Dataset Information

Development and Application of a Water Temperature Related Physiologically Based Pharmacokinetic Model for Enrofloxacin and Its Metabolite Ciprofloxacin in Rainbow Trout.

ABSTRACT: Enrofloxacin (ENR) has been approved for the treatment of infections in aquaculture, but it may cause tissue residue. This research aimed to develop and validate a water temperature related PBPK model, including both ENR and ciprofloxacin (CIP), in rainbow trout, and to predict further their residue concentrations and the withdrawal periods for ENR at different water temperatures. With the published concentrations data, a flow-limited PBPK model including both ENR and CIP sub-models was developed to predict ENR and CIP concentrations in tissues and plasma/serum after intravenous, oral, or immersion administration. A Monte Carlo simulation including 500 iterations was further incorporated into this model. Based on the model and Monte Carlo analysis, the withdrawal intervals were estimated for different dosage regimens and at different water temperatures, ranging from 80 to 272 degree-days. All of these values were shorter than the labeled withdrawal period (500 degree-days) in fish. This model provided a useful tool for predicting the tissue residues of ENR and CIP in rainbow trout under different dosage regimens and at different water temperatures.

SUBMITTER: Yang F

PROVIDER: S-EPMC7874017 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Development and Application of a Water Temperature Related Physiologically Based Pharmacokinetic Model for Enrofloxacin and Its Metabolite Ciprofloxacin in Rainbow Trout.

Yang Fan F Yang Fang F Wang Dan D Zhang Chao-Shuo CS Wang Han H Song Zhe-Wen ZW Shao Hao-Tian HT Zhang Mei M Yu Meng-Li ML Zheng Yang Y

Frontiers in veterinary science 20210125

Enrofloxacin (ENR) has been approved for the treatment of infections in aquaculture, but it may cause tissue residue. This research aimed to develop and validate a water temperature related PBPK model, including both ENR and ciprofloxacin (CIP), in rainbow trout, and to predict further their residue concentrations and the withdrawal periods for ENR at different water temperatures. With the published concentrations data, a flow-limited PBPK model including both ENR and CIP sub-models was develope ...[more]

PMID: 33585600

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Project description:Zoonotic intestinal pathogens threaten human health and cause huge economic losses in farming. Enrofloxacin (ENR) shows high antibacterial activity against common intestinal bacteria. However, its poor palatability and low aqueous solubility limit the clinical application of ENR. To obtain an ENR oral preparation with good palatability and high solubility, a granule containing an amorphous ENR solid dispersion (ENR-SD) was prepared. Meanwhile, a PBPK model of ENR in pigs was built based on the physiological parameters of pigs and the chemical-specific parameters of ENR to simulate the pharmacokinetics (PK) of ENR-SD granules in the intestinal contents. According to the results of parameter sensitivity analysis (PSA) and the predicted PK parameters at different doses of the model, formulation strategies and potential dose regimens against common intestinal infections were provided. The DSC and XRD results showed that no specific interactions existed between the excipients and ENR during the compatibility tests, and ENR presented as an amorphous form in ENR-SD. Based on the similar PK performance of ENR-SD granules and the commercial ENR soluble powder suggesting continued enhancement of the solubility of ENR, a higher drug concentration in intestinal contents could not be obtained. Therefore, a 1:5 ratio of ENR and stearic acid possessing a saturated aqueous solubility of 1190 ± 7.71 µg/mL was selected. The predictive AUC24h/MIC90 ratios against Campylobacter jejuni, Salmonella, and Escherichia coli were 133, 266 and 8520 (>100), respectively, suggesting that satisfactory efficacy against common intestinal infections would be achieved at a dose of 10 mg/kg b.w. once daily. The PSA results indicated that the intestinal absorption rate constant (Ka) was negatively correlated with the Cmax of ENR in the intestine, suggesting that we could obtain higher intestinal Cmax using P-gp inducers to reduce Ka, thus obtaining a higher Cmax. Our studies suggested that the PBPK model is an excellent tool for formulation and dose design.

Project description:In this project, effects of chronic temperature changes on the transcriptome of the rainbow trout heart (Oncorhynchus mykiss) were examined. Ectothermic animals of north-temperate latitudes experience large seasonal changes in temperature which strongly affect the rate of body functions. To compensate for the effects of temperature changes ectotherms can respond to chronic temperature changes by increasing the quantity of tissue or enzyme needed for different physiological tasks, or by expressing proteins isoforms which are more appropriate for the new thermal conditions. On the other hand, proteins which are needed in lesser amounts in the new thermal regime could be depressed or down-regulated. Although expression of proteins can be changed by multiple mechanisms during synthesis and degradation, temperature dependent changes in transcription of genes is probably the most important factor in modifying the proteome of the tissues. Rainbow trout are active throughout their thermal tolerance range (0-25°C). Maintenance of adequate cardiac function at different thermal conditions requires a thorough change of the cardiac phenotype which appears as compensatory changes in relative heart mass, energy metabolism, nervous and humoral control of cardiac contractility and in electrical and mechanical properties of the trout heart. Such an extensive structural and functional remodeling of the heart probably necessitates both qualitative and quantitative changes among the numerous macromolecules which constitute the cardiac phenotype and cannot, therefore, be solely based on posttranslational modification of proteins but is expected to require differential gene expression. As a power supply of the circulatory system, the heart is in the focal point of physiological plasticity and sets limits for the activity level of the animal in different thermal conditions. Although several aspects of heart function have been studied in thermally acclimated fish and a number of structural changes have been noticed on exposure to different temperatures, the cellular and molecular mechanisms involved in chronic thermal stress of the fish heart are only partially elucidated. An interesting and poorly examined feature of the cold-acclimated phenotype of the trout heart is the increased heart mass which attenuates the depressive effect of low temperature on cardiac pump function. The heart is a complex organ composed of multiple tissues which together provide the system all necessary qualifications for cardiac pump function. In addition to the contractile and metabolic machinery of the cardiac myocytes, the amount and quality of the extracellular matrix also contribute to the properties of the heart as a muscular pump. Due to the complexity of the heart an enormous amounts of research efforts are needed to find out and examine all crucial aspects of cardiac plasticity required for thermal acclimation. In this regard the screening of gene expression by cDNA micro arrays might provide a broader view to genomic basis of cardiac remodeling under changing temperatures and aid to reveal the candidate genes which are important for thermal acclimation and which might remain unnoticed by traditional biochemical and physiological methods. In the present study we the steady-state effects of temperature acclimation on gene expression of the rainbow trout heart were screened by micro array analysis. Keywords: parallel sample

Project description:In this project, effects of chronic temperature changes on the transcriptome of the rainbow trout heart (Oncorhynchus mykiss) were examined. Ectothermic animals of north-temperate latitudes experience large seasonal changes in temperature which strongly affect the rate of body functions. To compensate for the effects of temperature changes ectotherms can respond to chronic temperature changes by increasing the quantity of tissue or enzyme needed for different physiological tasks, or by expressing proteins isoforms which are more appropriate for the new thermal conditions. On the other hand, proteins which are needed in lesser amounts in the new thermal regime could be depressed or down-regulated. Although expression of proteins can be changed by multiple mechanisms during synthesis and degradation, temperature dependent changes in transcription of genes is probably the most important factor in modifying the proteome of the tissues. Rainbow trout are active throughout their thermal tolerance range (0-25Â°C). Maintenance of adequate cardiac function at different thermal conditions requires a thorough change of the cardiac phenotype which appears as compensatory changes in relative heart mass, energy metabolism, nervous and humoral control of cardiac contractility and in electrical and mechanical properties of the trout heart. Such an extensive structural and functional remodeling of the heart probably necessitates both qualitative and quantitative changes among the numerous macromolecules which constitute the cardiac phenotype and cannot, therefore, be solely based on posttranslational modification of proteins but is expected to require differential gene expression. As a power supply of the circulatory system, the heart is in the focal point of physiological plasticity and sets limits for the activity level of the animal in different thermal conditions. Although several aspects of heart function have been studied in thermally acclimated fish and a number of structural changes have been noticed on exposure to different temperatures, the cellular and molecular mechanisms involved in chronic thermal stress of the fish heart are only partially elucidated. An interesting and poorly examined feature of the cold-acclimated phenotype of the trout heart is the increased heart mass which attenuates the depressive effect of low temperature on cardiac pump function. The heart is a complex organ composed of multiple tissues which together provide the system all necessary qualifications for cardiac pump function. In addition to the contractile and metabolic machinery of the cardiac myocytes, the amount and quality of the extracellular matrix also contribute to the properties of the heart as a muscular pump. Due to the complexity of the heart an enormous amounts of research efforts are needed to find out and examine all crucial aspects of cardiac plasticity required for thermal acclimation. In this regard the screening of gene expression by cDNA micro arrays might provide a broader view to genomic basis of cardiac remodeling under changing temperatures and aid to reveal the candidate genes which are important for thermal acclimation and which might remain unnoticed by traditional biochemical and physiological methods. In the present study we the steady-state effects of temperature acclimation on gene expression of the rainbow trout heart were screened by micro array analysis.

Project description:Piscine orthoreovirus genotype 3 (PRV-3) was first discovered in Denmark in 2017 in relation to disease outbreaks in rainbow trout (Oncorhynchus mykiss). While the virus appears to be widespread in farmed rainbow trout, disease outbreaks associated with detection of PRV-3 have only occurred in recirculating aquaculture systems, and has predominantly been observed during the winter months. To explore the possible effects of water temperature on PRV-3 infection in rainbow trout, an in vivo cohabitation trial was conducted at 5, 12, and 18°C. For each water temperature, a control tank containing mock-injected shedder fish and a tank with PRV-3 exposed fish were included. Samples were collected from all experimental groups every 2nd week post challenge (WPC) up until trial termination at 12 WPC. PRV-3 RNA load measured in heart tissue of cohabitants peaked at 6 WPC for animals maintained at 12 and 18°C, while it reached its peak at 12 WPC in fish maintained at 5°C. In addition to the time shift, significantly more virus was detected at the peak in fish maintained at 5°C compared to 12 and 18°C. In shedders, fish at 12 and 18°C cleared the infection considerably faster than the fish at 5°C: while shedders at 18 and 12°C had cleared most of the virus at 4 and 6 WPC, respectively, high virus load persisted in the shedders at 5°C until 12 WPC. Furthermore, a significant reduction in the hematocrit levels was observed in the cohabitants at 12°C in correlation with the peak in viremia at 6 WPC; no changes in hematocrit was observed at 18°C, while a non-significant reduction (due to large individual variation) trend was observed at cohabitants held at 5°C. Importantly, isg15 expression was positively correlated with PRV-3 virus load in all PRV-3 exposed groups. Immune gene expression analysis showed a distinct gene profile in PRV-3 exposed fish maintained at 5°C compared to 12 and 18°C. The immune markers mostly differentially expressed in the group at 5°C were important antiviral genes including rigi, ifit5 and rsad2 (viperin). In conclusion, these data show that low water temperature allow for significantly higher PRV-3 replication in rainbow trout, and a tendency for more severe heart pathology development in PRV-3 injected fish. Increased viral replication was mirrored by increased expression of important antiviral genes. Despite no mortality being observed in the experimental trial, the data comply with field observations of clinical disease outbreaks during winter and cold months.

Dataset Information

Development and Application of a Water Temperature Related Physiologically Based Pharmacokinetic Model for Enrofloxacin and Its Metabolite Ciprofloxacin in Rainbow Trout.

Publications

Development and Application of a Water Temperature Related Physiologically Based Pharmacokinetic Model for Enrofloxacin and Its Metabolite Ciprofloxacin in Rainbow Trout.

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