RESUMEN
Pharmacokinetic studies of the drugs in the milk are often limited due to infrequent sampling associated with milking. Alternatively, frequent sample collection with repeated milking may increase drug elimination. The objective of this study was to determine the feasibility of continuously sampling the udder using ultrafiltration. An ultrafiltration probe was placed into the gland cisterns through mammary parenchyma of normal and mastitic quarters of 6 mature mid-lactation Jersey cows with naturally occurring subclinical mastitis. An ultrafiltration probe was secured to the caudal or lateral aspect of the udder depending on the quarter being sampled. The timed interval samples were collected at 0, 2, 4, 6, 8, 12, 18, 24, 28, 32, 36, 48, 60, 72, 84, and 96 h after drug administration. Plasma samples were collected at the same time points. Each cow received 2.2 mg/kg of flunixin intravenously before milking at time 0. All cows were routinely milked by machine every 12 h. Flunixin concentrations in plasma, whole milk, and milk ultrafiltrates were analyzed by use of ultra-high-performance liquid chromatography with mass spectrometric detection. We found no significant effects on the appearance of the milk or the ability to milk the cows after implantation of the ultrafiltration probes. The concentration of flunixin collected from the ultrafiltration probes in the mastitic quarters tended to be greater than that of the healthy quarters. We concluded that collection of ultrafiltration samples from the mammary gland of cows provides a viable means to continuously assess drug concentrations in the milk while continuing to milk the cow normally. This study demonstrates the utility of continuous sampling of milk via ultrafiltration for future pharmacokinetic studies in cattle.
Asunto(s)
Clonixina/análogos & derivados , Mastitis Bovina/diagnóstico , Leche/química , Ultrafiltración/veterinaria , Administración Intravenosa/veterinaria , Animales , Bovinos , Cromatografía Líquida de Alta Presión/veterinaria , Clonixina/sangre , Clonixina/farmacocinética , Estudios de Factibilidad , Femenino , Lactancia , Glándulas Mamarias Animales/metabolismo , Espectrometría de Masas/veterinariaRESUMEN
Our objective was to assess the ability of 3 herbal products to eliminate experimentally induced Streptococcus uberis mastitis. These herbal products, also known as phytoceuticals, are used in organically managed dairy cattle to maintain or promote udder health. The products tested were an intramammary product, a topical product, and a product applied to the vulvar area. These products are not approved by the US Food and Drug Administration for treatment of mastitis but they are sold to enhance milk quality or for maintenance or improvement of udder health. Each of the products contains at least one component shown to have antibacterial activity. In this study, we successfully challenge-inoculated 25 lactating dairy cows maintained under organic conditions with an isolate of S. uberis. All challenged cows were positive for S. uberis by milk culture after challenge. When cows met predefined criteria indicating the presence of clinical mastitis, treatment with 1 of the 3 products was initiated based upon a predetermined random allocation. Culture of aseptically collected quarter milk samples was performed before, during, and following challenge with S. uberis. Eight, 8, and 9 cows received the intravulvar, intramammary, and topical treatments, respectively. Milk from all cows that were treated with phytoceuticals were culture-positive for S. uberis at every time point following treatment through 168 h following the last phytoceutical treatment. Based upon the presence of clinical signs and for humane reasons, 2 intravulvar-treated cows, 1 topical-treated, and 4 intramammary-treated cows received intramammary antibiotic therapy. We concluded that the phytoceuticals tested, as dosed and used in this trial, did not produce bacterial cures in S. uberis-induced mastitis.
Asunto(s)
Antibacterianos/farmacología , Mastitis Bovina/tratamiento farmacológico , Leche/efectos de los fármacos , Preparaciones de Plantas/farmacología , Infecciones Estreptocócicas/veterinaria , Streptococcus/efectos de los fármacos , Animales , Bovinos , Femenino , Lactancia , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/microbiología , Mastitis Bovina/microbiología , Leche/microbiología , Distribución Aleatoria , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/microbiologíaRESUMEN
The objective of this study was to compare active drug concentrations in the plasma vs. different effector compartments including interstitial fluid (ISF) and pulmonary epithelial lining fluid (PELF) of healthy preruminating (3-week-old) and ruminating (6-month-old) calves. Eight calves in each age group were given a single subcutaneous (s.c.) dose (8 mg/kg) of danofloxacin. Plasma, ISF, and bronchoalveolar lavage (BAL) fluid were collected over 96 h and analyzed by high-pressure liquid chromatography. PELF concentrations were calculated by a urea dilution assay of the BAL fluids. Plasma protein binding was measured using a microcentrifugation system. For most preruminant and ruminant calves, the concentration-time profile of the central compartment was best described by a two-compartment open body model. For some calves, a third compartment was also observed. The time to maximum concentration in the plasma was longer in preruminating calves (3.1 h) vs. ruminating calves (1.4 h). Clearance (CL/F) was 385.15 and 535.11 mL/h/kg in preruminant and ruminant calves, respectively. Ruminant calves maintained higher ISF/plasma concentration ratios throughout the study period compared to that observed in preruminant calves. Potential reasons for age-related differences in plasma concentration-time profiles and partitioning of the drug to lungs and ISF as a function of age are explored.
Asunto(s)
Antibacterianos/farmacocinética , Líquidos Corporales/química , Bovinos/fisiología , Digestión/fisiología , Fluoroquinolonas/farmacocinética , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Área Bajo la Curva , Fluoroquinolonas/química , Fluoroquinolonas/metabolismo , SemividaRESUMEN
Drug use in livestock has received increased attention due to welfare concerns and food safety. Characterizing heterogeneity in the way swine populations respond to drugs could allow for group-specific dose or drug recommendations. Our objective was to determine whether drug clearance differs across genetic backgrounds and sex for sulfamethazine, enrofloxacin, fenbendazole and flunixin meglumine. Two sires from each of four breeds were mated to a common sow population. The nursery pigs generated (n = 114) were utilized in a random crossover design. Drugs were administered intravenously and blood collected a minimum of 10 times over 48 h. A non-compartmental analysis of drug and metabolite plasma concentration vs. time profiles was performed. Within-drug and metabolite analysis of pharmacokinetic parameters included fixed effects of drug administration date, sex and breed of sire. Breed differences existed for flunixin meglumine (P-value<0.05; Cl, Vdss ) and oxfendazole (P-value<0.05, AUC0â∞ ). Sex differences existed for oxfendazole (P-value < 0.05; Tmax ) and sulfamethazine (P-value < 0.05, Cl). Differences in drug clearance were seen, and future work will determine the degree of additive genetic variation utilizing a larger population.
Asunto(s)
Antiinfecciosos/farmacocinética , Antiinflamatorios no Esteroideos/farmacocinética , Antinematodos/farmacocinética , Clonixina/análogos & derivados , Fenbendazol/farmacocinética , Fluoroquinolonas/farmacocinética , Sulfametazina/farmacocinética , Porcinos/metabolismo , Animales , Antiinfecciosos/sangre , Antiinflamatorios no Esteroideos/sangre , Antinematodos/sangre , Bencimidazoles/sangre , Ciprofloxacina/sangre , Clonixina/sangre , Clonixina/farmacocinética , Enrofloxacina , Femenino , Fenbendazol/sangre , Fluoroquinolonas/sangre , Masculino , Factores Sexuales , Especificidad de la Especie , Sulfametazina/análogos & derivados , Sulfametazina/sangreRESUMEN
5-Hydroxy-flunixin concentrations in milk samples were quantified by two commercially available screening assays--CHARM® and enzyme-linked immunoabsorbant assay (ELISA)--to determine whether any concentrations could be detected above the tolerance limit of 2 ng g⻹ from different regions in the United States. Milk samples came from large tanker trucks hauling milk to processing plants, and had already been screened for antibiotics. Positive results for flunixin residues based on a screening assay were confirmed by ultra-HPLC with mass spectrometric detection. Of the 500 milk samples analysed in this study, one sample was found to have a 5-hydroxy-flunixin concentration greater than the tolerance limit. The results of this study indicate that flunixin residues in milk are possible. Regulatory agencies should be aware that such residues can occur, and should consider incorporating or expanding flunixin screening tests as part of routine drug monitoring in milk. Larger studies are needed to determine the true prevalence of flunixin residues in milk from other regions in the United States as well as different countries.
Asunto(s)
Antiinflamatorios no Esteroideos/metabolismo , Clonixina/análogos & derivados , Residuos de Medicamentos/análisis , Contaminación de Alimentos , Inspección de Alimentos , Leche/química , Animales , Bovinos , Cromatografía Líquida de Alta Presión , Clonixina/análisis , Clonixina/metabolismo , Industria Lechera/legislación & jurisprudencia , Ensayo de Inmunoadsorción Enzimática , Contaminación de Alimentos/legislación & jurisprudencia , Manipulación de Alimentos , Inspección de Alimentos/legislación & jurisprudencia , Adhesión a Directriz , Legislación Alimentaria , Leche/normas , Espectrometría de Masa por Ionización de Electrospray , Transportes , Estados Unidos , United States Department of Agriculture , United States Food and Drug AdministrationRESUMEN
Quantitative structure-activity relationship (QSAR) models have been widely used to study the permeability of chemicals or solutes through skin. Among the various QSAR models, Abraham's linear free-energy relationship (LFER) model is often employed. However, when the experimental conditions are complex, it is not always appropriate to use Abraham's LFER model with a single set of regression coefficients. In this paper, we propose an expanded model in which one set of partial slopes is defined for each experimental condition, where conditions are defined according to solvent: water, synthetic oil, semi-synthetic oil, or soluble oil. This model not only accounts for experimental conditions but also improves the ability to conduct rigorous hypothesis testing. To more adequately evaluate the predictive power of the QSAR model, we modified the usual leave-one-out internal validation strategy to employ a leave-one-solute-out strategy and accordingly adjust the Q(2) LOO statistic. Skin permeability was shown to have the rank order: water > synthetic > semi-synthetic > soluble oil. In addition, fitted relationships between permeability and solute characteristics differ according to solvents. We demonstrated that the expanded model (r(2) = 0.70) improved both the model fit and the predictive power when compared with the simple model (r(2) = 0.21).
Asunto(s)
Mezclas Complejas/farmacocinética , Relación Estructura-Actividad Cuantitativa , Piel/efectos de los fármacos , PermeabilidadRESUMEN
Flunixin, a widely used non-steroidal anti-inflammatory drug, was a leading cause of violative residues in cattle. The objective of this analysis was to explore how the changes in pharmacokinetic (PK) parameters that may be associated with diseased animals affect the predicted liver residue of flunixin in cattle. Monte Carlo simulations for liver residues of flunixin were performed using the PK model structure and relevant PK parameter estimates from a previously published population PK model for flunixin in cattle. The magnitude of a change in the PK parameter value that resulted in a violative residue issue in more than one percent of a cattle population was compared. In this regard, elimination clearance and volume of distribution affected withdrawal times. Pathophysiological factors that can change these parameters may contribute to the occurrence of violative residues of flunixin.
Asunto(s)
Clonixina/análogos & derivados , Hígado/química , Modelos Teóricos , Animales , Antiinflamatorios no Esteroideos/análisis , Antiinflamatorios no Esteroideos/farmacocinética , Bovinos , Clonixina/análisis , Clonixina/farmacocinética , Contaminación de Alimentos , Método de MontecarloRESUMEN
The objective of this study was to develop a population pharmacokinetic (PK) model and predict tissue residues and the withdrawal interval (WDI) of flunixin in cattle. Data were pooled from published PK studies in which flunixin was administered through various dosage regimens to diverse populations of cattle. A set of liver data used to establish the regulatory label withdrawal time (WDT) also were used in this study. Compartmental models with first-order absorption and elimination were fitted to plasma and liver concentrations by a population PK modeling approach. Monte Carlo simulations were performed with the population mean and variabilities of PK parameters to predict liver concentrations of flunixin. The PK of flunixin was described best by a 3-compartment model with an extra liver compartment. The WDI estimated in this study with liver data only was the same as the label WDT. However, a longer WDI was estimated when both plasma and liver data were included in the population PK model. This study questions the use of small groups of healthy animals to determine WDTs for drugs intended for administration to large diverse populations. This may warrant a reevaluation of the current procedure for establishing WDT to prevent violative residues of flunixin.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Bovinos/sangre , Clonixina/análogos & derivados , Residuos de Medicamentos/farmacocinética , Modelos Biológicos , Método de Montecarlo , Algoritmos , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Clonixina/administración & dosificación , Clonixina/farmacocinética , Simulación por Computador , Vías de Administración de Medicamentos , Femenino , Hígado/metabolismo , MasculinoRESUMEN
Quantitative structure-activity relationship (QSAR) models are being used increasingly in skin permeation studies. The main idea of QSAR modelling is to quantify the relationship between biological activities and chemical properties, and thus to predict the activity of chemical solutes. As a key step, the selection of a representative and structurally diverse training set is critical to the prediction power of a QSAR model. Early QSAR models selected training sets in a subjective way and solutes in the training set were relatively homogenous. More recently, statistical methods such as D-optimal design or space-filling design have been applied but such methods are not always ideal. This paper describes a comprehensive procedure to select training sets from a large candidate set of 4534 solutes. A newly proposed 'Baynes' rule', which is a modification of Lipinski's 'rule of five', was used to screen out solutes that were not qualified for the study. U-optimality was used as the selection criterion. A principal component analysis showed that the selected training set was representative of the chemical space. Gas chromatograph amenability was verified. A model built using the training set was shown to have greater predictive power than a model built using a previous dataset [1].
Asunto(s)
Química/métodos , Compuestos Inorgánicos/farmacocinética , Compuestos Orgánicos/farmacocinética , Permeabilidad , Relación Estructura-Actividad Cuantitativa , Piel/efectos de los fármacos , Compuestos Inorgánicos/química , Modelos Estadísticos , Compuestos Orgánicos/químicaRESUMEN
The objective of this study was to determine if the plasma pharmacokinetics and milk elimination of flunixin (FLU) and 5-hydroxy flunixin (5OH) differ following intramuscular and subcutaneous injection of FLU compared with intravenous injection. Twelve lactating Holstein cows were used in a randomized crossover design study. Cows were organized into 2 groups based on milk production (<20 or >30 kg of milk/d). All cattle were administered 2 doses of 1.1mg of FLU/kg at 12-h intervals by intravenous, intramuscular, and subcutaneous injections. The washout period between routes of administration was 7d. Blood samples were collected from the jugular vein before FLU administration and at various time points up to 36 h after the first dose of FLU. Composite milk samples were collected before FLU administration and twice daily for 5d after the first dose of FLU. Samples were analyzed by ultra-HPLC with mass spectrometric detection. For FLU plasma samples, a difference in terminal half-life was observed among routes of administration. Harmonic mean terminal half-lives for FLU were 3.42, 4.48, and 5.39 h for intravenous, intramuscular, and subcutaneous injection, respectively. The mean bioavailability following intramuscular and subcutaneous dosing was 84.5 and 104.2%, respectively. The decrease in 5OH milk concentration versus time after last dose was analyzed with the nonlinear mixed effects modeling approach and indicated that both the route of administration and rate of milk production were significant covariates. The number of milk samples greater than the tolerance limit for each route of administration was also compared at each time point for statistical significance. Forty-eight hours after the first dose, 5OH milk concentrations were undetectable in all intravenously injected cows; however, one intramuscularly injected and one subcutaneously injected cow had measurable concentrations. These cows had 5OH concentrations above the tolerance limit at the 36-h withdrawal time. The high number of FLU residues identified in cull dairy cows by the United States Department of Agriculture Food Safety Inspection Service is likely related to administration of the drug by an unapproved route. Cattle that received FLU by the approved (intravenous) route consistently eliminated the drug before the approved withdrawal times; however, residues can persist beyond these approved times following intramuscular or subcutaneous administration. Cows producing less than 20 kg of milk/d had altered FLU milk clearance, which may also contribute to violative FLU residues.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Clonixina/análogos & derivados , Leche/química , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/análisis , Antiinflamatorios no Esteroideos/sangre , Bovinos , Clonixina/administración & dosificación , Clonixina/análisis , Clonixina/sangre , Clonixina/farmacocinética , Residuos de Medicamentos/análisis , Femenino , Inyecciones Intramusculares/veterinaria , Inyecciones Intravenosas/veterinaria , Inyecciones Subcutáneas/veterinariaRESUMEN
Tulathromycin is a macrolide antimicrobial labeled for treatment of bacterial pneumonia in cattle and swine. The purpose of the present research was to evaluate tissue concentrations of tulathromycin in the caprine species. A tandem mass spectrometry regulatory analytical method that detects the common fragment of tulathromycin in cattle and swine was validated with goat tissues. The method was used to study tulathromycin depletion in goat tissues (liver, kidney, muscle, fat, injection site, and lung) over time. In two different studies, six juvenile and 25 market-age goats received a single injection of 2.5 mg/kg of tulathromycin subcutaneously; in a third study, 18 juvenile goats were treated with 2.5, 7.5, or 12.5 mg/kg tulathromycin weekly with three subcutaneous injections. Mean tulathromycin tissue concentrations were highest at injection site samples in all studies and all doses. Lung tissue concentrations were greatest at day 5 in market-age goats while in the multi-dose animals concentrations demonstrated dose-dependent increases. Concentrations were below limit of quantification in injection site and lung by day 18 and in liver, kidney, muscle, and fat at all time points. This study demonstrated that tissue levels in goats are very similar to those seen in swine and cattle.
Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Disacáridos/administración & dosificación , Disacáridos/farmacocinética , Cabras/metabolismo , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/farmacocinética , Tejido Adiposo , Animales , Antibacterianos/sangre , Disacáridos/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Residuos de Medicamentos , Femenino , Compuestos Heterocíclicos/sangre , Infusiones Subcutáneas , Riñón , Hígado , Pulmón , Masculino , Músculo Esquelético , Reproducibilidad de los Resultados , Distribución TisularRESUMEN
Physiologically based pharmacokinetic (PBPK) models, which incorporate species- and chemical-specific parameters, could be useful tools for extrapolating withdrawal times for drugs across species and doses. The objective of this research was to develop a PBPK model for goats to simulate the pharmacokinetics of tulathromycin, a macrolide antibiotic effective for treating respiratory infections. Model compartments included plasma, lung, liver, muscle, adipose tissue, kidney, and remaining poorly and richly perfused tissues. Tulathromycin was assumed to be 50% protein bound in plasma with first-order clearance. Literature values were compiled for physiological parameters, partition coefficients were estimated from tissue:plasma ratios of AUC, and the remaining model parameters were estimated by comparison against the experimental data. Three separate model structures were compared with plasma and tissue concentrations of tulathromycin in market age goats administered 2.5 mg/kg tulathromycin subcutaneously. The best simulation was achieved with a diffusion-limited PBPK model and absorption from a two-compartment injection site, which allowed for low persistent concentrations at the injection site and slower depletion in the tissues than the plasma as observed with the experimental data. The model with age-appropriate physiological parameters also predicted plasma concentrations in juvenile goats administered tulathromycin subcutaneously. The developed model and compilation of physiological parameters for goats provide initial tools that can be used as a basis for predicting withdrawal times of drugs in this minor species.
Asunto(s)
Antibacterianos/farmacocinética , Disacáridos/farmacocinética , Cabras/metabolismo , Compuestos Heterocíclicos/farmacocinética , Modelos Biológicos , Animales , Antibacterianos/sangre , Simulación por Computador , Disacáridos/sangre , Cabras/sangre , Compuestos Heterocíclicos/sangre , Sensibilidad y Especificidad , Programas Informáticos , Distribución TisularRESUMEN
Despite the recent growth of the organic dairy industry, organic producers and veterinarians have limited information when choosing mastitis treatments for animals in organic dairy production. Organic producers commonly administer homeopathic or other plant-based products without having research evaluating the efficacy of these products and using estimated or no withholding times to treat mastitis and other health problems in their herds. In this pilot study, we attempted to identify several active ingredients of Phyto-Mast (Penn Dutch Cow Care, Narvon, PA), a plant-based mastitis treatment used on organic dairy farms, and to quantify the product residue in milk and plasma after intramammary administration. We developed an assay to quantify thymol (one of the active ingredients in Phyto-Mast) in milk and plasma using gas chromatography and mass spectrometry (GC-MS). Thymol is a volatile aromatic compound with antiinflammatory properties. As a model for dairy cows, 5 healthy, lactating alpine dairy goats were given 5 mL of Phyto-Mast per udder half. For 10 d following treatment, we analyzed blood and milk samples for thymol residues using GC-MS. The GC-MS assay was very sensitive for thymol detection, to a concentration of 0.01 µg/mL in plasma. Using thymol as a marker, Phyto-Mast was detectable and quantifiable in plasma beginning with the 15-min posttreatment sample, but was no longer detectable in the 4-h posttreatment sample. Thymol residues were only detected in the 12-h posttreatment milk sample. An inflammatory response was not evident in the udder following phytoceutical administration. Although this study provides information about the elimination of thymol, the product contains several other active chemicals, which may have different pharmacokinetic behaviors. Further analysis and additional study animals will help to determine a milk withholding time for Phyto-Mast. Given the recent growth of the organic dairy industry, understanding the pharmacokinetics of therapeutics used in organic production and developing accurate withholding recommendations will help to ensure milk safety.
Asunto(s)
Antiinfecciosos Locales/análisis , Residuos de Medicamentos/análisis , Glándulas Mamarias Animales/metabolismo , Mastitis/veterinaria , Leche/química , Fitoterapia/veterinaria , Timol/análisis , Angelica sinensis , Animales , Antiinfecciosos Locales/sangre , Antiinfecciosos Locales/uso terapéutico , Industria Lechera/métodos , Vías de Administración de Medicamentos , Femenino , Gaultheria , Glycyrrhiza uralensis , Cabras , Mastitis/tratamiento farmacológico , Mastitis/metabolismo , Proyectos Piloto , Timol/sangre , Timol/uso terapéutico , Thymus (Planta)RESUMEN
Tulathromycin, a novel triamilide in the macrolide class, is labeled for treatment of bacterial pneumonia in cattle and swine. This manuscript evaluates pharmacokinetics of tulathromycin in goats. In two different studies, six juvenile and ten market-age goats received a single injection of 2.5 mg/kg of tulathromycin subcutaneously; in a third study, 18 juvenile goats were treated with 2.5, 7.5, or 12.5 mg/kg tulathromycin weekly with three subcutaneous injections. Pharmacokinetic parameters estimated from the plasma concentrations from single injections were similar between the two groups of goats and to previously reported parameters in cattle and swine. Mean terminal half-lives were 59.1 ± 7.6 and 61.2 ± 8.7 h for juvenile and market-age goats, respectively. In the multi-dose study, pharmacokinetic parameters estimated from plasma concentrations demonstrated significant differences at P < 0.05 among repeated injections but not among doses. Overall, pharmacokinetic parameters in goats are similar to those reported in cattle and swine, and tulathromycin may prove a useful drug for treating respiratory disease in goats.
Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Disacáridos/administración & dosificación , Disacáridos/farmacocinética , Cabras/sangre , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/farmacocinética , Envejecimiento , Animales , Antibacterianos/sangre , Área Bajo la Curva , Disacáridos/sangre , Esquema de Medicación , Femenino , Semivida , Compuestos Heterocíclicos/sangre , MasculinoRESUMEN
Medicating drinking water with tetracycline is commonly used in swine production systems to treat and prevent disease outbreaks. However, little information is known of the pharmacokinetics of this medication in water formulations. Twenty-four barrows, divided into 1 control group (of nontreated animals) and 3 equally sized treatments groups (n = 6/group), were treated with tetracycline water medication for 5 d at 125, 250, and 500 mg/L. Blood samples were collected at 0 (prestudy), 4, 8, 12, 24, 32, 48, 56, 72, 80, 96, and 104 h after exposure. Data analyses consisted of a noncompartmental pharmacokinetic analysis and statistical analysis of steady state concentrations with repeated measures ANOVA and multiple-comparison testing to determine whether plasma concentrations differed among groups. Derived pharmacokinetic parameters were consistent with previously published feed and intravenous data. Plasma tetracycline concentrations at steady state were 0, 0.33, 0.47, and 0.77 microg/mL for 0-, 125-, 250-, and 500-mg/L exposures, respectively. Treatment group steady-state plasma concentrations were significantly different from plasma concentrations in control animals (P < 0.0001); however, whereas the 125- and 250-mg/L groups were significantly different from the 500-mg/L group (P < 0.0001), their mean plasma tetracycline concentrations did not differ from one another. Furthermore, the study showed that tetracycline oral bioavailability is very small. The dose response curve also shows that concentrations of plasma tetracycline increase linearly, yet not in a 1 to 1 ratio, to the direct increase in water medication dose.
Asunto(s)
Antibacterianos/farmacocinética , Porcinos/metabolismo , Tetraciclina/farmacocinética , Administración Oral , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Masculino , Pruebas de Sensibilidad Microbiana/veterinaria , Distribución Aleatoria , Tetraciclina/administración & dosificación , Tetraciclina/sangre , Tetraciclina/orinaRESUMEN
Combination drug therapy increases the chance for an adverse drug reactions due to drug-drug interactions. Altered disposition for sulfamethazine (SMZ) when concurrently administered with flunixin meglumine (FLU) in swine could lead to increased tissue residues. There is a need for a pharmacokinetic modeling technique that can predict the consequences of possible drug interactions. A physiologically based pharmacokinetic model was developed that links plasma protein binding interactions to drug disposition for SMZ and FLU in swine. The model predicted a sustained decrease in total drug and a temporary increase in free drug concentration. An in vivo study confirmed the presence of a drug interaction. Neither the model nor the in vivo study revealed clinically significant changes that alter tissue disposition. This novel linkage approach has use in the prediction of the clinical impact of plasma protein binding interactions. Ultimately it could be used in the design of dosing regimens and in the protection of the food supply through prediction and minimization of tissue residues.
Asunto(s)
Antiinfecciosos/farmacocinética , Antiinflamatorios no Esteroideos/farmacocinética , Proteínas Sanguíneas/metabolismo , Clonixina/análogos & derivados , Modelos Biológicos , Sulfametazina/farmacocinética , Porcinos/metabolismo , Animales , Antiinfecciosos/sangre , Antiinflamatorios no Esteroideos/sangre , Cromatografía Líquida de Alta Presión , Clonixina/sangre , Clonixina/farmacocinética , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Farmacocinética , Unión Proteica , Sulfametazina/sangre , Porcinos/sangre , Distribución TisularRESUMEN
Dermal risk assessments are most often concerned with the occupational and environmental exposure to a single chemical and then determining solute permeability through in vitro or in vivo experimentation with various animal models and/or computational approaches. Oftentimes, the skin is exposed to more than one chemical that could potentially modulate dermal permeability of the chemical that could cause adverse health effects. The focus of this article is to demonstrate that these formulation effects on dermal permeability can occur with simple solvent formulations or complex industrial formulations and that these effects can be modeled within the context of a linear solvation energy relationship (LSER). This research demonstrated that formulation-specific strength coefficients (r p a b v) predicted (r(2) = 0.75-0.83) changes in the dermal permeability of phenolic compounds when formulated with commercial metal-working fluid (MWF) formulations or 50% ethanol. Further experimentation demonstrated that chemical-induced changes in skin permeability with 50% ethanol are strongly correlated (r(2) = 0.91) to similar changes in an inert membrane-coated fiber (MCF) array system consisting of three chemically diverse membranes. Changes in specific strength coefficients pertaining to changes in hydrogen donating ability (Deltab) and hydrophobicity (Deltav) across membrane systems were identified as important quantitative interactions associated with ethanol mixtures. This solvatochromatic approach along with the use of a MCF array system holds promise for predicting dermal permeability of complex chemical formulations in occupational exposures where performance additives can potentially modulate permeability of potential toxicants.
Asunto(s)
Permeabilidad/efectos de los fármacos , Fenómenos Fisiológicos de la Piel , Solventes/metabolismo , Toxicología/métodos , Animales , Etanol/metabolismo , Modelos Teóricos , Fenol/metabolismo , Porcinos , Agua/metabolismoRESUMEN
A system coefficient approach is proposed for quantitative assessment of the solvent effects on membrane absorption from chemical mixtures. The complicated molecular interactions are dissected into basic molecular interaction forces via Abraham's linear solvation energy relationship (LSER). The molecular interaction strengths of a chemical are represented by a set of solute descriptors, while those of a membrane/chemical mixture system are represented by a set of system coefficients. The system coefficients can be determined by using a set of probe compounds with known solute descriptors. Polydimethylsiloxane (PDMS) membrane-coated fibres and 32 probe compounds were used to demonstrate the proposed approach. When a solvent was added into the chemical mixture, the system coefficients were altered and detected by the system coefficient approach. The system coefficients of the PDMS/water system were (0.09, 0.49, -1.11, -2.36, -3.78, 3.50). When 25% ethanol was added into the PDMS/water system, the system coefficients were altered significantly (0.38, 0.41, -1.18, -2.07, -3.40, 2.81); and the solvent effect was quantitatively described by the changes in the system coefficients (0.29, -0.08, -0.07, 0.29, 0.38, -0.69). The LSER model adequately described the experimental data with a correlation coefficient (r(2)) of 0.995 and F-value of 1056 with p-value less than 0.0001.
Asunto(s)
Dimetilpolisiloxanos/química , Membranas Artificiales , Modelos Biológicos , Modelos Químicos , Siliconas/química , Absorción , Dimetilpolisiloxanos/metabolismo , Cinética , Relación Estructura-Actividad Cuantitativa , Análisis de Regresión , Siliconas/metabolismo , Solventes/químicaAsunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Clonixina/análogos & derivados , Animales , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/metabolismo , Área Bajo la Curva , Clonixina/sangre , Clonixina/metabolismo , Clonixina/farmacocinética , Semivida , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Unión Proteica , PorcinosRESUMEN
A risk assessment of the food safety implications of drugs used in food-producing animals is an essential component of the regulatory approval process for products containing these drugs. This ensures that there is negligible risk to human health if these drugs are used according to the instructions that appear on the approved label. A relative paucity of approved products for veterinary species; however, forces veterinarians worldwide to use drugs in an extralabel manner to treat disease and alleviate suffering in animals. In food-producing animals, this may result in residues that are potentially harmful to the human consumer. This review describes how risk assessment principles can be extended to evaluate the risks posed by different classes of extralabel drug use. Risk management practices in the United States and Europe are summarized and contrasted to illustrate the application of these principles.