Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

Lin, Zhoumeng; Fisher, Jeffrey W.; Wang, Ran; Ross, Matthew K.; Filipov, Nikolay M.

doi:10.1016/j.taap.2013.08.010

Cited by 59 publications

(33 citation statements)

References 114 publications

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“…4). Of note, compared to the ion intensities of ATR, DE and DIP in the 125 mg/kg group, the corresponding ion intensities were somewhat lower at the 250 mg/kg group, likely caused by the previously suggested autoinduction metabolism of ATR (Fraites et al 2011;Lin et al 2013b). …”

Section: Metabolites and Metabolic Pathways Altered By Atrazine Exposurementioning

confidence: 72%

“…In order to shed light into ATR's mode of action and aid the search for reliable biomarkers of ATR exposure, we developed physiologically based pharmacokinetic (PBPK) models for ATR in rodents of different ages (Lin et al 2011;Lin et al 2013b) that can be used for target organ dosimetry based on ATR's peripheral biomarkers of exposure, i.e., plasma/urine levels of ATR and/or its metabolites, desethylatrazine (DE), desisopropylatrazine (DIP), and didealkylatrazine (DACT). We (Ross and Filipov 2006;Ross et al 2009) and others (Barr et al 2007;Chevrier et al 2011;Fraites et al 2011) have generated rodent and human data on the ATR's kinetics and metabolite profile in plasma and/or urine that, with the help of PBPK modeling, can be used for ATR exposure dosimetry.…”

Section: Introductionmentioning

confidence: 99%

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Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways

Lin

Roede

et al. 2014

Toxicology

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, N. M. (2014). Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α -linolenate, tryptophan, tyrosine and other major metabolic pathways. Retrieved from http://krex.ksu.edu Published Version InformationCitation: Lin, Z., Roede, J. R., He, C., Jones, D. P., & Filipov, N. M. (2014). Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α -linolenate, tryptophan, tyrosine and other major metabolic pathways. Toxicology, 326, 130-141. adult male C57BL/6 mice, the present study aimed to investigate effects of a 10-day oral ATR exposure (0, 5, 25, 125, or 250 mg/kg) on the mouse plasma metabolome and to determine metabolic pathways affected by ATR that may be reflective of ATR's effects on the brain and useful to identify peripheral biomarkers of neurotoxicity. Four h after the last dosing on day 10, plasma was collected and analyzed with high-performance, dual chromatography-Fouriertransform mass spectrometry that was followed by biostatistical and bioinformatic analyses. CopyrightATR exposure (≥5 mg/kg) significantly altered plasma metabolite profile and resulted in a dosedependent increase in the number of metabolites with ion intensities significantly different from the control group. Pathway analyses revealed that ATR exposure strongly correlated with and disrupted multiple metabolic pathways. Tyrosine, tryptophan, linoleic acid and α-linolenic acid metabolic pathways were among the affected pathways, with α-linolenic acid metabolism being affected to the greatest extent. Observed effects of ATR on plasma tyrosine and tryptophan metabolism may be reflective of the previously reported perturbations of brain dopamine and serotonin homeostasis, respectively. ATR-caused alterations in the plasma profile of α-linolenic acid metabolism are a potential novel and sensitive plasma biomarker of ATR effect and plasma metabolomics could be used to better assess the risks, including to the brain, associated with ATR overexposure.

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Section: Metabolites and Metabolic Pathways Altered By Atrazine Exposurementioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways

Lin

Roede

et al. 2014

Toxicology

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“…For therapeutic purposes, the target organ of an initiated treatment, such as the lungs for respiratory diseases, should be included in the models (Baneyx et al, 2014). Regarding risk assessment application, the target organ of toxicity, such as the brain for neurotoxicants, needs to be included in the model (Lin et al, 2011(Lin et al, , 2013. The fat should also be selected as a single compartment for highly lipophilic compounds (Evans & Andersen, 2000).…”

Section: Model Structurementioning

confidence: 99%

Mathematical modeling and simulation in animal health – Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment

Lin

Gehring

Mochel

et al. 2016

Vet Pharm & Therapeutics

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This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

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“…As introduced before, another helpful approach in the estimation of withdrawal times is PBPK modeling, which can be used to predict both the concentrations and the cumulative excreted amounts of drugs in the milk [17, 18]. Therefore, future studies that extend the published tulathromycin PBPK model in juvenile and market-age meat goats [10] to lactating goats are needed to compare the estimated withdrawal intervals from different approaches (NLME-PK vs. PBPK), and then to determine a more accurate estimate to protect food safety.…”

Section: Discussionmentioning

confidence: 99%

Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach

et al. 2016

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BackgroundExtra-label use of tulathromycin in lactating goats is common and may cause violative residues in milk. The objective of this study was to develop a nonlinear mixed-effects pharmacokinetic (NLME-PK) model to estimate tulathromycin depletion in plasma and milk of lactating goats. Eight lactating goats received two subcutaneous injections of 2.5 mg/kg tulathromycin 7 days apart; blood and milk samples were analyzed for concentrations of tulathromycin and the common fragment of tulathromycin (i.e., the marker residue CP-60,300), respectively, using liquid chromatography mass spectrometry. Based on these new data and related literature data, a NLME-PK compartmental model with first-order absorption and elimination was used to model plasma concentrations and cumulative excreted amount in milk. Monte Carlo simulations with 100 replicates were performed to predict the time when the upper limit of the 95% confidence interval of milk concentrations was below the tolerance.ResultsAll animals were healthy throughout the study with normal appetite and milk production levels, and with mild-moderate injection-site reactions that diminished by the end of the study. The measured data showed that milk concentrations of the marker residue of tulathromycin were below the limit of detection (LOD = 1.8 ng/ml) 39 days after the second injection. A 2-compartment model with milk as an excretory compartment best described tulathromycin plasma and CP-60,300 milk pharmacokinetic data. The model-predicted data correlated with the measured data very well. The NLME-PK model estimated that tulathromycin plasma concentrations were below LOD (1.2 ng/ml) 43 days after a single injection, and 62 days after the second injection with a 95% confidence. These estimated times are much longer than the current meat withdrawal time recommendation of 18 days for tulathromycin in non-lactating cattle.ConclusionsThe results suggest that twice subcutaneous injections of 2.5 mg/kg tulathromycin are a clinically safe extra-label alternative approach for treating pulmonary infections in lactating goats, but a prolonged withdrawal time of at least 39 days after the second injection should be considered to prevent violative residues in milk and any dairy goat being used for meat should have an extended meat withdrawal time.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0884-4) contains supplementary material, which is available to authorized users.

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Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

Cited by 59 publications

References 114 publications

Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways

Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways

Mathematical modeling and simulation in animal health – Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment

Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach

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