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Geosmin (GSM) is a ubiquitous odorant found in aquatic environments and organisms, with significant impacts on drinking water and aquaculture. However, its transfer from contaminated water to fish tissues is poorly investigated, resulting in limited information on its bioconcentration and environmental behavior. Fugacity and one-compartment models were developed to describe the fate, transformation, and transport of GSM in an air-water-fish system and analyze its uptake, distribution, and elimination kinetics in channel catfish (Ictalurus punctatus). The results showed that the fugacity model calculations indicated that 81.3 % of GSM was found in water for all microcosm. The primary mass transfer processes from water were water-air diffusion process (T21v) and that from water to fish (T2 f), with values of 67.3 and 22.54 μg/h, respectively. The emission rate (E2) and area (A2) in water parameters are most sensitive to GSM concentration, impacting the distribution and variance of contaminant concentration. Kinetic studies in fish revealed that GSM primarily accumulate in the muscle and skin, with the earthy-odor burden of fish contributed by the former, reaching 86.59 %. The uptake rate constant (kup), depuration rate constant (kde), and half-lives (t1/2) fell within the ranges of 0.737–3.534 L/(kg·h), 0.024–0.097 1/h, and 7.1–28.9 h, respectively. Bioaccumulation factors (BAFs) for GSM in fish skin, muscle, and liver tissues were 105.79, 61.71, and 51.22 L/kg, respectively. GSM was effectively depurated by other tissues within 72 h, while 18.16 % remained in skin. The liver demonstrated the most accurate curve (R2=0.97), followed by skin and muscle, with the gill showing the worst simulation. This work offers insights into understanding the fate and mass transfer flux of trace odorants in environmental and biological phases.

Lizhi Chen,1,* Yunyun Yang,1,2,* Xuebin Wang,1,* Chenyu Wang,2 Weiwei Lin,3 Zheng Jiao,2,4 Zhuo Wang1 1Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China; 2Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of China; 3Department of Pharmacology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China; 4Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zheng JiaoDepartment of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Shanghai, 200030, People’s Republic of ChinaTel +86 21 2220 0000 ext 3021Email jiaozhen@online.sh.cnZhuo WangDepartment of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, People’s Republic of ChinaTel/Fax +86-21-31162299Email wztgyx223@163.comPurpose: In this study, we aimed to establish a tacrolimus population pharmacokinetic model and better understand the drug-drug interaction between Wuzhi capsule and tacrolimus in Chinese renal transplant recipients.Patients and Methods: We performed a population pharmacokinetic analysis using a non-linear mixed-effects model to determine the suitable Wuzhi capsule dose in combination with tacrolimus. Data on 1378 tacrolimus steady-state concentrations were obtained from 142 patients who received kidney transplant in Changhai Hospital and Huashan Hospital. Demographic characteristics, laboratory tests, genetic polymorphisms, and co-medications were evaluated.Results: The one-compartment model best described data. Our final model identified creatinine clearance rate, hematocrit, Wuzhi capsule dose, CYP3A5*3 genetic polymorphisms, and tacrolimus daily dose as significant covariates for tacrolimus clearance, with the value of 14.4 L h− 1, and the between-subject variability (BSV) was 25.4%. The Wuzhi capsule showed a dose-dependent effect on tacrolimus pharmacokinetics, demonstrating a stronger inhibitory effect than inductive effect.Conclusion: Our model can accurately describe population pharmacokinetics of tacrolimus when combined with different doses of Wuzhi capsule. Additionally, this model can be used for individualizing tacrolimus dose following kidney transplantation.Keywords: renal transplantation, inhibitory effect, one-compartment model, CYP3A5

Japanese dace Tribolodon hakonensis rearing experiments were conducted to estimate parameters related to 137Cs uptake and excretion processes. Fish (initial mean total length 256 mm, 136 g) were reared at 20 °C for 182 days using the same daily ingestion rate (1% of body weight for 6 days per week) with three feeding regimens: feeding contaminated pellets (80.7 Bq/kg-dry of 137Cs) throughout the experiments (137Cs uptake group), feeding contaminated and non-contaminated pellets respectively for days 0–40 and days 42–180 (137Cs uptake–excretion group), and feeding non-contaminated pellets throughout the experiments (control group). Samples were taken periodically. The 137Cs concentrations in muscle tissues (MU) and whole bodies (WB) were measured using Ge detectors. The 137Cs concentrations in fish that had grown to 240 g by day 182 reached 45.5 Bq/kg-wet in MU and 37.0 Bq/kg-wet in WB in the 137Cs uptake group. A one-compartment model incorporating the growth coefficient estimated that the biological half-lives of 137Cs in MU and WB excluding the growth dilution effect (216 days and 233 days, respectively) were longer than the apparent biological half-lives (100 days and 104 days) observed in the 137Cs uptake–excretion group. The developed method can contribute to promoting precise prediction of radiocesium contamination of fish affected by the Fukushima fallout. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) constitute a heterogeneous group of synthetic compounds widely used in industrial applications. The estimation of PFAS half-life (t 1/2) is essential to quantify their persistence, their toxicity and mechanism of action in humans. The purpose of this review is to summarize the evidence on PFAS half-lives in humans from the available literature, and to investigate the limitations and uncertainties characterizing half-life estimation. The search was conducted on PubMed, Scopus, and Embase databases up to July 03, 2023 and was aimed at identifying all papers that estimated PFAS half-life in human populations. We excluded studies on temporal trends or providing estimates of half-life based solely on renal clearance. As persistent and ongoing exposures can influence half-life estimation, we decided to include only studies that were conducted after the main source of exposure to PFAS had ceased. A random-effects meta-analysis was conducted on studies that reported perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) or perfluorohexanesulfonic acid (PFHxS) half-life estimation. Risk of bias was evaluated using the OHAT tool. A total of 13 articles were included in the review, with 5 studies conducted in exposed general populations and 8 studies conducted in exposed workers; the estimated mean half-life ranged from 1.48 to 5.1 years for PFOA, from 3.4 to 5.7 years for total PFOS, and from 2.84 to 8.5 years for PFHxS. High heterogeneity among studies was observed; potential reasons include the variability among the investigated populations, discrepancies in considering ongoing exposures, variability in PFAS isomeric compositions, accounting for background exposure, time since exposure stopped and methods used for half-life estimation. Despite the efforts made to better understand PFAS toxicokinetics, further studies are needed to identify important characteristics of these persistent chemicals. Biomonitoring studies should focus on persistent and unaccounted sources of exposure to PFAS and on individual characteristics potentially determining half-life, to ensure accurate estimates. [ABSTRACT FROM AUTHOR]

Intake fraction, which is the fraction of emissions that are inhaled by people, quantifies the "exposure efficiency" of an emission source. We use three methods to estimate intake fractions for vehicle emissions in US urban areas. First, we use a one-compartment steady-state mass-balance model, incorporating meteorological and demographic data. Second, we use an empirical emissions-to-concentration relationship for vehicle carbon monoxide developed for 15 US urban areas. Third, we analyze model results for benzene and diesel particulate matter from the US Environmental Protection Agency's National-scale Air Toxics Assessment (NATA). The population-weighted mean intraurban intake fraction for nonreactive gaseous vehicle emissions in US urban areas is estimated to be in the range 7-21 per million, with a best estimate of 14 per million. The intake fraction for diesel particles is 4 per million, based on NATA results. An intake fraction of 4 per million means that 4mg of pollution are inhaled per kg emitted. Intake fraction values for urban vehicle emissions are usually higher in winter than in summer because of seasonal variability in the atmospheric mixing height. The results presented in this work can be used in health risk assessments, cost-benefit analyses, and other investigations that require a summary of the emission-to-intake relationship. (C) 2004 Elsevier Ltd. All rights reserved.

Abstract The growth of summer legumes as green manures (GM) may influence the soil C pool, thereby affecting soil quality and productivity in a traditional cropping system. However, there is a lack of research on whether the inclusion of GM crops enhances the C economy under semiarid conditions. An ongoing field experiment was conducted on Cumulic Haplustoll in the northwest region of China to (i) quantify the biomass C release patterns of three GM legumes; (ii) evaluate the effect of the GM legumes on the soil organic carbon (SOC) stock (0–20 cm depth), and (iii) estimate the soil C dynamics for the GM systems under semiarid conditions in more detail. The results showed that the percentages of the remaining GM C in the soil after one year of decomposition averaged 26% and 33% for the above-ground and below-ground residues, respectively. Thus, the 5-yr growth of GM legumes continuously significantly improved the SOC and easily oxidized organic carbon (EOOC) concentrations, as well as the corresponding stocks (except for soybean) (P < 0.01), compared with the original soil at the 0–20 cm depth. We estimated the annual decomposition rate of SOC as 1%, and the C added by the crops that remained in the SOC as 23% each year using the one-compartment model. The mean turnover time of the SOC at equilibrium was estimated to be 22 years, indicating that the loess soil was not C saturated and still had the potential for C sequestration. In general, Huai bean performed better on biomass production, C accumulation, and soil C sequestration than mung bean and soybean under the dryland conditions during the 5-yr period of this study. Consequently, the cultivation of leguminous GM during the summer is a better option than bare fallow to improve the soil fertility and environmental sustainability not only in the Loess Plateau of China but also in other similar dryland regions. Graphical abstract Unlabelled Image Highlights • Green manure crops accumulated 938–1082 kg C/ha each year. • More than 220 kg C of biomass remained in the soil after one year decomposition. • Green manure crops significantly increased the original SOC stock by 5.6%. • A minimum C input of 0.68 Mg C/ha was estimated to maintain the original SOC stock. • Mean 8.8% of the SOC at topsoil was derived from the new C addition by the crops. [ABSTRACT FROM AUTHOR]

Pollution by microplastics in aquatic ecosystems is a worldwide problem, and the role of microplastics as vectors of pollutants has been a concern. Although small microplastics are thought to have a greater effect than large microplastics as vectors of pollutants, the impact of the size of microplastics on their ability to serve as vectors of pollutants has not been quantified. In this study, we conducted the 14-day experiment (7 days of exposure and 7 days of depuration) with polystyrene microplastics (2-μm or 10-μm diameter) and anthracene. On the last day of the exposure period, the concentration of anthracene in the muscle of Java medaka exposed to both anthracene and 2-μm polystyrene microplastics was the highest (47.4 ± 15.2 μg/g-muscle) of any group, followed by the group exposed to both anthracene and 10-μm polystyrene microplastics (23.0 ± 4.2 μg/g-muscle) and the group exposed to only anthracene (11.2 ± 2.2 μg/g-muscle). These results demonstrated that the size of microplastics was a critical determinant of their ability to serve as vectors of anthracene. The concentrations of anthracene and fine microplastics in the environment are sufficiently low that the effect of microplastics as vectors of anthracene may be observed only under experimental conditions that are unlikely to occur in the present environment. However, because pollution by plastics is expected to become more serious in the future, careful thought and proactive action will be needed to ensure that the impact of microplastics as vectors of pollutants does not become demonstrable under future environmental conditions. [Display omitted] • Polystyrene microplastics (PS-MP) enhanced anthracene accumulation in Java medaka. • 2-μm PS-MP were more effective vectors of anthracene than 10-μm PS-MP. • The size of PS-MP is one of the critical determinants of their role as vectors. • The vector effect of PS-MP may be observed only under experimental conditions. [ABSTRACT FROM AUTHOR]

Flavan-3-ols are claimed to be responsible for the cardioprotective effects of cocoa. Alkalized cocoa powder (ALC), commonly used for many non-confectionary products, including beverages, provides less (+)-catechin, (−)-epicatechin, and procyanidins and more (−)-catechin than nonalkalized cocoa powder (NALC). This may affect the plasma appearance of monomeric flavan-3-ol stereoisomers after consumption of NALC vs. ALC. Within a randomized, crossover trial, 12 healthy nonsmokers ingested a milk-based cocoa beverage providing either NALC or ALC. Blood was collected before and within 6 h postconsumption. (+)-Catechin, (−)-catechin, and epicatechin were analyzed in plasma by HPLC as sum of free and glucuronidated metabolites. Pharmacokinetic parameters were obtained by a one-compartment model with nonlinear regression methods. For epicatechin in plasma, total area under the curve within 6 h postconsumption (AUC0−6h) and incremental AUC0−6h were additionally calculated by using the linear trapezoidal method. After consumption of NALC and ALC, (+)-catechin and (−)-catechin were mostly not detectable in plasma, in contrast to epicatechin. For epicatechin, total AUC0−6h was different between both treatments, but not incremental AUC0−6h. Most kinetic parameters were similar for both treatments, but they varied strongly between individuals. Thus, epicatechin is the main monomeric flavan-3-ol in plasma after cocoa consumption. Whether NALC should be preferred against ALC due to its higher (−)-epicatechin content remains unclear with regard to the results on incremental AUC0−6h. Future studies should investigate epicatechin metabolites in plasma for a period up to 24 h in a larger sample size, taking into account genetic polymorphisms in epicatechin metabolism and should consider all metabolites to understand inter-individual differences after cocoa intake.

Objective To simplify the calculation of T>MIC and evaluate meropenem regimens based on the simple mathematical model of T>MIC reported in literature for two-compartment model. Methods Six meropenem regimens were designed according to the recommended dose with the infusion duration of 0.5 h and 3 h. Four different MIC susceptibility breakpoint of meropenem against clinical microbiologic flora were used to formulate different T>MIC. Each T>MIC was calculated by both the simple and two-compartment model of T>MIC.Meropenem regimens were evaluated for different bacterial infections based on the simple model of T>MIC with 40%~100% of the T>MIC% as the target. The t-test suggested no significant difference between the pairs of T>MIC calculated by the two models. Results and Conclusion Simple model of T>MIC can replace the two-compartment model. Meropenem regimens can be optimized based on this simple model of T>MIC conveniently and quickly. [ABSTRACT FROM AUTHOR]

Pharmacokinetics (PK) is a branch of pharmacology dedicated to the study of the time course of drug concentrations, from absorption to excretion from the body. PK dynamic models are often based on homogeneous, multi-compartment assumptions, which allow to identify the PK parameters and further predict the time evolution of drug concentration for a given subject. One key characteristic of these time series is their high variability among patients, which may hamper their correct stratification. In the present work, we address this variability by estimating the PK parameters and simultaneously clustering the corresponding subjects using the time series. We propose an expectation maximization algorithm that clusters subjects based on their PK drug responses, in an unsupervised way, collapsing clusters that are closer than a given threshold. Experimental results show that the proposed algorithm converges fast and leads to meaningful results in synthetic and real scenarios. [ABSTRACT FROM AUTHOR]

In mice, renal function evaluated by serum creatinine has limitations. Gold standard methods using radioactive markers are cumbersome. We aimed to develop the iohexol plasma clearance as a simple assessment of renal function in conscious mice. We used two groups of mice: testing and validation, formed by 16 animals (8 male and 8 female) each. Iohexol was injected intravenously into the tail vein (6.47 mg), and tail tip blood samples were collected at 1, 3, 7, 10, 15, 35, 55, and 75 min. Iohexol plasma clearances were calculated in two ways: (1) two-compartment model (CL2) using all time points and (2) one-compartment model (CL1) using only the last four points. In the testing group, CL1 overestimated the true clearance (CL2). Therefore, CL1 was recalculated applying a correction factor calculated as the ratio between CL2/CL1. The latter was considered as the simplified method. CL2 averaged 223.3 ± 64.3 μl/min and CL1 252.4 ± 76.4 μl/min, which lead to a CF of 0.89. Comparable results for CL2, CL1, and simplified method were observed in the validation group. Additionally, we demonstrated the capacity of the simplified method to quantitatively assess different degrees of renal function in three mouse models: hyperoxaluric-CKD (87.4 ± 28.3 μl/min), heminephrectomized (135-0 ± 50.5 μl/min), and obese (399.6 ± 112.1 μl/min) mice. We have developed a simple and reliable method to evaluate renal function in conscious mice under diverse clinical conditions. Moreover, the test can be repeated in the same animal, which makes the method useful to examine renal function changes over time. [ABSTRACT FROM AUTHOR]

To predict internal metal concentrations in animals under specific environmental exposures, the relationship between the exposure concentrations and values of toxicokinetic parameters must be known. At high exposure levels, the availability of carriers transporting metal ions through cellular membranes may become limited, thereby decreasing the assimilation rates ( k). Furthermore, increased metal concentrations in food may result in greater damage to the gut and reduce the assimilation efficiency and/or increase the elimination rate ( k). Therefore, k should decrease and k should increase with increasing metal concentrations. In fact, our study on Tribolium castaneum exposed to Cu at 500, 1000, 2000 and 4000 mg kg of dry flour showed that with increasing Cu concentrations, k decreased from 0.0042 day at 500 mg kg to 0.0026 day at 4000 mg kg in females and from 0.0029 to 0.001 day in males and k increased from 0.027 to 0.064 day and from 0.018 to 0.04 day in females and males, respectively. Significant differences in k between the sexes were observed at 2000 and 4000 mg kg, whereas significant differences between treatments were found for k in males. Copper was efficiently regulated by T. castaneum: an eightfold increase in exposure concentrations resulted in only a ca. twofold increase in the internal concentration. No Cu effect on the respiratory metabolism of T. castaneum was found. [ABSTRACT FROM AUTHOR]

Previous studies indicated that essential and xenobiotic metals differ substantially in terms of their toxicokinetics. Whether these differences are due to different assimilation rates, different elimination rates, or both, and whether all metals are regulated in a similar manner but with different efficiency remains unclear. To compare the mechanisms responsible for the regulation of different metals, parameters for toxicokinetic models have to be tested under exposures to the identical molar concentration of those metals. In this study, the cricket Gryllus assimilis was exposed to Zn or Cd at 2.5, 10, and 40 mM kg −1 dry food. The body concentrations of the metals were not perfectly regulated by the crickets. For Zn, a clear increase in the body concentration was found only at the highest treatment; whereas at the lowest treatment, the internal concentration remained unchanged throughout the experiment. At the lowest Zn concentration, the assimilation ( k A ) [day −1 ] and elimination ( k E ) [day −1 ] rate constants were balanced ( k A =0.024, k E =0.024). When increasing the Zn exposure, k A decreased to 0.018 at 10 mM kg −1 and 0.01 at 40 mM kg −1 , and k E increased to 0.05 and 0.07, respectively. Therefore, the body concentration of Zn was regulated by simultaneously changing the assimilation and elimination rate. By contrast, even at the lowest treatment, a significant increase in Cd concentration was observed in the crickets. The equilibrium Cd concentration resulted almost exclusively from increasing k E from 0.17, through 0.28 to 0.61 at 2.5, 10 and 40 mM kg −1 . The k A for Cd did not reveal any clear trend. Zn was more efficiently regulated by crickets than was Cd: a 16-fold increase in exposure concentration (from 2.5 to 40 mM Zn kg −1 ) resulted only in a twofold increase of internal concentration, whereas the identical increase in Cd exposure concentration resulted in almost a sevenfold increase in internal concentration of this metal. [ABSTRACT FROM AUTHOR]

Abstract There is a growing movement within biology to transform the undergraduate curriculum. A major goal is to actively engage students so that they perceive biology as an evidence-based science with testable hypotheses that are supported by experimental data. This resource is the fourth module in a series that engages students in inquiry-based activities to introduce them to the process of scientific modeling and validation. The modules are a self-contained series of self-study guides for undergraduates, both with and without calculus. The modules are designed so that students can complete them without additional assistance, making them suitable for use as stand-alone biophysics computer labs or for a discovery-based active-learning course. In this module, students learn the basics of the one-compartment model of pharmacokinetics and why it predicts an exponential decay. Students compare the models predictions with experimental data for the elimination of piperacillin in healthy volunteers. During the data analysis, students discover that the fitted initial concentration predicts the distribution volume, that the fitted rate constant predicts the drug half-life, and the utility of semi-log plots. Students use graphical residual analysis to discover systematic deviations in the original fit. By reanalyzing the longer-time serum-only data, students discover that the systematic errors in the fit can be eliminated, indicating the true range of applicability of the model. This module is the fourth in a series that are being developed with the support of a National Science Foundation Course, Curriculum, and Laboratory Improvement grant. The modules are based on teaching materials I've been working on over the last 8 years for my undergraduate biophysics classes. These new courses have been developed in response to a movement within the biological sciences that calls for more quantitative content for undergraduates in biological and health sciences. I have found this module to be extremely effective in the three semesters that I have used it in my undergraduate classroom. Student engagement with the material is high as they can readily appreciate the significance of the data analyzed in the module. Students also respond well to the active-learning approach. By actually doing the fits themselves, they gain a more detailed understanding of the scientific process of model development and validation. Many have reported gaining real satisfaction in discovering new insights about the experimental results (that were not quantitatively compared with any pharmacokinetic model).

Abstract: In this work, we demonstrate how fractional calculus and time-scale calculus can be combined beautifully to solve and fit a modeling problem. In addition, a cross-validation technique is used to evaluate the fitted model. The specific application that we consider is the one-compartment model. The one-compartment model is a first-order differential equation that describes drug concentration over time. It turns out that approximating the solution by using a fractional model allows us to get more accurate results for model fitting. To quantitatively verify this insight, we compare between a first-order model and an-order fractional model using real data for drug concentration. Then the mean squared error and a cross-validation method are used to determine the model that provides the best fit and predictions for unseen data. [Copyright &y& Elsevier]

Abstract: The applicability of diffusive gradients in thin-films (DGT) as a biomimic surrogate was investigated to determine the bioavailable heavy metal concentrations to earthworm (Eisenia foetida). The relationships between the amount of DGT and earthworm uptake; DGT uptake and the bioavailable concentrations of heavy metals in soils were evaluated. The one-compartment model for the dynamic uptake of heavy metals in the soil fitted well to both the earthworm (R2 =0.641–0.990) and DGT (R2 =0.473–0.998) uptake data. DGT uptake was linearly correlated with the total heavy metal concentrations in the soil (aqua regia), the bioavailable heavy metal concentrations estimated by fractions I+II of the standard measurements and testing (SM&T) and physiologically based extraction test (PBET, stomach+intestine). The coefficients of determination (R2) of DGT uptake vs. aqua regia were 0.433, 0.929 and 0.723; vs. SM&T fractions (I+II) were 0.901, 0.882 and 0.713 and vs. PBET (stomach+intestine) were 0.913, 0.850 and 0.649 for Pb, Zn and Cu, respectively. These results imply that DGT can be used as a biomimic surrogate for the earthworm uptake of heavy metals in contaminated soils as well as predict bioavailable concentrations of heavy metals estimated by SM&T (I+II) and PBET as a human oral bioavailable concentrations of heavy metals. [Copyright &y& Elsevier]

We study the properties of the power-transformation model to improve the non-additivity in regression, proposed by Goto (1992). This power additive transformation (PAT) model is an extension of the Box and Cox power transformation (BCPT) model and then includes the Bleasdale's simplified model and the one-compartment model as special cases. We describe the procedure to obtain the maximum likelihood estimates of the PAT model and discuss some issues in the maximum likelihood estimation, especially the consistency of the estimates and the effect of the error variance on the parameter estimation. We also provide two examples to illustrate the aspect of the PAT model, compared with the BCPT model. The results suggest that the PAT model provides reasonable transformations for improving the non-additivity in the data and is useful for identifying the nonlinear function form even when there is no strong knowledge on the data-generating process. [ABSTRACT FROM AUTHOR]

Rate constants for uptake and elimination of chemicals in organisms are often related to partition coefficients (typically the octanol–water partition coefficient). We show that the well-mixed one-compartment model for toxico-kinetics implies that the elimination rate is inversely proportional to the square root of the partition coefficient. When chemical exchange is limited by diffusion in the boundary layers adjacent to the interface, two-film models are appropriate, which have more complex implications for the relationships between the exchange rates and the partition coefficient. We also show that the popular steady-flux approximation of the two-film model is not a conceptual generalization of the one-compartment model, although it shares the first-order kinetics. We compare the kinetics of a series of models with an increasing number of well-mixed compartments for exchange, such that the two-film model results for an infinite number of compartments. The latter model formulation in terms of partial differential equations, and more in particular its boundary condition at the interface of the two media, is believed to be new. In the steady-flux approximation and in the model with single well-mixed boundary layers and low diffusivities, the elimination rate depends hyperbolically on the partition coefficient. The available data for abiotic systems (SPME fibers) supports a hyperbolic relationship, whereas the data for aquatic biota are less discriminating between a hyperbolic or a square root relationship with the partition coefficient. The daphnia data showed less scatter than the fish data, possibly due to the small variance in body sizes, since elimination rates are inversely proportional to body length. The square root relationship fitted these data best. [Copyright &y& Elsevier]

Design: A randomised, double-blind, prospective, placebo-controlled four-way study of the pharmacokinetics of single oral doses of flosequinan. We do not report the placebo data in this paper. Flosequinan was given at doses of 50, 100 and 150 mg, with a 2-week wash-out between periods. Blood samples were taken at a series of times up to 96 h after dosing. Setting: Clinical pharmacology unit in a pharmaceutical company. Participants: Eighteen healthy volunteers of both genders, aged from 18 years to 55 years. Main outcome measures: Plasma concentrations of flosequinan and of its metabolite, flosequinoxan. Results: We demonstrate that it is possible to model parent and metabolite concentration–time profiles simultaneously and, in doing so, to estimate the first-pass effect using data from an oral administration. In our modelling approach, we propose a reasonably wide class of statistical models, allowing for left censoring. Conclusions: A parent–metabolite model that ignores the first-pass results in misleading predictions in a case where significant first-pass metabolism occurs. Thus, in phase-I studies, the new approach described in this paper can provide additional knowledge that may be useful in future formal studies. [ABSTRACT FROM AUTHOR]

• The first systematic and formalized study of multiple intermittent intravenous infusions in a one-compartment pharmacokinetic model. • Particular solutions to the concentration and AUC, at non steady state conditions, with and without a loading dose, for both the infusion and elimination time periods in the entire time domain of therapy as a function of dose number. Compartment models in pharmacokinetics are generally described for a single dose and can only simulate drug concentration as a function of the first dosing interval. Our objective was to create a one-compartment model for constant rate repetitive intravenous intermittent infusions where drug concentration can be simulated as a function of real time. The analytical solutions to differential equations that were set for the time periods of drug infusion and elimination after an intermittent intravenous infusion were used to derive sequences patterns and determine the partial sums of mathematical series for multiple intermittent infusion doses. The model's original theory was supplemented with explicit solutions to the concentration and AUC, at non steady state conditions, with and without a loading dose, for both the infusion and elimination time periods after repetitive intermittent intravenous infusions. The validity and accuracy of these formulas in calculating drug concentration and AUC was verified by mathematical proofs, numerical methods and the principle of superposition. Drug concentration and AUC can be simulated using the newly described one-compartment pharmacokinetic model in the entire time-domain of therapy after multiple and repetitive intermittent intravenous infusions and not just within the first dosing interval. [ABSTRACT FROM AUTHOR]

Pharmacokinetic studies of drug and metabolite concentrations in the blood are usually conducted as crossover trials, especially in phases I and II. A longitudinal series of measurements is collected on each subject within each period. However, much of the dependence among such observations, within and between periods, is generally ignored in analyzing this type of data. Usually, only a random coefficient model is fitted for the parameters in the nonlinear mean function, along with allowing the variance to depend on the mean so that it changes over time. Here, we develop models to allow more fully for the structure of the crossover study. We introduce two levels of variance components, for the subjects and for the periods within subjects, and also an autocorrelation within periods. We also retain the time-varying variance, using a separate variance function for this, different from that for the mean. We apply this model to a phase I study of the drug flosequinan and its metabolite. This drug was developed for the treatment of heart failure. Because the metabolite also exhibits an active pharmacologic effect, study of both the parent drug and the metabolite is of interest. We find that the autocorrelation is the element in the covariance structure that most improves the fit of the model but that two levels of variance components can also be necessary. [ABSTRACT FROM AUTHOR]

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HCl (mean 60 mg, range 10-225 mg) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65-630 ng·ml and from 5 to 55 ng·ml, whereas the peak concentrations were 124-1255 ng·ml and 10 - 301 ng·ml for methadone and EDDP, respectively. The calculated ratios between the area under the curve (AUC) for methadone and the AUC for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml·min·kg, whereas the mean elimination rate constant (β) and plasma half-life ( tβ) were 0.026·h (range 0.013-0.053·h) and 31.2 h (range 13-53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance. [ABSTRACT FROM AUTHOR]

The area function method for assessing zero-order ( k) drug absorption rates was compared to four other methods under conditions where variation occurs in the plasma concentration data and in the elimination rate constant ( k or k) for one- or two-compartment models. For deviant k values of a one-compartment model, the most accurate recovery of k occurred with the area function method and nonlinear least-squares regression, followed by the Wagner-Nelson and moment analysis methods. With deviant k values for a two-compartment model, the order of superiority of the methods was: area function ≈ nonlinear regression > Loo-Riegelman > moment analysis. Moment analysis should generally be reserved for use as an estimation rather than calculation technique. The area function procedure offers particular advantages in ease of data analysis and accuracy of recovered parameters. [ABSTRACT FROM AUTHOR]

Abstract Background Cadmium is a widespread environmental pollutant with adverse effects on kidneys and bone, but with insufficiently elucidated public health consequences such as risk of end-stage renal diseases, fractures and cancer. Urinary cadmium is considered a valid biomarker of lifetime kidney accumulation from overall cadmium exposure and thus used in the assessment of cadmium-induced health effects. We aimed to assess the relationship between dietary cadmium intake assessed by analyses of duplicate food portions and cadmium concentrations in urine and blood, taking the toxicokinetics of cadmium into consideration. Methods In a sample of 57 non-smoking Swedish women aged 20-50 years, we assessed Pearson's correlation coefficients between: 1) Dietary intake of cadmium assessed by analyses of cadmium in duplicate food portions collected during four consecutive days and cadmium concentrations in urine, 2) Partial correlations between the duplicate food portions and urinary and blood cadmium concentrations, respectively, and 3) Model-predicted urinary cadmium concentration predicted from the dietary intake using a one-compartment toxicokinetic model (with individual data on age, weight and gastrointestinal cadmium absorption) and urinary cadmium concentration. Results The mean concentration of cadmium in urine was 0.18 (+/- s.d.0.12) μg/g creatinine and the model-predicted urinary cadmium concentration was 0.19 (+/- s.d.0.15) μg/g creatinine. The partial Pearson correlations between analyzed dietary cadmium intake and urinary cadmium or blood concentrations were r = 0.43 and 0.42, respectively. The correlation between diet and urinary cadmium increased to r = 0.54 when using a one-compartment model with individual gastrointestinal cadmium absorption coefficients based on the women's iron status. Conclusions Our results indicate that measured dietary cadmium intake can reasonably well predict biomarkers of both long-term kidney accumulation (urine) and short-term exposure (blood). The predictions are improved when taking data on the iron status into account.

Flavan-3-ols are claimed to be responsible for the cardioprotective effects of cocoa. Alkalized cocoa powder (ALC), commonly used for many non-confectionary products, including beverages, provides less (+)-catechin, (−)-epicatechin, and procyanidins and more (−)-catechin than nonalkalized cocoa powder (NALC). This may affect the plasma appearance of monomeric flavan-3-ol stereoisomers after consumption of NALC vs. ALC. Within a randomized, crossover trial, 12 healthy nonsmokers ingested a milk-based cocoa beverage providing either NALC or ALC. Blood was collected before and within 6 h postconsumption. (+)-Catechin, (−)-catechin, and epicatechin were analyzed in plasma by HPLC as sum of free and glucuronidated metabolites. Pharmacokinetic parameters were obtained by a one-compartment model with nonlinear regression methods. For epicatechin in plasma, total area under the curve within 6 h postconsumption (AUC0–6h) and incremental AUC0–6h were additionally calculated by using the linear trapezoidal method. After consumption of NALC and ALC, (+)-catechin and (−)-catechin were mostly not detectable in plasma, in contrast to epicatechin. For epicatechin, total AUC0–6h was different between both treatments, but not incremental AUC0–6h. Most kinetic parameters were similar for both treatments, but they varied strongly between individuals. Thus, epicatechin is the main monomeric flavan-3-ol in plasma after cocoa consumption. Whether NALC should be preferred against ALC due to its higher (−)-epicatechin content remains unclear with regard to the results on incremental AUC0–6h. Future studies should investigate epicatechin metabolites in plasma for a period up to 24 h in a larger sample size, taking into account genetic polymorphisms in epicatechin metabolism and should consider all metabolites to understand inter-individual differences after cocoa intake. [ABSTRACT FROM AUTHOR]

Flavan-3-ols are claimed to be responsible for the cardioprotective effects of cocoa. Alkalized cocoa powder (ALC), commonly used for many non-confectionary products, including beverages, provides less (+)-catechin, (-)-epicatechin, and procyanidins and more (-)-catechin than nonalkalized cocoa powder (NALC). This may affect the plasma appearance of monomeric flavan-3-ol stereoisomers after consumption of NALC vs. ALC. Within a randomized, crossover trial, 12 healthy nonsmokers ingested a milk-based cocoa beverage providing either NALC or ALC. Blood was collected before and within 6 h postconsumption. (+)-Catechin, (-)-catechin, and epicatechin were analyzed in plasma by HPLC as sum of free and glucuronidated metabolites. Pharmacokinetic parameters were obtained by a one-compartment model with nonlinear regression methods. For epicatechin in plasma, total area under the curve within 6 h postconsumption ( AUC 0-6h ) and incremental AUC 0-6h were additionally calculated by using the linear trapezoidal method. After consumption of NALC and ALC, (+)-catechin and (-)-catechin were mostly not detectable in plasma, in contrast to epicatechin. For epicatechin, total AUC 0-6h was different between both treatments, but not incremental AUC 0-6h . Most kinetic parameters were similar for both treatments, but they varied strongly between individuals. Thus, epicatechin is the main monomeric flavan-3-ol in plasma after cocoa consumption. Whether NALC should be preferred against ALC due to its higher (-)-epicatechin content remains unclear with regard to the results on incremental AUC 0-6h . Future studies should investigate epicatechin metabolites in plasma for a period up to 24 h in a larger sample size, taking into account genetic polymorphisms in epicatechin metabolism and should consider all metabolites to understand inter-individual differences after cocoa intake.

An equation for the mean residence time (MRT) of drug in the body is derived for the system where drug is injected intravenously into a one-compartment model and eliminated by a single, capacity-limited process. This MRT is a complex function of dose, volume, V, and K but degenerates into the classical volume/clearance expression under limiting low-dose conditions ( K ≫ C). The equation was validated by comparison of the MRT obtained by direct calculation versus numerical area estimation for simulated data. The equation may be useful analytically in the estimation of the fundamental Michaelis-Menten parameters, V and K, from experimental data. [ABSTRACT FROM AUTHOR]