Elimination Rate Constant Research Articles

Contribution of ingestive/dietary uptake to bioaccumulation of organics in worms

Ingestive uptake is critical for understanding the accumulation and trophic transfer of chemicals and synthesized particles in general. This study explored the contribution of ingestion in the bioaccumulation of chemicals focusing on worms. Novel theory and equations were developed to derive fractional ingestive contribution, fs, from a broad range of dietary uptake and accumulation studies, and to build a small dataset of fs (n = 43) from relevant toxicokinetic and bioaccumulation measurements. Worm fs could be fitted to log KOW-based sigmoidal models with small errors (RSE < 0.15, RMSE<0.15). The basis and limitations of the applied fs equations were elaborated. These included the assumption that aqueous-based and dietary-based elimination rate constants (kTw and kTS) may be statistically equivalent, as demonstrated using fish and worm data. Bioaccumulation and toxicokinetic parameters obtained at under-exposed conditions can also result in non-sensical, negative fs. The developed fs theory suggested a novel way to model bioaccumulation in the presence of aqueous and solid sources, and the potential to consolidate bioaccumulation data in their variant forms and definitions for assessment, modeling, and benchmarking purposes. While the presented fs-log KOW dependence remained to be explored in other species, the importance of ingestive uptake for high-log KOW chemicals questioned the validity of characterizing and regulating bioaccumulation potential of hydrophobic organics – for which dietary uptake matters – using aqueous-only bioconcentration factor (BCF). This question, along with other less important ones, is yet to be explored in future works.

Toxicokinetics and responses of multiple biomarkers of sediment-associated fluoroquinolones in an ecologically important freshwater snail Bellamya aeruginosa

Fluoroquinolones (FQs) have the propensity to accumulate in sediments once introduction into aquatic environments, thereby posing potential threats to benthic organisms, yet the ecotoxicity of sediment-associated FQs remains unclear. In this study, the toxicokinetics and responses of multiple biomarkers in Bellamya aeruginosa, exposed to the three commonly used FQs (norfloxacin, NOR; ciprofloxacin, CIP; levofloxacin, LEVO) at environmentally relevant concentrations were investigated under sediment exposure scenario. The results revealed that FQs were effectively ingested by B. aeruginosa from sediments, CIP showing the highest bioaccumulation (180.59 μg/kg), followed by NOR (74.49 μg/kg) and LEVO (36.02 μg/kg). CIP exhibiting a highest uptake rate constant (Ks) (4.64 g/(g.d)) and the lowest elimination rate constant (Ke) (0.05 g/(g.d)). The descending order of biological half-life is as follows: CIP (13.62 d), LEVO (8.14 d), and NOR (6.83 d). NOR induced the activity of superoxide dismutase, catalase, and glutathione-S-transferase while CIP and LEVO depressed their activities and increased malondialdehyde content, indicating a more pronounced oxidative damage to B. aeruginosa caused by CIP and LEVO than NOR. Furthermore, all three FQs were found to induce DNA damage and elevate acetylcholinesterase activity, suggesting distinct genotoxic and neurotoxic effects. Interestingly, despite its low bioaccumulation potential, LEVO exhibited high toxicity towards B. aeruginosa. These findings enhance our understanding of the ecotoxicity of FQs in sediments, providing further evidence of their potential ecological risks.

Reversal of insulin resistance to combat type 2 diabetes mellitus by newer thiazolidinedione's in fructose induced insulin resistant rats

In our pursuit of discovering new antidiabetic agents to manage type 2 diabetes mellitus (T2DM), our approach aimed to identify the bioactive feature/pharmacophore responsible for PPAR-γ expression, as it is accountable for the glucose homeostasis and lipid metabolism. This was achieved by pharmacophore model generation, screening of rationally designed newer thiazolidinedione's library, identifying synthesizing and characterizing the top ten molecules (5a-5j) for their (Invitro &invivo) antidiabetic activity. Preliminary screening of all the ligands by Invitro glucose uptake assay in L6 myotubes (skeletal muscle cell line of rats) revealed compound 5b and 5f stimulated the glucose uptake with 79.29 ± 1.02 % and 74.58 ± 1.02 % respectively compared to pioglitazone with 82.36 ± 0.98 %. This was validated by PPAR-γ TF expression assay, which highlighted a dose dependent increase in transactivation of PPAR-γ. These compounds 5b and 5f were evaluated in fructose induced insulin resistance rat model. Where the treatment with 5b and 5f markedly increased the exogenous clearance of glucose and exogenous insulin via OGTT and ITT respectively, also improved the glucose utilization by significantly increasing content of glycogen and uptake of glucose in rat hemidiaphragm and reversed insulin resistance. Likewise a significant decreased in the VLDL and triglyceride levels was seen in 5b and 5f treated groups compared to insulin resistant (IR) group. It improved glycogenesis by catabolism of glucose and maintained glycaemic control. Similarly it had marked action on enzymatic oxidative biomarkers. Compound 5b displayed better, improved T1/2 (half-life) of 4.21 h and Kel (elimination constant) of 0.381 was noticed in comparison to compound 5f indicating the pharmacokinetic profile. Insilico studies like DFT calculations refined the geometry of 5b and 5f ligands, docking and molecular simulation provided the insights in binding affinity, dynamic behaviour and stability of ligands in PPAR-γ ligand binding domain. MM/GBSA provided the energetics of 5b and 5f in binding pocket. Finally network pharmacology identified ADIPOQ (adiponectin), NR1C3 (PPAR-γ), SLC2A4 (GLUT4), and LEP (leptin) proteins associate with compound 5b and 5f and enriched in Adipocytokine pathway, and PPAR-γ signaling pathway.

Pharmacokinetics of pulmonary indacaterol in rat lung using molecular imprinting solid-phase extraction coupled with RP-UPLC

Indacaterol, a β2 agonist prescribed for long-term management of patients with chronic obstructive pulmonary disease and asthma. In this study the first MISPE cartridges was developed using indacaterol as a template for its selective extraction from rat lung tissues, enabling precise pharmacokinetic evaluation at the drug’s site of action. A molecular imprinting polymer was synthesized using indacaterol as a template, methacrylic acid as a functional monomer and ethylene glycol dimethacrylate as a cross-linker with a molar ratio (1: 4: 20). The polymer was characterized by a high binding capacity of 9840 ± 0.86 and high selectivity with an imprinting factor of 4.53 ± 0.12. The synthesized polymer was utilized as a sorbent in solid-phase extraction to purify and extract indacaterol from lung tissue matrix. The optimum molecularly imprinted solid-phase extraction (MISPE) conditions were 20.0 mg of molecular imprinting polymer and non-imprinting polymer, acetonitrile as the loading solvent, acetonitrile: water (20: 80; by volume) as the washing solvent, and methanol: acetic acid (90: 10; by volume) as the eluting solvent. A pharmacokinetic study was performed for indacaterol in rat lungs using the synthesized and optimized MISPE cartridge as a tool for sample purification. These parameters were determined in the lung tissues of rats emphasizing the local exposure of indacaterol to its target organ. The Cmax and Tmax were 51.020 ± 2.810 µg mL− 1 and 0.083 ± 0.001 h, respectively. The AUC 0−24 and AUC0 − inf were 175.920 ± 1.053 and 542.000 ± 5.245 µg h mL− 1, respectively. The elimination rate constant was 0.014 ± 0.00012 h− 1 and the half-life time was 48.510 ± 0.012 h. This study successfully developed and optimized MISPE cartridges using indacaterol as a template, enabling precise pharmacokinetic evaluation in rat lung tissues. The cartridges demonstrated high binding capacity and selectivity, providing crucial insights into the local exposure of indacaterol at its site of action.

B-280 Nmr-based biomaker measurement determines high-dose methotrexate elimination rates in lymphoma and leukemia treatment

Abstract Background The cytotoxic methotrexate (MTX) is used in high doses in lymphoma and acute lymphocytic leukemia (ALL) treatment. A therapeutic plasma dose range is crucial to minimize MTX accumulation and prolonged exposure, which can lead to myelosuppression and other adverse effects. Determining MTX elimination prior to drug administration is difficult, given its non-linear clearance. Here we present a model to predict MTX elimination rates based on metabolite measurement in patients receiving high-dose methotrexate, using nuclear-magnetic resonance (NMR) spectroscopy. Methods A series of 26 residual sera from patients receiving MTX infusions as per treatment protocols for CNS lymphoma (MATRIX protocol, 3.5 g/m2 over four hours) and ALL (GMALL protocol, 1.5 g/m2 over 24 hours) were collected from patients at the University Hospital Regensburg at four timepoints (t0, t24, t42, and t48). Serum was NMR-measured in five replicates. NMR spectra for each sample were characterized and relevant parameters extracted. First order elimination constants were modeled for two MTX dosage regimes (&amp;lt;4 g, ≥4 g) using characterized NMR features from samples measured at t0. Results Metabolomic and lipidomic biomarkers measured at baseline (t0) were able to accurately predict MTX elimination rate constant k, determined by fitting MTX levels at a t24, t42, and t48, using first order c(t)∼c0*e(-kt) kinetic function (&amp;gt;4 g: R2 = 0.475, p-value &amp;lt; 0.05; ≤4 g: R2 = 0.918, p-value &amp;lt; 0.01) (Fig. A). Results were cross-validated with five-time repeated three-fold cross-validation. Performance values are given as means of the folds. Conclusions NMR-measured biomarkers can predict dose-dependent MTX elimination rates in patients receiving high-dose MTX, presenting a novel method to predict MTX clearance, allowing for personalized dose-monitoring and minimization of adverse events. Validation with a larger cohort is required.

Strong enhancement on diclofenac degradation in Cu(II)/H2O2 system by adding ascorbic acid: Efficiency, mechanism and influencing factors

Utilization of trace Cu(II) (at μM level) inherently existing in wastewater to activate hydrogen peroxide (H2O2) has exhibited significant potential to remove aqueous organic contaminants. Nevertheless, the Cu(II)/H2O2 system was only efficient under alkaline conditions. Herein, ascorbic acid (H2A), an environmentally benign and natural reductant, was introduced to broaden pH range of Cu(Ⅱ)/H2O2 process by expediting the Cu(II)/Cu(I) cycle. The H2A/Cu(Ⅱ)/H2O2 system performed well in degrading diclofenac across a wide pH range from 4.0 to 9.0, and its kinetic rate constant of diclofenac elimination was 247 times greater than its counterpart without H2A at the optimal pH of 6.0, outperforming the performance of most previously reported reductant-enhanced Cu(Ⅱ)/H2O2 system. Electron paramagnetic resonance analysis, periodate colorimetric method, and in situ Raman spectroscopy tests indicated that hydroxyl radical (HO), rather than Cu(III), was the dominant reactive species of diclofenac degradation. Thirteen degradation products of diclofenac were identified by LC-Q-TOF-MS, and five different elimination pathways were proposed. Furthermore, the presence of SO42− exerted an insignificant influence on diclofenac degradation, while the addition of Cl−, HCO3− and humic acid slightly suppressed the abatement of diclofenac. H2A/Cu(Ⅱ)/H2O2 system was still highly efficient in degrading diclofenac in actual water matrix (i.e., reservoir water and lake water). Overall, this study provided an eco-friendly approach to enhance the oxidation capacity of the Cu(II)/H2O2 system over a wide pH range, which might be a potential technology for degrading refractory organic pollutants in water treatment.

Accumulation kinetics of polystyrene nano- and microplastics in the waterflea Daphnia magna and trophic transfer to the mysid Limnomysis benedeni

Despite the pervasive presence of nano- and microplastics (NMPs) in aquatic environments, their movement through food chains remains poorly understood. In this study, we explored the uptake of polystyrene plastics (PSPs) of varying sizes (26, 500, and 4800 nm) in Daphnia magna and their subsequent transfer to the freshwater mysid Limnomysis benedeni, shedding light on the intricate dynamics of NMP transfer in freshwater ecosystems. Our results show that in D. magna the internal concentration of 4800 nm PSPs was 4–10 times higher than that of 26 and 500 nm PSPs, respectively. The uptake rate constants in daphnids decreased in the following order: 4800 nm (2.4 ± 0.5 L/g·h) > 26 nm (1.7 ± 0.4 L/g·h) > 500 nm (0.6 ± 0.1 L/g·h) PSPs. Importantly, only a small fraction (1–5 %) of the PSPs ingested by D. magna was transferred to L. benedeni. Additionally, larger particle sizes were associated with a higher extent of transfer in the food chain. Elimination rate constants in L. benedeni were found to be 0.03 ± 0.03, 0.1 ± 0.2, and 0.2 ± 0.8 per hour for 26, 500, and 4800 nm PSPs, respectively. Fluorescence observations revealed that PSPs were predominantly located in the stomach and intestine of L. benedeni. Furthermore, the calculated trophic transfer factor, based on the mass of particles accumulated in the organisms, was <1 for all PSP treatments. Our results indicate that NMPs can be transferred along the daphnia-mysids food chain, and that there is no evidence of biomagnification along this chain. These findings underscore the importance of understanding particle size effects on NMP transfer and accumulation in aquatic food webs, offering valuable insights for assessing the ecological risks associated with NMP pollution in freshwater ecosystems.

A Minimal PBPK Model Describes the Differential Disposition of Silica Nanoparticles In Vivo.

Nanoparticles (NPs) have emerged as promising candidates for drug delivery due to their tunable physical and chemical properties. Among these, silica nanoparticles (SiNPs) are particularly valued for their biocompatibility and adaptability in applications like drug delivery and medical imaging. However, predicting SiNP biodistribution and clearance remains a significant challenge. To address this, we developed a minimal physiologically-based pharmacokinetic (mPBPK) model to simulate the systemic disposition of SiNPs, calibrated using in vivo PK data from mice. The model assesses how variations in surface charge, size, porosity, and geometry influence SiNP biodistribution across key organs, including the kidneys, lungs, liver, and spleen. A global sensitivity analysis identified the most influential parameters, with the unbound fraction and elimination rate constants for the kidneys and MPS emerging as critical determinants of SiNP clearance. Non-compartmental analysis (NCA) further revealed that aminated SiNPs exhibit high accumulation in the liver, spleen, and kidneys, while mesoporous SiNPs primarily accumulate in the lungs. Rod-shaped SiNPs showed faster clearance compared to spherical NPs. The mPBPK model was extrapolated to predict SiNP behavior in humans, yielding strong predictive accuracy with Pearson correlation coefficients of 0.98 for mice and 0.92 for humans. This model provides a robust framework for predicting the pharmacokinetics of diverse SiNPs, offering valuable insights for optimizing NP-based drug delivery systems and guiding the translation of these therapies from preclinical models to human applications.

Utilising paired measurements of phosphatidylethanol to monitor early success in alcohol abstinence.

Phosphatidylethanol (PEth) is a specific and persisting marker of ethanol (alcohol) consumption. Early success of medically necessary abstinence can be assessed by monitoring PEth disappearance at a biologically plausible rate. This requires an understanding of PEth elimination, its variability and its determinants. To achieve this, we characterised PEth elimination in drinkers who voluntarily abstained. We aimed to derive a nomogram from the data to assist practitioners in recognising abstinence. Twenty-nine usual drinkers who were prepared to abstain from alcohol consumption for 4 weeks were recruited. Erythrocyte PEth was measured weekly. A population pharmacokinetic model for PEth was developed, describing the time-course of PEth elimination. Estimates were derived for population average, inter-individual variability in PEth half-life and any covariate influences. These estimates informed a nomogram of PEth elimination that incorporated a boundary separating continued abstinence from resumed drinking. The nomogram was tested to identify drinking events among participants. The model estimated a population average elimination rate constant (k) of 0.088 day-1, corresponding to a half-life of 7.9 days with a residual coefficient of variation of 8.5%. Elimination was first order and no covariate influences were identified. The nomogram was internally assessed as predictively accurate for 21 successfully abstinent participants and in detecting alcohol consumption in 2 further participants, using a 99.9% prediction interval. The value of PEth in distinguishing alcohol abstinence from consumption is enhanced by using a nomogram to confirm abstinence within weeks of its medically necessary imposition. Further work will establish the value of this approach in clinical practice.

Toxicokinetics and Mussel Watch: Addressing Interspecies Differences for Coastal Cadmium Contamination Assessment.

Bivalves are often employed for biomonitoring contaminants in marine environments; however, in these large-scale programs, unavoidably, using multiple species presents a significant challenge. Interspecies differences in contaminant bioaccumulation can complicate data interpretation, and direct comparisons among species may result in misleading conclusions. Here, we propose a robust framework based on toxicokinetic measurements that accounts for interspecies differences in bioaccumulation. Specifically, via a recently developed double stable isotope tracer technique, we determined the toxicokinetics of cadmium (Cd)─a metal known for its high concentrations in bivalves and significant interspecies bioaccumulation variability─in six widespread bivalve species including mussels (Perna viridis, Mytilus unguiculatus, Mytilus galloprovincialis) and oysters (Magallana gigas, Magallana hongkongensis, Magallana angulata). Results show that oysters generally have higher Cd uptake rate constants (ku: 1.18-3.09 L g-1 d-1) and lower elimination rate constants (ke: 0.008-0.017 d-1) than mussels (ku: 0.21-0.64 L g-1 d-1; ke: 0.018-0.037 d-1). The interspecies differences in tissue Cd concentrations are predominantly due to Cd uptake rather than elimination. Utilizing toxicokinetic parameters to back-calculate Cd concentrations in seawater, we found that the ranking of Cd contamination levels at the six sites markedly differs from those based on tissue Cd concentrations. We propose that this approach will be useful for interpreting data from past and future biomonitoring programs.

First-in-human evaluation of 6-bromo-7-[11C]methylpurine, a PET tracer for assessing the function of multidrug resistance-associated proteins in different tissues

PurposeMultidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer’s and chronic respiratory disease. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to measure MRP1 function in rodents. In this study, [11C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues.MethodsThirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (kE, h− 1) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology.ResultsMean kE and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h− 1 (− 4 ± 24%), cerebellum: 0.033 ± 0.009 h− 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h− 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h− 1 (30 ± 38%), lungs: 0.875 ± 0.095 h− 1 (− 3 ± 11%), myocardium: 0.641 ± 0.105 h− 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h− 1 (14 ± 16%), and liver: 0.685 ± 0.072 h− 1 (7 ± 9%). Significant sex differences were found for kE in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women.ConclusionLAFOV PET/CT with [11C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of kE in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [11C]BMP was in the typical range of 11C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans.Trial registrationEudraCT 2021-006348-29. Registered 15 December 2021.

Preparation of formic acid modified industrial zero-valent iron (FA-ZVIbm) for CdII-EDTA removal: CdII capturing and self-enhanced oxidative degradation of EDTA

Cadmium (Cd) contamination is highly toxic to human health, and the complexed Cd in wastewater is tricky to remove owing to its stable chelating structure. In this study, industrial zero-valent iron (ZVI) was modified by ball-milling with tiny formic acid (FA), and the as-prepared sample (FA-ZVIbm) was attempted in the treatment of CdII-ethylenediaminetetraacetic acid (CdII-EDTA). Little FA addition to ball-milling could dramatically improve the performance of FA-ZVIbm towards CdII-EDTA elimination and raise the elimination rate constant by more than 200 times. Results ascertained that the (HCOO)2FeII shell formed on FA-ZVIbm promoted CdII-EDTA decomplexation and activation of dissolved O2 to reactive oxygen species (ROS) for oxidative degradation of EDTA ligands. CdII-EDTA was instantly decomplexation by Fe3+ replacement, and the decomplexed Cd2+ was rapidly captured by FA-ZVIbm. At the same time, the EDTA ligands underwent oxidative degradation, avoiding the re-chelation ecological hazard. Interestingly, we found that replacement decomplexation has a synergistic mechanism for activating dissolved O2 to ROS, facilitating oxidative destruction of EDTA ligands. Furthermore, the FA-ZVIbm fixed-bed reactor could remediate CdII-EDTA contaminated environmental water one-stop, and the effluent stably meets the emission standards. This study demonstrated that FA-ZVIbm could be a viable approach for CdII-EDTA decontamination and clarified the remediation mechanism.

Population pharmacokinetics of mycophenolate in patients treated for interstitial lung disease (EVER-ILD study).

Mycophenolate mofetil (MMF) has been used to treat interstitial lung disease (ILD), but mycophenolate (MPA) pharmacokinetics was not reported for this use. This ancillary study of the EVER-ILD protocol aimed at describing the pharmacokinetic variability of MPA using population modelling in ILD. Concentrations of MPA were measured during an 8-h course for 27 ILD patients treated with 1000 mg MMF b.i.d. Absorption, distribution and elimination of MPA were described using population compartment models with first-order transfer and elimination rate constants, while accounting for both absorption peaks using gamma absorption models. The pharmacokinetics of MPA was best described using a two-compartment model and two gamma absorption models, model performances of this model were still similar to those of a one gamma absorption model. This pharmacokinetics seemed to be notably influenced by body weight, renal function and inflammatory status. The distribubtion value area under the concentration curve between two administrations of MMF was AUC12 = 52.5mg.h/L in median (interquartile range: 42.2-58.0mg.h/L). This is the first study reporting MPA pharmacokinetics in ILD. This pharmacokinetics appears to be similar to other indications and should be further investigated in future studies.

Protocatechuic acid enhanced the selective degradation of sulfonamide antibiotics in Fe(III)/peracetic acid process under actually neutral pH conditions

The practical application of the Fe-catalyzed peracetic acid (PAA) processes is seriously restricted due to the need for narrow pH working range and poor anti-interference capacity. This study demonstrates that protocatechuic acid (PCA), a natural and eco-environmental phenolic acid, significantly enhanced the removal of sulfonamide antibiotics in Fe(III)/PAA process under actually neutral pH conditions (6.0–8.0) by complexing Fe(III). With sulfamethoxazole (SMX) as the model contaminant, the pseudo-first-order rate constant of SMX elimination in PCA/Fe(III)/PAA process was 63.5 times higher than that in Fe(III)/PAA process at pH 7.0, surpassing most of the previously reported strategies-enhanced Fe-catalyzed PAA processes (i.e., picolinic acid and hydroxylamine etc.). Excluding the primary contribution of reactive species commonly found in Fe-catalyzed PAA processes (e.g., •OH, R-O•, Fe(IV)/Fe(V) and 1O2) to SMX removal, the Fe(III)-peroxy complex intermediate (CH3C(O)OO-Fe(III)-PCA) was proposed as the primary reactive species in PCA/Fe(III)/PAA process. DFT theoretical calculations indicate that CH3C(O)OO-Fe(III)-PCA exhibited stronger oxidation potential than CH3C(O)OO-Fe(III), thereby enhancing SMX removal. Four potential removal pathways of SMX were proposed and the toxicity of reaction solution decreased with the removal of SMX. Furthermore, PCA/Fe(III)/PAA process exhibited strong anti-interference capacity to common natural anions (HCO3−, Cl−and NO3−) and humic acid. More importantly, the PCA/Fe(III)/PAA process demonstrated high efficiency for SMX elimination in actual samples, even at a trace Fe(III) dosage (i.e., 5 μM). Overall, this study provided a highly-efficient and eco-environmental strategy to remove sulfonamide antibiotics in Fe(III)/PAA process under actually neutral pH conditions and to strengthen its anti-interference capacity, underscoring its potential application in water treatment.

Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK).

The evidence of rivaroxaban's pharmacokinetics in obese compared with non-obese populations remains inconclusive. We aimed to compare the pharmacokinetic profile of rivaroxaban between obese and non-obese populations under fed state. Participants who met the study's eligibility criteria were assigned into one of two groups: obese (body mass index ≥35 kg/m2) or non-obese (body mass index 18.5-24.9 kg/m2). A single dose of rivaroxaban 20 mg was orally administered to each participant. Nine blood samples over 48 h, and multiple urine samples over 18 h were collected and analyzed for rivaroxaban concentration using ultra-performance liquid chromatography coupled with tandem mass detector. Pharmacokinetic parameters were determined using WinNonlin software. Thirty-six participants were recruited into the study. No significant changes were observed between obese and non-obese participants in peak plasma concentration, time to reach peak plasma concentration, area under the plasma concentration-time curve over 48 h or to infinity, elimination rate constant, half-life, apparent volume of distribution, apparent clearance, and fraction of drug excreted unchanged in urine over 18 h. Rivaroxaban's exposure was similar between the obese and non-obese subjects, and there were no significant differences in other pharmacokinetic parameters between the two groups. These results suggest that dose adjustment for rivaroxaban is probably unwarranted in the obese population.

Towards process-based modelling and parameterisation of bioaccumulation in humans across PFAS congeners

Per- and polyfluoroalkyl substances (PFAS) are a large class of stable toxic chemicals which have ended up in the environment and in organisms in significant concentrations. Toxicokinetic models are needed to facilitate extrapolation of bioaccumulation data across PFAS congeners and species. For the present study, we carried out an inventory of accumulation processes specific for PFAS, deviating from traditional Persistent Organic Pollutants (POPs). In addition, we reviewed toxicokinetic models on PFAS reported in literature, classifying them according to the number of compartments distinguished as a one-compartment model (1-CM), two-compartment model (2- CM) or a multi-compartment model, (multi-CM) as well as the accumulation processes included and the parameters used. As the inventory showed that simple 1-CMs were lacking, we developed a generic 1-CM of ourselves to include PFAS specific processes and validated the model for legacy perfluoroalkyl acids. Predicted summed elimination constants were accurate for long carbon chains (>C6), indicating that the model properly represented toxicokinetic processes for most congeners. Results for urinary elimination rate constants were mixed, which might be caused by the exclusion of reabsorption processes (renal reabsorption, enterohepatic circulation). The 1-CM needs to be improved further in order to better predict individual elimination pathways. Besides that, more data on PFAS-transporter specific processes are needed to extrapolate across PFAS congeners and species.

Integrated models of population pharmacokinetics and exposure response to optimize dosage regimen for anaprazole sodium in duodenal ulcer

Anaprazole sodium enteric-coated tablet is a novel proton pump inhibitor which has been approved for the treatment of duodenal ulcer. The aim of this study is to provide reliable information for the design of an optimal dosage regimen. Population pharmacokinetics and exposure-response models were integrated to evaluate the pharmacokinetic parameters and covariates of Anaprazole and its metabolite M21-1, and subsequently provided dosage suggestions based on clinical trials and simulation data. A pharmacokinetic model incorporating two-compartment for the parent drug and one-compartment for the metabolite, with both first-order and zero-order mixed absorption was used to describe the pharmacokinetics of Anaprazole and M21-1. Age emerged as a significant covariate affecting the elimination rate constant of M21-1, with clearance decreasing as age advances. No correlation was observed between the pharmacokinetics of Anaprazole or M21-1 and the adverse reactions under the current dosages. BMI might be the influence factor of the mild gastrointestinal adverse reactions. Meanwhile, Anaprazole had a good healing rate (94.0 %) in duodenal ulcer patients and the exposure-response analysis indicated that the cured results were not influenced by the exposure parameters of parent drug or metabolite. In conclusion, the drug is safe when dosing between 20 and 100 mg once a day.

Fate of synthetic chemicals in the agronomic insect pest Spodoptera littoralis: experimental feeding-contact assay and toxicokinetic model.

Insecticides prevent or reduce insect crop damage, maintaining crop quality and quantity. Physiological traits, such as an insect's feeding behavior, influence the way insecticides are absorbed and processed in the body (toxicokinetics), which can be exploited to improve species selectivity. To fully understand the uptake of insecticides, it is essential to study their total uptake and toxicokinetics independent of their toxic effects on insects. We studied the toxicokinetics (TK) of insecticidally inactive test compounds incorporating agro-like structural motifs in larvae of the Egyptian cotton leafworm (Spodoptera littoralis,Lepidoptera),and their distribution across all biological matrices, using laboratory experiments and modeling. We measured Spodoptera larval behavior and temporal changes of whole-body concentrations of test compounds during feeding on treated soybean leaf disks and throughout a subsequent depuration period. Differences in the distribution of the total quantities of compounds were found between the biological matrices leaf, larva, and feces. Rate constants for uptake and elimination of test compounds were derived by calibrating a toxicokinetic model to the whole-body concentrations. Uptake and elimination rate constants depended on the physicochemical properties of the test compounds. Increasing hydrophobicity increased the bioaccumulation potential of test compounds. Incomplete quantities in larval matrices indicated that some compounds may undergo biotransformation. As fecal excretion was a major elimination pathway, the variable time of release and number of feces pellets led to a high variability in the body burden. We provide quantitative models to predict the toxicokinetics and bioaccumulation potential of inactive insecticide analogs (parent compounds) in Spodoptera.

The Effect of Zinc Concentration on Bioaccumulation in Milkfish &lt;i&gt;(Chanos chanos)&lt;/i&gt; Use of &lt;sup&gt;65&lt;/sup&gt;Zn as a Radioactive Tracer

Bioaccumulation studies of zinc (Zn) in milkfish (Chanos chanos) have been carried out in the laboratory using a 65Zn radiotracer. The research was conducted to determine the effect of Zn concentration on the ability of Chanos chanos to accumulate and release these contaminants. Zn absorption follows the single-compartment model, and experiments were carried out until stable conditions were achieved. The stages of research were biota collection, acclimatization, bioaccumulation, and elimination. Acclimatization was carried out for biota adaptation in the experimental environment. Bioaccumulation was carried out for 7 days by placing the biota in an aquarium filled with seawater added with 65Zn radiotracer contaminants. The elimination process involves the release of contaminants from the biota by placing them in contaminant-free seawater for 7 days. The results of the bioaccumulation experiment showed that the concentration factor (CF) ranged from 0.67 - 18.18 mLgr-1 at a concentration of ZnCl2 of 1.5 ppm, and the absorption constant (ku) 1.878 - 3.267d-1 and R2 was 0.0276. The release of contaminants in depuration experiments was highest at ZnCl2 2 ppm concentrations. The percentage of retention during depuration was between 14.61 - 79.91 %, the elimination constant (ke) was 8.681, and R2 was 0.7213.

Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail

PurposeAdefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CLR) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail.MethodsData from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination.ResultsA one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h−1 vs. 5.18 h−1) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (Km) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (Vmax) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min.ConclusionThe popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high Km value suggests that assessing renal OAT1 activity by CLR has no relevant misspecification error with the cocktail doses used.