humor volume relative to older adults. The model predicted an IOP reduction of 26.3 and 30.6%, at 10 and 15 microgram doses, respectively, in young adults. The PK-PD model developed is useful for product design and patient dosing by predicting eye drug concentration and effect time-courses in response to implant administration at various doses, frequencies, and release rates.

The Plasma Concentration Profiles and Pharmacokinetics of Levetiracetam among Thai Adult Patients Undergoing Intermittent Hemodialysis

Background: Levetiracetam is a second-generation antiepileptic drug that is primarily eliminated in urine via glomerular filtration and requires dose adjustment in patients with renal insufficiency. However, there are still a lack of evidence on pharmacokinetics including dialysis clearance of levetiracetam among patients undergoing intermittent hemodialysis. Objective: To assess the plasma concentrations and pharmacokinetic parameters of levetiracetam in patients undergoing intermittent hemodialysis. Materials and Methods: A pharmacokinetic study was conducted on six Thai adult patients receiving intermittent hemodialysis. The patients received levetiracetam 1,000 to 1,500 mg administered by intravenous injection once daily. Blood samples were obtained prior to hemodialysis, during the hemodialysis session, and post-hemodialysis to investigate levetiracetam pharmacokinetic parameters in each phase of treatments. Results: Five of six patients had residual urine volume of more than 50 mL/day. The Pharmacokinetic parameters derived from the present study were as followed, the median dialysis clearance was 9.07 L/hour (IQR 7.13, 12.17), the median elimination rate constant (Ke) was 0.30 hour⁻¹ (IQR 0.24, 0.56), and the median elimination halflife (t½) during hemodialysis session was 2.34 hours (IQR 1.25, 2.91). The present study found the median percentage of levetiracetam plasma concentration reduction after four hours of hemodialysis was 76.89% (IQR 69.02, 85.43). Overall, plasma concentration of levetiracetam was decreased during intermittent hemodialysis sessions. Conclusion: The findings of the present study support the use of LEV dosing of 1,000 to 1,500 mg/day and a supplemental dose after each hemodialysis session should be considered. Levetiracetam dose reduction in patients undergoing intermittent hemodialysis will lead to subtherapeutic plasma concentrations. Levetiracetam plasma concentration should be monitored in patients receiving intermittent hemodialysis. Keywords: Levetiracetam; Hemodialysis; Pharmacokinetics; Antiepileptic drug

Toxicokinetics and toxicodynamics of chromium in the soil invertebrate Enchytraeus crypticus (Oligochaeta)

Chromium emissions led to increased concentrations in soil, where it can affect soil organisms to relevant levels. With the aim of better understanding the effects of Cr throughout time, its toxicokinetics-toxicodynamics (TKTD) were evaluated in the soil model organism Enchytraeus crypticus to assess the development of internal concentrations and consequent toxic effects. To achieve this goal, organisms were exposed in LUFA 2.2 soil spiked with increasing CrCl3 concentrations. During the 21-day exposure period, survival, internal concentrations, and reproduction were evaluated at several time points up to 21 days. Uptake and elimination rate constants were 0.0044 kg soil/kg organism/day and 0.023 per day, respectively. Internal Cr concentrations increased with time, generally reaching equilibrium within 14 days with an estimated LC50inter (based on internal metal concentrations) of 57.7 mg Cr/kg body DW. Internal Cr concentrations were regulated by the organisms up to exposure to 360 mg Cr/kg soil DW, where the elimination rate was highest, but at 546 mg Cr/kg soil DW the animals were no longer able to eliminate Cr, and the internal concentrations were well above the estimated LC50inter. At day 21, exposure to 546 mg Cr/kg soil DW significantly reduced survival by 23 %, while reproduction EC50 was 344 mg Cr/kg soil DW. This study highlights the advantages of using a TKTD approach to understand the development of internal metal concentrations in time and relate it to the phenotypical effects observed. Toxicity is better understood when also taking into account time and not just exposure concentration alone.

The effect of sulfidation and soil type on the uptake of silver nanoparticles in annelid Enchytraeus crypticus

Hazard assessment of silver nanoparticles is crucial as their presence in agricultural land is increasing through sewage sludge application. This study compared the uptake and elimination kinetics in the annelid Enchytraeus crypticus of AgNPs with different core sizes and coatings in Lufa 2.2 soil, and of Ag2S NPs (simulating aged AgNPs) in three different soils. For both experiments, AgNO3 was used as ionic control. E. crypticus was exposed to soil spiked at 10 μg Ag g−1 dry soil for 14 days and then transferred to clean soil for a 14-day elimination phase. The uptake rate constants were similar for 3–8 nm and 60 nm AgNPs and AgNO3, but significantly different between 3 and 8 nm and 50 nm AgNPs. The uptake kinetics of Ag from Ag2S NPs did not significantly differ compared to pristine AgNPs. Therefore, Ag bioavailability was influenced by AgNP form and characteristics. Uptake and elimination rate constants of both Ag forms (AgNO3 and Ag2S NPs) significantly differed between different test soils (Lufa 2.2, Dorset, and Woburn). For AgNO3, significantly higher uptake and elimination rate constants were found in the Dorset soil compared to the other soils, while for Ag2S NPs this soil showed the lowest uptake and elimination rate constants. Therefore, not only the form and characteristics but also soil properties affect the bioavailability and uptake of Ag nanoparticles.

Bioaccumulation Screening of Neutral Hydrophobic Organic Chemicals in Air-Breathing Organisms Using In Vitro Rat Liver S9 Biotransformation Assays.

To advance methods for bioaccumulation assessment of organic substances in air-breathing organisms, the present study developed an in vitro approach for screening neutral hydrophobic organic substances for their bioaccumulation potential in air-breathing organisms consisting of (1) depletion assays for chemicals in rat liver S9 subcellular fractions, (2) in vitro-in vivo extrapolation, and (3) whole-organism bioaccumulation modeling to assess the biomagnification potential of neutral organic substances in the rat. Testing of the in vitro method on 14 test chemicals of potentially biomagnifying substances showed that the bioassays could be conducted with a high level of reproducibility and that in vitro-derived elimination rate constants were in good agreement with in vivo-determined elimination rate constants in the rat. Exploring the potential of the in vitro approach for screening organic chemicals for bioaccumulation in air-breathing organisms indicated that chemical substances that exhibit a depletion rate constant in the S9 in vitro bioassay ≥0.3 h-1 are not expected to biomagnify in rats independent of their octanol-water partitioning coefficient (KOW ) or octanol-air partitioning coefficient (KOA ). The high level of reproducibility achieved in the test, combined with the good agreement between in vitro-derived and in vivo-determined depuration rates, suggests that the in vitro approach in combination with a KOA - and KOW -based screening approach has good potential for screening chemicals in commerce for their bioaccumulation potential in air-breathing organisms in a cost-effective and expedient manner, especially if the bioassay can be automated. Environ Toxicol Chem 2022;41:2565-2579. © 2022 SETAC.

Selenocoxib-3, a novel anti-inflammatory therapeutic effectively resolves colitis.

Ulcerative colitis (UC) is an idiopathic, chronic and relapsing colonic inflammatory disease. Despite the involvement of diverse intricate mechanisms, COX mediated inflammatory pathway is crucial in the pathophysiology of colitis. Thus, COX inhibition is imperative for managing colitis-associated inflammation. However, the use of COX inhibitory classical non-steroidal anti-inflammatory drugs (NSAIDs) for inflammation resolution has been linked to sudden increased flare-ups. Therefore, considering the anti-inflammatory and pro-resolution effects of antioxidant and essential trace element Selenium (Se), a Seleno-derivative of Celecoxib called Selenocoxib-3 was characterized and evaluated for its favourable pharmacokinetics, safety margins and anti-inflammatory therapeutic potential in DSS-induced experimental colitis. The serum pharmacokinetic profiling [elimination rate constant (K) and clearance (Cl) and toxicity profiling suggested enhanced efficacy, therapeutic potential and lesser toxicity of Selenocoxib-3 as compared to its parent NSAID Celecoxib. In vivo studies demonstrated that Selenocoxib-3 efficiently resolves the gross morphological signs of DSS-induced colitis such as diarrhoea, bloody stools, weight loss and colon shortening. Further, intestinal damage evaluated by H & E staining and MPO activity suggested of histopathological disruptions, such as neutrophil infiltration, mucodepletion and cryptitis, by Selenocoxib-3. The expression profiles of COX-1/2 demonstrated mitigation of pro-inflammatory mediators thereby promoting anti-inflammatory efficacy of Selenocoxib-3 when compared with Celecoxib. The current study suggests translational applicability of Se-containing novel class of COX inhibitors for efficiently managing inflammatory disorders such as UC.

Model-Informed Rationale for Early Therapeutic Drug Monitoring of Colistin in Critically Ill Patients.

Adequate colistin exposure is important for microbiological clearance. This study was performed in critically ill patients >18 years old to develop a simplified nonparametric pharmacokinetic (PK) model of colistin for routine clinical use and to determine the role of dose optimization. The Non-Parametric Adaptive Grid algorithm within the Pmetrics software package for R was used to develop a PK model from 47 patients, and external validation of the final model was performed in 13 patients. A 1-compartment multiplicative gamma error model with 0-order input and first-order elimination of colistin was developed with creatinine clearance and serum albumin as covariates on elimination rate constant. An R2 for observed vs individual predicted colistin concentrations of 0.92 was obtained in the validation cohort. High interindividual variability in colistin steady-state area under the plasma concentration-time curve (AUC) from from 120 hours to 144 hours (coefficient of variation=80.1%) and a high interoccasion variability (median coefficient of variation of AUC from time 0 to hours predicted every 8hours for initial 96hours after starting colistin=23.8) was predicted in patients who received this antibiotic for a period of over 152hours (n=22). With the model-suggested dose regimen, only 20% of simulated profiles achieved AUC from time 0 to 24 hours in the range of 50 to 60mg• h/L due to high variability in population PK. In this group of patients, steady-state colistin concentrations were predicted to be achieved >96hours after initiation of colistimethate sodium. This study advocates the need for early and repeated therapeutic drug monitoring and dose optimization in critically ill patients to achieve adequate therapeutic concentration of colistin.

Tracking cellular transformation of As(III) in HepG2 cells by single-cell focusing/capillary electrophoresis coupled to ICP-MS

The cellular metabolism of metals is highly critical to elucidate their potential cytotoxicity or cell protection mechanism. In this work, an asymmetric serpentine microfluidic device (ASMD) with high sampling efficiency and excellent focusing performance was developed for single-cell focusing. ASMD coupling with ICP-MS ensures single-cell assay to provide the information for trivalent arsenic (As(III)) uptake by HepG2 cells, which reveals the heterogeneity of cellular arsenic distribution, and elucidates the arsenic elimination behaviors in single HepG2 cells. Further, the metabolism and transformation of As(III) in HepG2 cells was tracked by hyphenating capillary electrophoresis (CE) separation with ICP-MS. The results for single-cell analysis and arsenic elimination kinetics illustrated that the half-life of arsenic elimination is 0.9 ± 0.04 h with the elimination constant of 0.77 ± 0.03, i.e., 77% of accumulated As in HepG2 cells may be eliminated per hour. Moreover, arsenobetaine (AsB) was identified to be the main metabolite and biotransformation species of As in HepG2 cells. ASMD-ICP-MS and CE-ICP-MS are powerful for tracking the fate of metals or metal drugs in single cells to comprehensively understand their metabolic pathway and transformation behaviors.

Lower buprenorphine elimination rate constant is associated with lower opioid use

BackgroundOpioid craving is suggested to correlate with the rate of reduction in buprenorphine (BUP) plasma levels. No studies explored Buprenorphine elimination rate constant (BUP EL.R) as a predictor of opioid use or retention in BUP treatment.MethodsAnalysis was performed using data from a randomized controlled trial of 141 adults with opioid use disorder (OUD) randomized to Incentivized Adherence and Abstinence monitoring (I-AAM; experimental (n = 70) and treatment-as-usual; control (n = 71). In the I-AAM, structured access to unsupervised BUP doses was provided up to 28 days contingent of adherence measured by Therapeutic Drug Monitoring and abstinence by Urinary Drug Screens (UDS). In contrast, the treatment-as-usual (control) provided unstructured access to unsupervised doses was provided for up to 14 days considering UDS results. The primary outcome was percentage negative UDS. The secondary outcome, retention in treatment, was continuous enrollment in the study and analysis was via intention-to-treat. Significant bivariate correlations with the outcomes were adjusted for group allocation.ResultsA significant negative correlation between BUP EL.R and percentage negative opioid screens (Pearson correlation coefficient − 0.57, p < 0.01) was found. After adjusting for trial group, BUP EL.R was shown to be an independent predictor of percentage negative opioid screens (Standardized Beta Coefficient − 0.57, 95% CI − 221.57 to − 97.44, R2 0.322).ConclusionBUP EL.R predicted 32.2% of the variation in percentage negative opioid UDS and may serve as a potential promising tool in precision medicine of BUP treatment. Higher buprenorphine elimination is associated with higher positive opioid urine screens during treatment.Trial registrationISRCTN41645723 retrospectively registered on 15/11/2015.

Pharmacokinetics and Egg Residues of Oral Meloxicam in Bantam Cochin Chickens.

Backyard poultry are commonly treated in veterinary hospitals; however, there is limited information regarding appropriate dosing of medications and withdrawal times for eggs. Six healthy adult bantam Cochin hens were given a single oral dose of meloxicam (1 mg/kg). Meloxicam plasma concentrations and egg residues were analyzed by high-performance liquid chromatography. Noncompartmental analysis was used to calculate pharmacokinetic parameters. The apparent terminal half-life, maximum concentration, and time to maximum concentration were 5.94 ± 0.92 hours, 7.03 ± 2.68 µg/mL, and 2.83 ± 1.33 hours, respectively. Meloxicam was detected in egg whites for 4.8 ± 1.5 days and egg yolks for 9.8 ± 2.4 days. Results were compared with previous studies in white leghorn and Columbian Wyandotte hens. Bantam Cochin hens demonstrated a significantly longer mean apparent terminal half-life, greater area under the curve, smaller elimination rate constant, and longer egg residue times compared with white leghorn hens. However, the pharmacokinetic results from the bantam Cochin hens did not significantly differ from those reported for the Columbian Wyandotte hens. Until pharmacodynamic studies can be performed, dosing of oral meloxicam in bantam Cochins should follow recommendations for Columbian Wyandotte hens to reduce the likelihood of adverse effects. These results better inform appropriate dosing of meloxicam in domestic hens, as well as recommended withdrawal times for egg consumption.

Meropenem Population Pharmacokinetics and Simulations in Plasma, Cerebrospinal Fluid, and Brain Tissue.

Meropenem is a broad spectrum carbapenem used for the treatment of cerebral infections. There is a need for data describing meropenem pharmacokinetics (PK) in the brain tissue to optimize therapy in these infections. Here, we present a meropenem PK model in the central nervous system and simulate dosing regimens. This was a population PK analysis of a previously published prospective study of patients admitted to the neurointesive care unit between 2016 and 2019 who received 2 g of meropenem intravenously every 8 h. Meropenem concentration was determined in blood, cerebrospinal fluid (CSF), and brain microdialysate. Meropenem was described by a six-compartment model: two compartments in the blood, two in the CSF, and two in the brain tissue. Creatinine clearance and brain glucose were included as covariates. The median elimination rate constant was 1.26 h-1, the central plasma volume was 5.38 L, and the transfer rate constants from the blood to the CSF and from the blood to the brain were 0.001 h-1 and 0.02 h-1, respectively. In the first 24 h, meropenem 2 g, administered every 8 h via intermittent and extended infusions achieved good target attainment in the CSF and brain, but continuous infusion (CI) was better at steady-state. Administering a 3 g loading dose (LD) followed by 8 g CI was beneficial for early target attainment. In conclusion, a meropenem PK model was developed using blood, CSF, and brain microdialysate samples. An 8 g CI may be needed for good target attainment in the CSF and brain. Giving a LD prior to the CI improved the probability of early target attainment.

Environmental risk and possibilities of ciprofloxacin phytoremediation

The article considers antibiotics of the quinolone series, their using and mechanism of action. Based on the literature data, their application, distribution mechanisms, accumulation and behavior in environmental objects are considered. It is noted that the role of aquatic plants in the processes of biochemical degradation has not been sufficiently studied. Under the conditions of a laboratory model experiment, we studied the patterns of ciprofloxacin elimination by hydatophytes, i.e., aquatic plants completely submerged in water (Canadian pondweed, rigid hornwort, Eurasian watermilfoil). The spectral characteristics of ciprofloxacin were studied and quantitative estimates of the absorption of the antibiotic from solutions with submerged aquatic plants were made. We calculated elimination rate constants and phytoremediation potential. It was found that the rate of elimination of ciprofloxacin and phytoremediation potential depended on the type of aquatic plant and the initial concentration of the antibiotic. The highest elimination rate was found in models containing hornwort. Based on the data obtained, a conclusion was made about the prospects for the using of hydatophytes in phytopurification systems for post-treatment of wastewater from ciprofloxacin.

Abstract 2022: Model-informed pediatric drug development: oral vinorelbine in low-grade glioma as a case study

Abstract Objectives:Defining a safe and effective dose in children is one of the biggest challenges in pediatric drug development. Pharmacometric tools are proposed as powerful quantitative techniques to leverage and integrate the collected data from pediatric clinical trials. Here we demonstrate and discuss the applications of nonlinear mixed effects (NLME) models through a detailed example of oral vinorelbine (VNR) in pediatric cancers.Methods:A multicentric, open-label, single-arm intervention phase II study was conducted. Patients with recurrent/progressive Low-Grade Glioma (LGG), were included. Patients received 60 mg/m² of oral VNR on days 1, 8 and 15 during the first 28-day treatment cycle and 80 mg/m² from cycle 2 to 12. Population pharmacokinetic (PK) analysis was performed using a NLME modeling approach on Monolix®. Fifty SNPs on PK-related genes were genotyped. The Influence of demographic, biological and pharmacogenetic covariates on VNR PK parameters was investigated using a stepwise multivariate procedure.Results:PK analysis included 36 patients with a median age (range) of 11 (6-17) years. A three-compartments model, with a delayed double zero-order absorption and a linear elimination, best described VNR pharmacokinetics. Typical population estimates (between-subject variability, between-occasion variability) for the apparent central volume of distribution (Vc/F) and elimination rate constant (k10) were 803 L (47%, 41%) and 0.60 h-1 (18%, 16%), respectively. Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. Following covariate analysis, BSA, leukocytes count, and ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Additionally, ABCG2-rs2725264 A/G or G/G carriers and UGT2B7-rs7668258 T/T carriers showed higher k10 values. Conversely, age and sex had no significant effect on VNR PK.Conclusion:Higher doses may be necessary for children with LGG. A personalized dosing strategy, using BSA, leukocytes and ABCB1-rs2032582 SNP, could help to optimize the efficacy/toxicity balance of VNR in children. Model-informed drug development enabled efficiently a better understanding of PK of oral VNR in children and identifying several factors likely to explain the variability in VNR exposure and subsequent clinical outcomes. Citation Format: Mourad HAMIMED, Pierre LEBLOND, Aurélie DUMONT, Florence GATTACCECA, Emmanuelle TRESCH-BRUNEEL, Alicia PROBST, Pascal CHASTAGNER, Anne PAGNIER, Emilie DE CARLI, Natacha ENTZ-WERLÉ, Jacques GRILL, Isabelle AERTS, Didier FRAPPAZ, Anne-Isabelle BERTOZZI-SALAMON, Caroline SOLAS, Nicolas ANDRÉ, Joseph Ciccolini. Model-informed pediatric drug development: oral vinorelbine in low-grade glioma as a case study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2022.

Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice.

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[11C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1(−/−) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (kelim) was calculated from time–activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.

Formulation and Pharmacokinetic Evaluation of Ethyl Cellulose/HPMC-Based Oral Expandable Sustained Release Dosage of Losartan Potassium.

Prolonged retention of losartan potassium in the upper gastrointestinal tract is anticipated to increase its absorption and exposure to CYP450 enzyme subfamilies, undertaking its conversion to more potent (10-40 times) active metabolite, losartan carboxylic acid (LCA). Consistent with this, hydroxypropyl methylcellulose K4M/ethyl cellulose-based novel expandable films (EFs) containing losartan potassium (LP) suitable for prolonged retention in the stomach were developed. The films were prepared by solvent casting method. USP type II dissolution apparatus (0.1N HCl, 37°C, 100rpm) was used to perform the dissolution testing (drug release, unfolding behavior, film integrity, erosion, and water uptake) of the films. In vivo pharmacokinetic studies were carried out in rabbits. An HPLC-UV method was used for the quantification of the drug and its active metabolite in plasma. These folded films placed inside hard gelatin capsule shells unfolded to full dimensions in dissolution medium and provided sustained drug release throughout 12h. The plasma drug concentration-time curves obtained from the in vivo studies were used to determine pharmacokinetic parameters, such as area under the plasma drug concentration-time curve(AUC), area under first moment curve(AUMC), mean residence time (MRT), Cmax, Tmax, t1/2, ke, and Fr in comparison with that of the market formulation, Cozaar®. The novel EFs significantly changed the pharmacokinetic parameters of the drug and its active metabolite. The apparent elimination rate constant (ke) significantly decreased, while MRT and elimination half-life (t1/2) increased in both cases. The relative bioavailabilities (Fr) of both LP and E3174 using the novel formulation were higher than that of Cozaar®.

Simulation modelling the structure related bioaccumulation and biomagnification of per- and polyfluoroalkyl substances in aquatic food web

Until now, there is no bioaccumulation model to predict bioaccumulation of polyfluoroalkyl substances (PFASs) in aquatic organisms due to their unique amphiphilic properties. For the first time, protein contents instead of lipid contents of organisms were used in bioaccumulation models to predict the concentrations and reveal the accumulation mechanisms of PFASs in various aquatic organisms, based on the available data. Comparison between the modeled and measured results indicated the models were promising to predict the PFAS concentrations in the fishes at different trophic levels very well, as well as their bioaccumulation factors (BAF) and trophic magnification factors (TMF) of PFASs in fish. Both water and sediment are important exposure sources of PFASs in aquatic organisms. As the two main uptake pathways, the contribution of gill respiratory decreases while that of dietary intake increases with the chain length of PFASs increasing. Fecal excretion and gill respiration are the main pathways for fish to eliminate PFASs, and their relative contributions increase and decrease respectively with chain length. The short-chain (C6–C8) perfluoroalkyl acids (PFAAs) are greatly eliminated via gill respiratory quickly, leading to their very low BAFs. As the carbon chain length increases, dietary intake becomes dominant in the uptake, while elimination is mainly through fecal excretion with relatively low rates, especially in the fishes with high protein contents. For the very long chain (C12–C16) PFASs, they are very difficult to excrete with a low total elimination rate constant (ke = 0.463–0.743 d−1), thus leading to their high BAFs and TMFs. The high intake rate but low elimination rate, as well as the high water and sediment concentrations together contribute to the highest accumulated concentration perfluorooctane sulfonic acid in the fish of Taihu Lake.

Concentration-dependent toxicokinetics of novel PFOS alternatives and their chronic combined toxicity in adult zebrafish

The increasing use of perfluorooctanesulfonate (PFOS) alternatives has led to their release into the aquatic environment. This study sought to determine the effects of exposure concentration on the toxicokinetics of PFOS and its alternatives, including perfluorobutanesulfonic acid (PFBS), perfluorohexanesulfonic acid (PFHxS), chlorinated polyfluorinated ether sulfonate (F-53B) and sodium p-perfluorous nonenoxybenzenesulfonate (OBS) in adult zebrafish by exposure to mixtures of the five per- and polyfluoroalkyl substances (PFAS) at 1, 10, and 100 ng/mL for 28-day, followed by a 14-day depuration. PFAS predominantly accumulated in the blood and liver, and the bioconcentration factor (BCF) decreased in the order of F-53B > PFOS > OBS ≫ PFHxS > PFBS in whole-fish homogenates. The uptake rate constants and BCF of the short-chain PFAS (≤C6) positively correlated with increasing exposure concentration, while the long-chain PFAS (≥C8) exhibited a pattern of first increasing and then decreasing. A consistent increase in the elimination rate constants of short- and long-chain PFAS was observed with increasing exposure concentration. All PFAS form tight conformations with ZSA and ZL-FABP via hydrogen bonding as revealed by molecular docking analysis. Furthermore, chronic combined exposure to PFAS induced the occurrence of vacuolation and oxidative stress in the zebrafish liver. Our findings uniquely inform the concentration-dependent bioconcentration potential and health risks to aquatic organisms of these PFOS alternatives in the environment.

Passive sampling hydrophilic and hydrophobic bisphenol analogues using hydrophilic-lipophilic balance sorbent-embedded cellulose acetate membrane in surface waters

Bisphenol analogues (BPs) are ubiquitous emerging contaminants in water environments and have wide polarity ranges (1.65 < log Kow < 7.2). Integrated passive sampling strategy rarely contains hydrophilic and hydrophobic organics simultaneously, while the method has good application perspective in monitoring organic contaminants. This work evaluated passive sampling performance for fifteen BPs in a newly developed passive sampler, i.e., hydrophilic-lipophilic balance sorbent-embedded cellulose acetate membrane (HECAM). In the dynamic accumulation experiments, both hydrophilic and hydrophobic BPs (including moderately hydrophilic BPs) well followed first-order kinetic uptake in the HECAMs. The estimated uptake rate constants, elimination rate constants, and equilibrium partition coefficients for BPs ranged from 4.4 L g−1 d−1 to 14.7 L g−1 d−1, 0.22 d−1 to 0.72 d−1, and 3.99 to 4.64, respectively. The kinetic parameters for BPs in HECAM show limited correlations to log Kow values, which the rule differs from traditional passive sampler. In the study of elimination kinetics, three deuterium labeled compounds showed incomplete elimination in HECAM and did not follow first-order isotropic exchange kinetics. Dual sorption mechanisms including both adsorption and partition were found for chemicals in HECAM, which the partitioned part could release to water and the adsorbed part could not easily release to water from HECAM. As a result, performance reference compounds (PRCs) calibration may be inapplicable to HLB sorbent-based passive sampler. The field deployment of HECAM in coastal waters of Guangdong, China resulted in the detection of eleven BPs, which indicated that the waters have been polluted by various BPs. Finally, monitoring strategy of simultaneous passive sampling hydrophobic and hydrophilic organic contaminants in surface waters was recommended.