Elimination Rate Constant Research Articles

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.

A new Turkish pharmacokinetics software program for therapeutic drug monitoring of theophylline

In this study, it was aimed to develop a Turkish software with pharmacokinetic (PK) data for therapeutic drug monitoring and IV dose adjustment of narrow therapeutic index theophylline. The study involved three groups, each comprising two rabbits The dose required for the target concentration (15µg/mL) was calculated with the developed program according to the weight of the rabbits in the first group. Blood samples taken at certain times were analyzed by validated HPLC method to calculate the elimination rate constant (ke) after IV bolus administration. The r2 values for ke were found to be 0.86 and 0.95. The second dose calculated according to revised PK findings was administered and blood samples were taken. When the analyzed results and theoretical results were compared, the deviation was found to be 5.53% and 8.795%. The findings were taken as the population PK for other applications. IV multiple dose bolus and IV fast-slow combined infusion were administered to the second group and the third group, respectively. The results obtained from the analysis of blood samples taken at the times determined according to the application were compared with the theoretical results. As a result, although there is a high difference between theory and practice at low concentrations, there is very little variation at high concentrations. By using this program, it has been achieved to keep theophylline at the desired level without reaching the minimum toxic concentration and without falling below the minimum effective concentration. It is thought that deviations will be reduced with larger samples.

EPLERENONE FLOATING MICROSPHERES: RADIOGRAPHIC AND PHARMACOKINETIC STUDIES IN RABBITS

Objective: The objective of the present investigation was to evaluate gastro-retentive performance and pharmacokinetic parameters of Eplerenone-optimized floating microspheres compared with formulated floating tablets. Methods: Microsphere contains antihypertensive drug Eplerenone as a core material encapsulated with the polymeric membrane for sustained drug release were prepared by solvent diffusion-evaporation technique. The prepared microspheres were evaluated for qualitative and quantitative parameters. The optimized formulation showed favorable in vitro floating and drug release profile. The gamma scintigraphy of the formulation was carried out in rabbit in order to determine the floating ability of the final formulation with barium sulfate. Prolonged gastric residence time of over 12 h was achieved in all the animals. Eplerenone-loaded optimized formulation was orally administered to rabbit and blood samples were used to determine pharmacokinetic parameter by using WinNonlin software 3.0 version. Results: Eplerenone floating microsphere, which are compared with pharmacokinetic parameters of the Floating tablet showed improved parameters of Cmax; similarly, time to reach peak plasma concentration (t-max) for Eplerenone Floating microspheres was 4 times increased against Floating tablet formulation. The area under the curve (AUC) for formulated floating tablet was found to be 9.69 µg/ml, whereas for floating microspheres it was 16.28 µg/ml, for formulated floated tablet absorption rate constant Ka was 1.61 h, elimination rate constant was 0.112 h and elimination half-life 6.2 h. The comparison of these data undoubtedly shows that the Cmax was not much valid, but AUC was increased to about 1.68 times in case of floating microspheres, absorption rate constant was found to be decrease 3.22 times when related to the floating microspheres, whereas Ke was found to be decrease 2.11 times when equated to floating microspheres, elimination half-life was increased by almost about two times. Conclusion: Eplerenone floating microsphere, which are compared with pharmacokinetic parameters of the floating tablets showed enhanced parameters of the formulated due to floating nature of the present designed formulation.

EFFECT OF PEGYLATED POLYPROPYLENE IMINE DENDRITIC ARCHITECTURE ON PHARMACOKINETICS OF PYRAZINAMIDE ON RABBITS

Objective: This study sought to investigate the impact of pegylated polypropylene imine dendrimer-loaded pyrazinamide on drug delivery and assess this novel formulation's pharmacokinetic parameters. Methods: Various concentrations of pyrazinamide-loaded dendrimers were formulated in four distinct batches, with the most promising formulation selected for administration to New Zealand rabbits. Plasma concentrations of the drug were subsequently compared to those of the pure drug. Pharmacokinetic parameters, including maximum plasma concentration (Cmax), time to reach Cmax (tmax), the area under the curve (AUC), the area under the first moment curve (AUMC), elimination rate constant (λz), biological half-life (t1/2), and mean residence time (MRT), were meticulously determined. Results: The plasma drug concentration Vs time profile illustrated a sustained release pattern for the pyrazinamide drug-loaded dendrimer formulation compared to the pure drug. While a minor alteration was observed in peak plasma concentration, a notable divergence was noted in all other pharmacokinetic parameters. The AUC demonstrated a fourfold increase for pyrazinamide drug-loaded dendrimers, rising from 8657.94±295.10 to 34663.89±702.89 (ng/ml/h), and the mean residence time nearly doubled when compared to the pure drug. Conclusion: Pyrazinamide drug-loaded dendrimers exhibit significant potential for enhancing drug release compared to the pure drug. This novel formulation promises a substantial and sustained drug release profile, holding promise for improving therapeutic outcomes and patient compliance in the treatment of relevant conditions.

Toxicokinetics of the Antidepressant Fluoxetine and Its Active Metabolite Norfluoxetine in Caenorhabditis elegans and Their Comparative Potency.

The nematode Caenorhabditis elegans is a valuable model for ecotoxicological research, yet limited attention has been given to understanding how it absorbs, distributes, metabolizes, and excretes chemicals. This is crucial for C. elegans because the organism is known to have strong uptake barriers that are known to be susceptible to potential confounding effects of the presence of Escherichia coli as a food source. One frequently studied compound in C. elegans is the antidepressant fluoxetine, which has an active metabolite norfluoxetine. In this study, we evaluated the toxicokinetics and relative potency of norfluoxetine and fluoxetine in chemotaxis and activity tests. Toxicokinetics experiments were conducted with varying times, concentrations of fluoxetine, and in the absence or presence of E. coli, simulated with a one-compartment model. Our findings demonstrate that C. elegans can take up fluoxetine and convert it into norfluoxetine. Norfluoxetine proved slightly more potent and had a longer elimination half-life. The bioconcentration factor, uptake, and elimination rate constants depended on exposure levels, duration, and the presence of E. coli in the exposure medium. These findings expand our understanding of toxicokinetic modeling in C. elegans for different exposure scenarios, underlining the importance of considering norfluoxetine formation in exposure and bioactivity assessments of fluoxetine.

First-in-human study of CPL207280, a novel G-protein-coupled receptor 40/free fatty acid receptor 1 agonist, in healthy volunteers after single and multiple administration.

To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G-protein-coupled receptor 40 agonist developed to treat type 2 diabetes (T2D). The phase 1 study in healthy volunteers (White, age 18-55 years, body mass index 18.5-29.9 kg/m2 ) was performed after single (24 subjects, 5-480 mg) and multiple (32 subjects, 60-480 mg) once-daily administration of CPL207280. The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C-peptide, proinsulin, glucagon levels) observed during the 14-day treatment period. No deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration (Cmax ) or area under the plasma concentration-time curve up to 24 h. However, dose-normalized Cmax decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half-life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed. CPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single-daily administration and justifies further development of this therapy for patients with T2D.

Population Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim Biosimilar GP40141 and Reference Product in Healthy Volunteers to Evaluate Biosimilarity.

GP40141 is a romiplostim biosimilar. A Phase 1 clinical trial was previously conducted in healthy volunteers to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of GP40141 compared to the reference romiplostim (NCT05652595). Using noncompartmental analysis, the biosimilarity of PD end points was determined according to the classical criterion (0.8-1.25). PK end points were also in good agreement between GP40141 and the reference romiplostim; however, the confidence interval for the area under concentration-time curve from time 0 to the time of last measurement was slightly out of the bioequivalence range (0.91-1.29). Population PK/PD was used in the present study to characterize the individual PK and PD data of 56 healthy subjects in 2 cross-over periods of the Phase 1 clinical trial. Body weight and neutralizing antibodies to romiplostim were found to be important predictors of apparent volume of distribution and linear elimination constant, respectively. Within the framework of the conducted modeling, population estimates of PK/PD parameters were obtained, which were in agreement with literature data for the reference romiplostim. Additionally, values of intersubject variability, previously unreported for romiplostim in a healthy subject population, were derived. Covariate analysis, conducted during model development, as well as visual diagnostics and model-based simulations, demonstrated the absence of significant differences in PK and PD between GP40141 and romiplostim-ref.

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.

The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

Photocatalytic decomposition of methylene blue and methyl orange dyes using pistachio biochar/CoFe2O4/Mn-Fe-LDH composite as H2O2 activator

Photocatalysis has gained a lot more notice due to its simplicity, cost-effectiveness, and efficiency, especially for dye degradation. In this study, a novel composite (PBC/CoFe2O4/Mn-Fe-LDH) including pistachio biochar (PBC), CoFe2O4 magnetic nanoparticles, and Mn-Fe-layered doubled hydroxide (LDH) was produced using a co-precipitation method. The composite was utilized to remove methylene blue (MB) and methyl orange (MO) dyes from aqueous solutions by the photodegradation method. The Brunauer-Emmett-Teller (BET), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy-energy dispersive X-ray (SEM-EDX) analyses were used for characterization of the desired samples. The designed variables were pH (2-10), concentration of dye (10-30 mg.L−1), photocatalyst amount (0.2-1 g.L−1), H2O2 quantity (10-50 µL/100 mL), and time (10-50 min). The maximum degradation of MB and MO at optimal conditions (pH: 2 for MO and 10 for MB, dye concentration: 10 mg.L−1, catalyst mass: 1 g.L−1, time: 50 min, H2O2 value: 30 μL/100 mL) was obtained 99.10% and 99.89%, respectively. The scavenger effect investigation indicated that the species of OH• and O2•−, and h+ have the main function in the MB and MO degradation. The data were well explained by the pseudo-first-order kinetic model, and the constants for MB and MO dye elimination were established as 0.060 min−1 and 0.056 min−1, respectively. The PBC/CoFe2O4/Mn-Fe-LDH as a novel and promising composite could be useful for dye degradation in the photocatalytic reactor.

Effects of Resveratrol Co-Administration on Celecoxib Disposition and Pharmacokinetics in Healthy Volunteers

AbstractThe objective of the current study was to investigate the effects of resveratrol (RSV), a natural herbal remedy used as an adjacent anti-inflammatory supplement on, the pharmacokinetics of celecoxib in healthy male volunteers. Twelve healthy human participants were involved in two-period open-labeled trial. Celecoxib (200 mg) was given as a single oral dose under fasting conditions as a control phase. Afterward, RSV (500 mg) commenced as a single oral dose for ten days as a treatment phase. Blood samples were collected during the control and treatment phases and analyzed using the validated High-performance liquid chromatography (HPLC) method. RSV pre-exposure significantly increased the area under the curve (AUC0–24), peak plasma concentration (Cmax), absorption rate constant (ka), and prolongated half-life (t1/2), along with a decrease in elimination rate constant (ke). Meanwhile, the volume of distribution (Vd/F) and apparent total body clearance (CL/F) were significantly decreased for celecoxib. There was no significant change in the time it takes for celecoxib to reach the maximum concentration (tmax) was observed. The obtained results suggested the presence of a beneficial pharmacokinetic interaction between RSV and celecoxib. Consequently, combining resveratrol as an herbal remedy and celecoxib as an anti-inflammatory drug may synergistically reduce inflammation and osteoarthritis with minimal side effects.

Ocimum basilicum essential oil in pacu Piaractus mesopotamicus: anesthetic efficacy, distribution, and depletion in different tissues.

This study aimed to evaluate the anesthetic activity of Ocimum basilicum essential oil and the distribution and depletion of its major compounds in different tissues of the pacu, Piaractus mesopotamicus. Juveniles (319.08 ± 9.14g) were individually anesthetized with six concentrations of essential oil from O. basilicum (150, 180, 210, 240, 270, and 300mg L-1), while in a second experiment, fish (492.39 ± 51.51g) were subjected to a 10min immersion bath with essential oil from O. basilicum (300mg L-1). After anesthetic recovery, blood and tissue samples of the brain, gills, liver, spleen, and white muscle were collected at 0, 0.5, 1.0, 3.0, 6.0, 12.0, and 24h. A 300mg L-1 concentration induced anesthesia in the shortest time (193.11 ± 9.31), while at 270 and 300mg L-1 concentrations, the anesthetic recovery period was the longest (244.33 ± 12.44) Methyl chavicol and linalool were quantified in all tissue samples. The plasma concentrations of methyl chavicol differed (p < 0.05) at all evaluated times. Linalool decreased (p < 0.05) from 0 to 1h and decreased again only after 12h. Reduction percentages in 24h were 92.9% for methyl chavicol, and 97.2% for linalool. Elimination of the compounds methyl chavicol and linalool is slower in the gills, where lower elimination constants (0.03 and 0.15 per h) and longer half-lives (25.84 and 4.53h), respectively, are noted. In general, essential oil from O. basilicum compounds was readily eliminated, showing promising potential for use as an anesthetic in aquaculture.

Bioavailability and excretion profile of betacyanins – Variability and correlations between different excretion routes

The present study addresses the knowledge gap in betalain bioavailability, transformation and excretion. Analysis of renal and fecal excretion profiles in humans after consumption of beetroot revealed very low bioavailability (renal recovery of 0.13 %) and fast elimination of pigments (renal elimination rate constant of 0.16 h−1), while the majority of betalains underwent severe depletion during GI transit, evidenced by decarboxylation, deglucosidation and dehydrogenation. Betacyanin metabolite levels in human urine were positively associated with those in stools (p < 0.05), indicating significant impact of pigment metabolism in the gut on their bioavailability. In addition, the current study revealed large inter-individual and compositional variabilities of pigment after colonic fermentation compared with systemic metabolism, likely attributed to the increasing complexity of intestinal environment with diverse gut microbiota. To conclude, intestinal uptake and systemic metabolism of betacyanins are intimately associated with their intestinal biotransformation, with gut microbiota serving as a crucial factor.

Drug-Drug Interactions Pharmacokinetic Models with Extravascular Administration: Estimation of Elimination and Absorption Rate Constants

One and two-compartment pharmacokinetic models with drug-drug interactions are proposed. Two drugs are given orally simultaneously, so that their interaction affects the drug absorption process and subsequently the elimination process. The aim of this paper is to estimate the elimination and absorption rate constants by evaluating the data set of time and drug concentration. This data set was divided into two time phases: large-time elimination phase to estimate the elimination rate constant, and small-time absorption phase to estimate the absorption rate constant. Since the models are nonlinear, the Taylor expansion is employed to so that the Wagner-Nelson and the Loo-Riegelman methods can be used for estimation. Finally, simulations were performed using the generated arbitrary data set of time and concentration, instead of an actual data set, to derive the solution of drug concentration concerning time numerically. In these simulations we compared the original parameter values with their estimates for the one and two-compartment models, and we concluded that the two-compartment model produced better estimates than the one-compartment model. Qualitatively, the two-compartment model gives smaller drug concentration curve deviations between the original and the estimated curve compared with the one-compartment model.

Confocal Raman Spectroscopic Characterization of Dermatopharmacokinetics Ex Vivo.

Confocal Raman spectroscopy is being assessed as a tool with which to quantify the rate and extent of drug uptake to and its clearance from target sites of action within the viable epidermis below the skin's stratum corneum (SC) barrier. The objective of this research was to confirm that Raman can interrogate drug disposition within the living layers of the skin (where many topical drugs elicit their pharmacological effects) and to identify procedures by which Raman signal attenuation with increasing skin depth may be corrected and normalized so that metrics descriptive of topical bioavailability may be identified. It was first shown in experiments on skin cross-sections parallel to the skin surface that the amide I signal, originating primarily from keratin, was quite constant with depth into the skin and could be used to correct for signal attenuation when confocal Raman data were acquired in a "top-down" fashion. Then, using 4-cyanophenol (CP) as a model skin penetrant with a strong Raman-active C≡N functionality, a series of uptake and clearance experiments, performed as a function of time, demonstrated clearly that normalized spectroscopic data were able to detect the penetrant to at least 40-80 μm into the skin and to distinguish the disposition of CP from different vehicles. Metrics related to local bioavailability (and potentially bioequivalence) included areas under the normalized C≡N signal versus depth profiles and elimination rate constants deduced post-removal of the formulations. Finally, Raman measurements were made with an approved dermatological drug, crisaborole, for which delivery from a fully saturated formulation into the skin layers just below the SC was detectable.

Population Pharmacokinetics of Topiramate in Patients with Epilepsy Using Nonparametric Modeling.

Topiramate (TPM) is used for the treatment of various epileptic seizures and the prevention of migraine. This study aimed to develop a population pharmacokinetic model and identify covariates that influence TPM behavior in patients with epilepsy in Kuwait. Data were collected retrospectively from 108 patients (2 years old and above) with epilepsy who were treated with oral TPM and 174 TPM blood samples from 3 hospitals in Kuwait from 2009 to 2016. Data were randomly divided into 2 groups for model development and validation. The population pharmacokinetic model was built using the nonparametric modeling algorithm (Pmetrics). The model was evaluated internally through the visual predictive check method and externally using a new data set. A 1-compartment model with first-order elimination fitted the data well. Covariates showing a significant effect on the elimination rate constant were renal function and coadministration of carbamazepine (CBZ). The mean estimated clearance was 2.11 L/h; this was 50% higher for patients coadministered with CBZ. Age and sex were essential covariates for the volume of distribution (V). The visual predictive check of the final model could predict the measured concentrations. External validation further confirmed the favorable predictive performance of the model with low bias and imprecision for predicting the concentration in a particular population. TPM elimination was increased with CBZ coadministration and was affected by renal function. Meanwhile, age and sex were the main predictors for V. The predictive performance of the final model proved to be valid internally and externally.

Bioconcentration of carbamazepine, enalapril, and sildenafil in neotropical fish species.

Sewage effluents are the main source of entry of Human Pharmaceutical Active Ingredients (HPAIs) to surface water bodies. Carbamazepine (CBZ), psychiatric drug, enalapril (ENA) antihypertensive, and sildenafil (SIL), to treat erectile dysfunction, have been frequently detected in receiving wastewater and in wild fish species from Argentina. This study aimed to assess the bioconcentration of selected HPAIs in native fish species of the Del Plata Basin. In a first trial, the bioconcentration factors of CBZ, ENA, and SIL were obtained by exposing Cnesterodon decemmaculatus, respectively, to 135, 309, and 70μg/L during 96h. Then the bioconcentration kinetic of SIL was comparatively assessed in C. decemmaculatus and Piaractus mesopotamicus exposed, respectively, to 44.1 and 16.2μg/L during a one-week, followed by a four-day depuration phase. HPAIs concentrations in water and tissue were measured by HPLC-MS after 0.22μm filtration and direct injection or solid-liquid extraction, respectively. Bioconcentration factors obtained empirically (BCFe) for C. decemmaculatus were CBZ = 1.5, SIL = 1.4, and ENA = 0.007. Parameters estimated by the SIL bioconcentration kinetic model for C. decemmaculatus were: uptake rate constant (k1) = 5.5L/kg d, elimination rate constant during uptake phase (k2u) = 0.00175 d-1, maximum predicted tissue concentration (Ct(max)) = 138588μg/kg, estimated bioconcentration factor (BCFm) = 3143, lag time between the exposure and the first detection in tissue (tlag) = 0 d, elimination rate constant in the depuration phase (k2d) = 0.49 d-1 and half-life in the tissue (t1/2) = 1.4 d. The model parameters for P. mesopotamicus were k1: 7.3L/kg d, k2u: 0.0836 d-1, Ct(max): 1423μg/kg, BCFm: 88, tlag: 3.8 d in the uptake phase and k2d: 0.31 d-1 and t1/2: 2.3 d in the depuration phase. The reached conclusions were: 1) the bioconcentration capacity of CBZ and SIL are similar but around 200 times higher than ENA, 2) the time to reach the bioconcentration equilibrium for SIL is longer than 1week, then estimated BCFm are between 1 and 3 orders of magnitude higher than BCFe obtained after 96h exposure, but actual values need to be verified, 3) substantial differences (≈30 fold) were observed in the estimated BCF of SIL among species, indicating the need for further studies toward understanding such diversity to improve HPAIs ecological risk assessment worldwide.

Bioaccumulation of zinc by Portunus pelagicus: Nuclear application techniques that use radiotracer 65Zn to study influence of concentration of Zn in seawater

Zinc (Zn) is an essential trace metal, but also a potential toxicant to aquatic organisms. Zinc is one of the toxicants from various industrial and domestic activities whose waste is directly discharged into water. One of the marine organisms used as an indicator of pollution is the blue swimming crab (Portunus pelagicus). Bioaccumulation studies of Zn in Portunus pelagicus from Jakarta Bay were conducted in a radiotracer laboratory. Laboratory experiments were done to study the uptake and release of 65Zn radioisotope in Portunus pelagicus. The experiments conducted were biota collection, acclimatization, bioaccumulation, and elimination. This study was to determine the relationship between the amount of 65Zn released into the aquatic environment and its effect on Zn bioaccumulation ability and radiation dose received by Portunus pelagicus. Biokinetics parameters, such as concentration factors CF, uptake rate constant ku, elimination rate constant ke, and concentration factor steady state (CFss) were investigated. The results showed that an increase in concentration would decrease the rate of absorption and rate of elimination, and that the concentration factor CF values ​​varied from 7.82 - 60.62 ml.g-1 in Portunus pelagicus. The concentration factor at steady-state Zn was 25.55-59.47 ml.g–1, which is influenced by the concentration after 6 days of exposure. The depuration rate was observed to be high, with a value of retention 34.33 - 78.88 % of 65Zn absorbed by Portunus pelagicus, which was absent 7 days after exposure. Highlights Laboratory experiments lasting 14 days showed that Portunus pelagicus has the ability to accumulate the heavy metal zinc (Zn) from the environment and release it back into the water The highest bioaccumulation kinetics of zinc (Zn) metal in Portunus pelagicus during the 7-day experiment occurred at a contaminant concentration of 0.5 ppm with an absorption constant (ku) value of 0.7838 d-1 and a release constant value (ke) of 0.0892 d-1 Portunus pelagicus concentration factor (CF) has a moderate value and the smallest uptake constant (ku) and elimination constant (ke) value compared to other biota

A toxicokinetics approach using Enchytraeus crypticus to evaluate the efficiency of hydroxyapatite to remediate soils contaminated with rare earth elements

Extensive rare earth element (REE) mining activities pose threats to agricultural soils surrounding the mining areas. Here, low and high REE-contaminated soils from farmlands around mine tailings were remediated with hydroxyapatite. A toxicokinetic approach was applied to assess whether the use of hydroxyapatite reduced the bioavailability of REEs and thus inhibited their accumulation in the terrestrial organism Enchytraeus crypticus. Our results showed that addition of hydroxyapatite increased soil pH, DOC and anion contents. CaCl2-extractable REE concentrations significantly decreased, indicating the stabilization by hydroxyapatite. The influence of hydroxyapatite on the REE accumulation in enchytraeids was quantified by fitting a toxicokinetic model to dynamic REE body concentrations. The estimated uptake (Ku) and elimination rate constants (Ke), and bioaccumulation factor (BAF) for REEs were in the range of 0.000821 – 0.122 kgsoil/kgworm day−1, 0.0224 – 0.136 day−1, and 0.00135 – 1.96, respectively. Both Ku and BAF were significantly reduced by over 80% by hydroxyapatite addition, confirming the decreased REE bioavailability. Low atomic number REEs had higher BAFs in slightly contaminated soil, suggesting a higher bioaccumulation potential of light REEs in soil organisms. Overall, chemical stabilization with amendments can attenuate the bioavailability of REEs and reduce the potential ecological risk of contaminated agricultural soils near REE mining areas.

POTENTIAL HERB-DRUG INTERACTION OF DECALEPIS HAMILTONII VIA P-GP MEDIATED PHARMACOKINETIC INTERACTION WITH FEXOFENADINE IN RATS: AN IN SITU AND IN VIVO STUDY

Objective: The objective of this study was to investigate the influence of Decalepis hamiltonii (D. hamiltonii), a traditional plant used in herbal medicine, on the intestinal absorption and pharmacokinetics of fexofenadine, a substrate of P-glycoprotein (P-gp), in rats. Methods: In situ intestinal perfusion tests were conducted to assess the intestinal permeability of fexofenadine. P-gp ATPase activity was also evaluated to understand the modulatory effects of D. hamiltonii on P-gp. An in vivo pharmacokinetic investigation was performed by administering oral fexofenadine to rats. Results: The in situ study results revealed that the effective permeation (Peff) of fexofenadine was significantly diminished (p&lt;0.001***) in aqueous extract of D. hamiltonii (AREDH, 200 mg/kg p. o.) pretreated group compared to normal control indicating modulation in absorption. Further, there was significant augmentation (p&lt;0.01**) of P-gp ATPase activity in AREDH pretreated group (200 mg/kg p. o.) compared normal control indicating P-gp inductive potential of D. hamiltonii. Pharmacokinetic study results revealed that the peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of fexofenadine was significantly downregulated (p&lt;0.001***) in AREDH pretreated group (200 mg/kg p. o.) compared to the normal control group indicating the compromised absorption and bioavailability. However, no significant changes were observed in fexofenadine half-life (T1/2 k10), time to reach peak plasma concentration (Tmax), or elimination rate constant (k10). Conclusion: In conclusion, D. hamiltonii significantly reduced the oral bioavailability of fexofenadine by promoting P-gp-mediated drug efflux during intestinal absorption. This suggests that the modulatory characteristics of D. hamiltonii may lead to herb-drug interactions when taken in combination with xenobiotics, emphasizing the importance of considering such interactions in clinical practice and further research.

A deuterium tracer experiment for simulating accumulation and elimination of organically bound tritium in an edible flatfish, olive flounder

Tritium (3H, T) is discharged by nuclear facilities into coastal oceans as tritiated water (HTO). When the concentration of HTO in seawater increases, the accumulation of organically bound tritium (OBT) in edible fish becomes a concern because of its longer residence time than HTO. To evaluate the accumulation potential of OBT in olive flounder (Paralichthys olivaceus), a commercially important edible fish in northeast Asia, we experimentally exposed the fish to seawater enriched with deuterium (2H, D) as a substitute for tritium. Progressive increases and decreases in the concentration of organically bound deuterium (OBD) were observed in the edible part (i.e., muscle) of the fish during the period of exposure to 2H (161 days) and the subsequent period of elimination of OBD (196 days). The measured concentration of OBD was analyzed using a newly developed single-compartment model to describe the metabolism of OBD in muscle via the following three transfer pathways: formation of OBD from 2H in water, elimination of OBD by catabolism, and ingestion of feed with natural abundance of OBD. The model estimates were in good agreement with the measured muscle OBD concentrations. The formation and elimination rate constants for OBD in the muscle were estimated by fitting our model to the measured data. The biological half-life of OBT in the muscle, estimated from the elimination rate constant, was 133 days, which was far longer than that of HTO in the free water of the muscle. Our model facilitates the estimation of OBT accumulation potential in olive flounder inhabiting coastal areas near nuclear facilities, and thus, will help to assess the radiation dose that humans are exposed to from ingesting seafood.