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1.
The purpose of this study was to determine whether Japanese quail (Coturnix japonica) would serve as a pharmacokinetic animal model for two small companion parrots: cockatiels (Nymphicus hollandicus) and Poicephalus parrots. Oxytetracycline (OTC) was the pharmacologic agent chosen for this study as it is eliminated primarily by renal glomerular filtration and undergoes minimal metabolism. A single intravenous injection of 20 mg/kg oxytetracycline hydrochloride was administered to the three study groups and blood samples were obtained at 5, 10, 15, and 30 min post-OTC injection as well as 1, 2, 4, 8, 12 and 24 h post-OTC injection. Quantification of plasma OTC was accomplished using a standardized microbial inhibition assay. Naïve-pooled data (NPD) analysis of the plasma concentration–time profile of OTC best fit a two-compartment open model for all three avian species. Noncompartmental analysis of the mean data yielded the following parameters for quail, cockatiels and Poicephalus parrots respectively: λz = 3.14, 4.57, 3.71 h; AUC = 38.9, 42.7, 49.6 μg·h/mL; and Cl = 514, 468, 403 mL/h/kg. Based on the similarity of these pharmacokinetic parameters, it appears that quail could be used as a model species to predict the appropriate OTC dosing regimen for small psittacine birds. A bootstrap procedure was also applied to these sparse data sets for both compartmental and noncompartmental analysis. The bootstrap procedure allowed for the calculation of variability of parameters; however, the estimates of the parameters were very similar to those calculated using the NPD and the data mean values.  相似文献   

2.
To determine the potential use of parenteral therapy in the treatment of chlamydiosis in psittacine birds, the disposition and toxicity of a long-acting oxytetracycline (OTC) was evaluated in Goffin's cockatoos. Following intramuscular and subcutaneous administration of 50 to 100 mg/kg body weight, plasma OTC concentrations of 7 to 15 micrograms/ml were obtained 3 hr following injection and declined with a terminal half-life between 8.9 to 14.7 hr. Plasma concentrations in excess of 1.0 microgram/ml were maintained for 48 to 68 hr. Multiple-dose treatment of 100 mg/kg subcutaneously every 3 days for 30 days caused focal necrosis and scabs at the injection site but no other clinical or serological evidence of adverse effects. Long-term treatment did not result in accumulation or alteration in the disposition of OTC. Based on this study, a dosage regimen of 50 to 100 mg/kg of OTC subcutaneously every 2-3 days would safely maintain plasma concentrations in excess of 1.0 microgram/ml and could potentially be used as an alternative to medicated feeds or daily oral dosing regimens for the treatment of chlamydiosis in psittacine birds.  相似文献   

3.
Separate groups of goats were used to determine drug depletion patterns in serum (n=10), tissue (n=20) and milk (n=8) following a single intramuscular (i.m.) dose of 20 mg/kg of a long-acting oxytetracycline (OTC) formulation (Liquamycin LA-200). Milk residues were also determined following a subcutaneous (s.c.) administration of the same product at the same dose. Serum samples were taken for 24 h post-treatment and tissues (fat, liver, kidney, muscle and injection site) collected at 4, 7, 14, 21 and 28 days following injection. Milk from lactating goats was collected every 12 h for 8 days following both the i.m. and s.c. treatments utilizing an intervening 5-week washout period. Residues in serum and tissue were measured using a microbial inhibition assay, while milk residues were measured using both a microbial inhibition assay and a validated HPLC method. The serum pharmacokinetic parameters of OTC in goats were determined, with a mean AUC=67.4 microg h/mL, mean terminal half-life=14.4 h, and apparent clearance=0.33 L/kg h. Tissue half-lives could not be determined with confidence because the collection times provided only two points at which residues could be measured for most tissues. Oxytetracycline residues in all goat tissue samples measured less then cattle tissue tolerance by 96 h postdosing. One-compartment model describing milk depletion data for i.m. and s.c. dosing had terminal slope half-lives of 20.1 and 36.1 h, respectively. By 96 h post-treatment none of the milk samples contained OTC residues in excess of the cattle milk tolerance (0.3 p.p.m.). For both milk and tissue, the upper-bound 99% confidence intervals for the samples taken from goats 96 h postdosing were lower than approved cow milk and tissue tolerances.  相似文献   

4.
OBJECTIVE: To determine for two commercial preparations of oxytetracycline (OTC) the pharmacokinetic behaviour, the presence of detectable milk residues and the penetration in milk of OTC administered by intravenous (IV) (conventional formulation [CF]) and intramuscular (IM) routes (CF and long-acting [LA] formulations) in goats producing milk. The effects of these formulations on plasma activity values of creatine kinase (CK) and lactate dehydrogenase (LDH) were also determined as indicators of tissue damage. PROCEDURE: Five healthy lactating goats producing 1.5+/-0.5 L/d milk and weighing 56.0+/-4.8 kg were used. Single doses of OTC chlorhydrate (CF) were administered (20 mg OTC/kg) by IV (Trial 1 IV) and IM (Trial 1 IM) routes and OTC dehydrate (LA) by the IM route. The same goats were first given IV CF, then IM CF followed by IM LA with 3 weeks between each treatment. Blood and milk samples were taken. The quantification of OTC was performed by HPLC and the plasma activities of CK and LDH enzymes were determined by spectrophotometry. The presence of OTC residues in milk was determined by a commercial reagent. The plasma pharmacokinetic parameters were calculated using a two-compartment model. RESULTS: Estimates of kinetic variables following IV administration were: Vss= 400.0+/-120.0 mL/kg and CL= 110.0+/-14.0 (mL/h)/kg. The t(fi) for IV= 3.0+/-0.3 h; IM, CF = 10.5+/-2.1 h and IM, LA = 15.1+/-3.1 h. The concentration of OTC in milk at 48 h was: IV= 0.6+/-0.4; IM CF= 1.1+/-0.2 and at 72 h (IM LA)= 0.6+/-0.1 microg/mL and the penetration in milk of OTC was: IV= 70.0+/-18.0; IM CF= 79.0+/-14.0 and IM LA= 66.0+/-6.0%. The areas under the curve of CK and LDH activities in plasma were calculated by the trapezoidal method. Values of CK and LDH IM, LA were greater (P < 0.05) than those observed for IM, CF at 2 and 3 days after administration of the antibiotic. Finally, the bioavailability of OTC CF = 92.0+/-22.0 and LA= 78.0+/-23.0% was suitable for its usage by the IM route in lactating goats. CONCLUSION: Plasma concentration-time values of OTC administered parenterally in production dairy goats showed similar bioavailability for the two pharmaceutical preaprations. The presence of detectable residues in milk indicates that milk should not be used for human consumption for 2 and 3 days after administration of conventional and long-acting formulations, respectively. The increments in CK and LDH activities after the IM administration of LA are consistent with the presence of tissue damage provoked by the pharmaceutical preparations at the injection site.  相似文献   

5.
Two commercially available long-acting oxytetracycline (OTC) formulations were administered by the intramuscular (i.m.) route to six healthy pigs at the recommended dose of 30 mg/kg. After 2 h the mean maximum concentration (C(max)) reached values of 8.1 +/- 2.2 and 15.4 +/- 11.1 microg/mL, respectively. These concentrations remained higher than 0.5 microg/mL for more than 5 days after drug administration. The area under the concentration time curve (AUC09 days) of each formulation was 255 +/- 76.5 and 399.2 +/- 123 microg. h/mL, respectively, and the mean residence time (MRT) was around 3 days for both formulations. No significant differences were observed between the pharmacokinetic parameters of the two formulations, showing the bioequivalence of the two formulations studied according to the criteria established by the Food and Drug Administration (FDA) and the Committee for Veterinary Medicinal Products (CVMP).  相似文献   

6.
Objective To investigate tissue residues of two longacting oxytetracycline (OTC) preparations in cattle.
Design A randomised drug residue trial.  

Animals


Two hundred and forty beef cattle in 24 groups of ten.
Procedure Two blind-coded 200 mg/mL OTC preparations were used in five treatment regimens of various combinations of injection sites (from one to five) and administrations (one or two). Five cattle from each group were slaughtered at 21, 30 and 60 days after injection and the injection site, urine, kidney and diaphragm muscle analysed for residues.
Results The OTC concentration exceeded the maximum residue limit in kidney in animals slaughtered 21 days after treatment, which is the prescribed withholding period. Concentration at the injection site was much greater than the maximum residue limit 30 days post-treatment, but not 45 days post-treatment. The residue was smaller when OTC had been injected in multiple sites. There was no difference between the two OTC preparations.
Conclusion A review of the maximum injection volume, site of injection and the withholding period is needed for long-acting OTC formulations.  相似文献   

7.
Bimazubute, M., Cambier, C., Baert, K., Vanbelle, S., Chiap, P., Gustin, P. Penetration of oxytetracycline into the nasal secretions and relationship between nasal secretions and plasma oxytetracycline concentrations after oral and intramuscular administration in healthy pigs. J. vet. Pharmacol. Therap. 34 , 176–183. The penetration of oxytetracycline (OTC) in plasma and nasal secretions of healthy pigs was evaluated during the first study, in response to oral dose of 20 mg of OTC per kg of body weight (bwt) per day as a 400 mg/kg feed medication (n = 5) and to intramuscular (i.m.)‐administered formulations at 10 mg/kg bwt (n = 5), 20 mg/kg bwt (n = 5), 40 mg/kg bwt (n = 5). Concentrations of OTC in plasma and nasal secretions were determined by a validated ultra‐high performance liquid chromatography associated to tandem mass spectrometry method (UPLC/MS/MS). The objectives were to select the efficacy treatment and to evaluate the possibility to predict nasal secretions concentrations from those determined in plasma. The animals were housed together in each experiment. In each group, the treatment was administered once daily during 6 consecutive days, and nasal secretions and plasma were collected after 4 and 24 h at day 2 and day 6. For oral administration, only one medicated feed was prepared and distributed to all the animals together and was consumed in approximately 1 h. To meet recommendations of efficacy for OTC in nasal secretions, only the i.m. of 40 mg/kg bwt associated to an inter‐dosing interval of 24 h provides and maintains concentrations in nasal secretions ≥1 μg/mL, appropriate to the MIC 50 and 90 of Pasteurella multocida and Bordetella bronchiseptica, respectively, the main pathological strains in nasal secretions. It has been demonstrated that, using a generalized linear mixed model (GLMM), OTC in the nasal secretions (μg/mL) can be predicted taking into account the OTC concentrations in plasma (μg/mL), according to the following equation: OTCnasal secretions = 0.28 OTCplasma?1.49. In a second study, the pharmacokinetic behaviour of OTC in plasma and nasal secretions of healthy pigs was investigated, after single‐dose i.m. of 40 mg/kg bwt of the drug. Blood samples and nasal secretions were collected at predetermined times after drug administration. The data collected in 10 pigs for OTC were subjected to non‐compartmental analysis. In plasma, the maximum concentration of drug (Cmax), the time at which this maximum concentration of drug (Tmax) was reached, the elimination half‐life (t½) and the area under the concentration vs. time curve (AUC) were, respectively, 19.4 μg/mL, 4.0, 5.1 h and 150 μg·h/mL. In nasal secretions, Cmax, Tmax, t½ and AUC were, respectively, 6.29 μg/mL, 4.0, 6.6 h and 51.1 μg·h/mL.  相似文献   

8.
Pharmacokinetics of oxytetracycline (OTC) were studied in 10 pigs after administration of 20 mg/kg body weight of either a conventional (OTC-C) or a long-acting (OTC-LA) preparation.
After intravenous administration of OTC-C the elimination half-life for OTC was 3.75 h, with approximately 75% of the dose being excreted in the urine in 1 week. Intramuscular (i.m.) injection of OTC-C resulted in plasma peak values after 4 h, while OTC-LA after i.m. administration produced the highest plasma levels within 1 h, although these were lower than with OTC-C.
For both preparations the bioavailability after i.m. administration was 95–100% and about 70% of the dose was excreted in the urine during the first week.
With OTC-C given i.m., plasma concentrations above 0.5 μg/ml were maintained for 28 h and with OTC-LA for 35 h indicating a weak retard effect of the latter.
Pronounced tissue damage at the injection site was seen 1 and 2 weeks after the administration of OTC-LA, while OTC-C produced very little irritation. OTC could be found at the injection site for 2 weeks, the concentrations being higher for OTC-LA than for OTC-C.  相似文献   

9.
A comparative pharmacokinetic study was conducted in rainbow trout (Salmo gairdneri) and African catfish (Clarias gariepinus) following intravenous (i.v.) and intramuscular (i.m.) administration of oxytetracycline (OTC) at a dose rate of 60 mg/kg body weight. Trout and catfish were kept in aerated tap water in tanks at constant temperatures of 12 degrees C and 25 degrees C, respectively. The two- and three-compartment open models adequately described plasma drug disposition in African catfish and rainbow trout respectively, following i.v. OTC administration. Compared to catfish (COP = 86 +/- 10 micrograms/ml) an eightfold higher extrapolated zero time concentration was obtained in trout (COP = 753 +/- 290 micrograms/ml). A significant difference was observed with respect to the relatively large apparent distribution volumes (Vd(area] after i.v. OTC administration (trout, mean value: 2.1 l/kg; catfish, mean value: 1.3 l/kg). The mean final elimination half-lives of both fish species were greater than previously reported in mammals (trout, 89.5 h; catfish, 80.3 h). A mean maximum plasma concentration (Cmax = 56.9 micrograms/ml) was obtained in trout at 4 h after i.m. administration of OTC. In catfish a lower Cmax of 43.4 micrograms/ml was determined at about 7 h. No significant difference was observed with respect to bioavailability following i.m. administration of OTC (trout, 85%; catfish, 86%).  相似文献   

10.
The American horseshoe crab, Limulus polyphemus, is regularly cultured and maintained in research laboratories and public aquaria. Rising concerns over the health of these captive animals makes the diagnosis and treatment of pathological conditions in L. polyphemus essential. This study investigated the kinetics of oxytetracyline following either intravascular or oral dosing. Oxytetracylcine is a broad-spectrum antibiotic used in the treatment of various bacterial diseases of aquatic animals. A noncompartmental model was developed to describe the pharmacokinetics of oxytetracycline (OTC) in the horseshoe crab. The following parameters were determined for a single intravascular bolus of 25 mg/kg OTC: AUC = 9524.60 microg.h/mL, MRT = 443.65 h, Clb = 0.044 mL/min/kg, Vd(ss) = 1.164 L/kg, t(1/2) = 128.3 h, Cmax = 55.90 microg/mL, C(ave) = 27.39 microg/mL. Following a single oral bolus of 25 mg/kg, these parameters were calculated: AUC = 5861.81 microg.h/mL, MRT = 395.89 h, Clb = 0.071 mL/min/kg, Vd(ss) = 1.688 L/kg, t(1/2) = 210.0 h, Cmax = 7.83 microg/mL, C(ave) = 2.89 microg/mL, F = 61.56%.  相似文献   

11.
The present study aimed to characterize the pharmacokinetic profile of oxytetracycline long‐acting formulation (OTC‐LA) in Thai swamp buffaloes, Bubalus bubalis, following single intramuscular administration at two dosages of 20 and 30 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 504 h. The plasma concentrations of OTC were measured by high‐performance liquid chromatography (HPLC). The concentrations of OTC in the plasma were determined up to 264 h and 432 h after i.m. administration at doses of 20 and 30 mg/kg b.w., respectively. The Cmax values of OTC were 12.11 ± 1.87 μg/mL and 12.27 ± 1.92 μg/mL at doses of 20 and 30 mg/kg, respectively. The AUClast values increased in a dose‐dependent fashion. The half‐life values were 52.00 ± 14.26 h and 66.80 ± 10.91 h at doses of 20 and 30 mg/kg b.w, respectively. Based on the pharmacokinetic data and PK–PD index (T > MIC), i.m. administration of OTC at a dose of 30 mg/kg b.w once per week might be appropriate for the treatment of susceptible bacterial infection in Thai swamp buffaloes.  相似文献   

12.
The pharmacokinetic properties of oxytetracycline were studied following a single injection of a long-acting formulation (20 mg/kg body weight) into the semimembranosus muscle of healthy dogs and of dogs that had been experimentally infected with Ehrlichia canis. The disposition curves of the long-acting oxytetracycline formulation before and after infection were best described by a bi-exponential decline after a first-order absorption. The mean maximum serum concentration (C max) following infection was significantly lower and the time taken to attain this concentration (t max) was significantly shorter than that in the healthy dogs. The mean apparent elimination half-life (t 1/2) was significantly increased following infection. The corresponding rate constant () was significantly decreased. The absorption half-life (t 1/2ab) was significantly decreased after infection. The volume of distribution at steady state (V dss) increased significantly following infection. It was concluded that the pharmacokinetic behaviour of a long-acting oxytetracycline in dogs after intramuscular administration is characterized by a two-compartment model with a slow elimination phase. This could be due to flip-flop kinetics. The febrile reaction in experimental E. canis infection affected some pharmacokinetic parameters of oxytetracycline.  相似文献   

13.
The pharmacokinetics of a long‐acting oxytetracycline (OTC) formulation (Liquamycin® LA‐200®) injected intramuscularly (i.m.) at a dose of 20 mg/kg were determined in four calves and 24 sheep to determine if the approved label dose for cattle provided a similar serum time/concentration profile in sheep. The AUC for the calves was 168±14.6 (μg ? h/mL) and was significantly less than the AUC for sheep (209±43 μg ? h/mL). Using the standard two‐stage approach and a one‐compartment model, the mean Cmax for the calves was 5.2±0.8 μg/mL, and for the sheep was 6.1±1.3 μg/mL. The mean terminal phase rate constants were 0.031 and 0.033 h, and the Vdss were 3.3 and 3.08 L/kg for the calves and sheep respectively. Analysis of the data using the standard two‐stage approach, the naive pooled‐data approach and a population model gave very similar results for both the cattle and sheep data. Sheep tissue residues of OTC in serum, liver, kidney, fat, muscle and injection site were measured at 1, 2, 3, 5, 7 and 14 days after a single i.m. injection of 20 mg/kg OTC. Half‐lives of OTC residues in the tissues were 38.6, 33.4, 28.6, 25.4, 21.3, and 19.9 h for injection site, kidney, muscle, liver, mesenteric fat and renal fat, respectively. The ratio of tissue to serum concentration was fairly consistent at all slaughter times, except for the fat and injection sites. The mean ratios were 1.72, 4.19, 0.11, 0.061, 0.84 and 827 for the liver, kidney, renal fat, mesenteric fat, muscle and injection sites, respectively. The tissue concentrations of OTC residues were below the established cattle tolerances for OTC in liver (6 p.p.m.), muscle (2 p.p.m.) and kidney (12 p.p.m.) by 48 h, and in injection site muscle by 14 days after the single i.m. injection of 20 mg/kg.  相似文献   

14.
The pharmacokinetic properties and local tolerance of three oxytetracycline formulations, one conventional (Engemycine, 10%) and two long-acting (Oxyter LA, 20% and Terramycin LA, 20%) were compared in clinically healthy cross-bred pigs following intramuscular injection of single doses (20 mg/kg body weight) in the neck region. Non-compartmental methods were used to calculate the pharmacokinetic parameters. Assessment of local tolerance was based on serum creatine phosphokinase (CPK) concentration and a combination of echographical, macroscopic and histological examinations of the intramuscular injection site. Statistically significant differences (one-way analysis of variance, F-test) were obtained between the three formulations in peak plasma concentration, peak time and mean residence time. Area under the curve did not differ significantly between the formulations. Using the Students t-test for paired data, the two long-acting formulations differed significantly in peak plasma concentration and peak time. Both of the long-acting formulations differed significantly from the conventional formulation in the peak time and mean residence time. All three formulations produced an increase in serum CPK concentrations. The increase in CPK concentration was present from 6 to 24 h post treatment for Terramycin LA, from 6 to 72 h for Oxyter LA and from 6 to 96 h for Engemycine (the conventional formulation). Echographical examination of the injection site showed lesions of an inflammatory type up to 96 h after IM injection of the drug products, whereas from 7 days the lesions represented primarily scar formation. Histological examination of tissue from the injection site did not correlate with echographical scores. The results obtained in this study show that the long-acting formulations provide significantly longer mean residence times of oxytetracycline than the conventional formulation, and that local tolerance at the IM injection site was similar for all three formulations under the experimental conditions used in this study. It can be concluded that the longacting formulations provide the advantage of a longer dosage interval when administered to pigs by intramuscular injection in the neck region at a dose of 20 mg/kg body weight.  相似文献   

15.
The influence of endotoxin on the disposition kinetics of oxytetracycline (OTC) (10 mg/kg) was investigated in five healthy ruminating male crossbred calves. The serum concentration-time data of OTC before and after endotoxin challenge were best described by a two-compartment open model. Repeated administration of Escherichia coli endotoxin (1 microg/kg, i.v.) at an interval of 12 h up to 48 h produced a clear rise in the body temperature and an increase in the pulse and respiration rates. Endotoxin caused a significant reduction in mean transit time in tissue compartment (MTTT) (P < or = 0.05), mean residence time in the peripheral tissue compartment (MRTT) (P < or = 0.05), mean residence time in the body (MRTB) (P < or = 0.05), elimination half-life (t1/2lambda2) (P < or = 0.05) and distribution space in tissues (VT) (P < or = 0.01) and at steady-state (Vd(ss)) (P < or = 0.01). Endotoxin had no effect on the distribution clearance (ClD), systemic clearance (Cl) and distribution half-life of OTC, while the values of first order rate constant of transfer of drug from tissue to central compartment (K21) and the zero time intercept at terminal phase (C2) were significantly high. The drug dosage regimens to maintain serum OTC concentrations of 0.5, 1, 2, 4, 6 and 8 microg/mL were also determined in febrile and clinically healthy animals.  相似文献   

16.
A field trial was performed under commercial feedlot conditions in western Canada to compare the efficacy of a new formulation of long-acting oxytetracycline (LA 30) to a standard long-acting oxytetracycline formulation (LA 20) and florfenicol (FLOR) for the treatment of undifferentiated fever (UF) in calves that received metaphylactic tilmicosin upon arrival at the feed-lot. Seven hundred and ninety-seven recently weaned, auction market derived, crossbred, beef calves suffering from UF were allocated to 1 of 3 experimental groups as follows: LA 30, which received intramuscular long-acting oxytetracycline (300 mg/mL formulation) at the rate of 30 mg/kg body weight (BW) at the time of allocation; LA 20, which received intramuscular long-acting oxytetracycline (200 mg/mL formulation) at the rate of 20 mg/kg BW at the time of allocation; or FLOR, which received intramuscular florfenicol administered at the rate of 20 mg/kg BW at the time of allocation and again 48 hours later. Two hundred and sixty-six animals were allocated to the LA 30 group, 265 animals were allocated to the LA 20 group, and 266 animals were allocated to the FLOR group. The relative efficacy of the LA 30 group, as compared with the LA 20 and FLOR groups, was assessed by comparing relapse, chronicity, wastage, and mortality rates. The overall mortality (RR = 0.50) rate in the LA 30 group was significantly (P < 0.05) lower than in the LA 20 group. However, the overall chronicity (RR = 2.56) and overall wastage (RR = 6.97) rates of the LA 30 group were significantly (P < 0.05) higher than in the LA 20 group. There were no significant (P > or = 0.05) differences in UF relapse rates or cause specific mortality rates between the LA 30 and LA 20 groups. In the economic analysis, there was an advantage of $28.59 CDN per animal in the LA 30 group compared with the LA 20 group. The overall chronicity (RR = 2.25) and overall wastage (RR = 2.80) rates of the LA 30 group were significantly (P < 0.05) higher than the FLOR group. There were no significant (P > or = 0.05) differences in UF relapse rates, overall mortality rates, or cause specific mortality rates between the LA 30 and FLOR groups. In the economic analysis, there was an advantage of $12.90 CDN per animal in the LA 30 group compared with the FLOR group. In summary, the results of this study indicate that it is more cost-effective to use a new formulation of long-acting oxytetracycline (300 mg/mL formulation administered at a rate of 30 mg/kg BW) than a standard long-acting oxytetracycline formulation (200 mg/mL formulation administered at a rate of 20 mg/kg BW) or florfenicol for the treatment of UF in feedlot calves that have previously received metaphylactic tilmicosin upon arrival at the feedlot.  相似文献   

17.
A physiologically based pharmacokinetic model (PBPK) for oxytetracycline (OTC) residues in sheep was developed using previously published data from a combined serum pharmacokinetic and tissue residue study [Craigmill et al. (2000) J. Vet. Pharmacol. Ther.23, 345]. Physiological parameters for organ weights and tissue blood flows were obtained from the literature. The tissue/serum partition coefficients for OTC were estimated from the serum and tissue residue data obtained at slaughter. The model was developed to include all of the tissues for which residue data were available (serum, kidney, liver, fat, muscle and injection site), and all of the remaining tissues were combined into a slowly perfused compartment with low permeability. Total body clearance of OTC calculated in the previous study was used as the starting value for clearance in the PBPK model, with the kidney being the only eliminating organ. The model was built using ACSL (Advanced Continuous Simulation Language) Graphic Modeler, and the model was fit to the serum and tissue data using the ACSL Math/Optimizer software (AEgis Technologies Group, Inc., Huntsville, AL, USA). A sensitivity analysis was also performed to determine which parameters had the greatest effect on the goodness of fit. Numerous strategies were tested to model the injection site, and a model providing a biexponential absorption of the drug from the injection bolus gave the best fit to the experimental data. The model was validated using the clearance parameters calculated from the traditional pharmacokinetic model for each individual animal in the PBPK model. This simple PBPK model well predicted OTC residues in sheep tissues after intramuscular dosing with a long-acting preparation and may find use for other species and other veterinary drugs.  相似文献   

18.
The pharmacokinetic-pharmacodynamic predictor of antimicrobial activity for tetracyclines is reported to be the area under the concentration-time curve at steady state (AUC(ss)) divided by the minimal inhibitory concentration of the targeted pathogen. Here, we estimate AUC(ss) values for oxytetracycline (OTC) in serum of rainbow trout Oncorhynchus mykiss by using a destructive sampling study design. Seventy-two rainbow trout were fed OTC-medicated feed at 74.7 +/- 1.5 mg/kg (mean +/- SD) body weight (BW) by oral gavage for 10 consecutive days. Serum was collected from nine fish at 1, 3, 6, 8, 10, 12, 15, and 22 d after dosing began. Serum OTC concentrations were measured by high-performance liquid chromatography with a 0.01-microg/mL limit of detection. The average OTC AUC(ss) was 29.2 microg x h/mL and was estimated using nonlinear mixed-effects modeling and bootstrap resampling techniques. The elimination half-life was estimated as 85.0 h, and the fraction of steady state achieved was estimated as 0.85. The calculated AUC(ss) (24.8 microg x h/mL) following 10 d of oral dosing with 75 mg OTC/kg BW was less than the estimated AUC(ss). Results suggest that the pharmacokinetics of OTC exposure, including the AUC(ss), is better evaluated by using multiday dosimetry than by using a standard single-dose protocol.  相似文献   

19.
After a single IV or IM dose of a long-acting oxytetracycline (OTC) preparation, serum concentrations were determined at various times in the ring-necked pheasant, great horned owl, and Amazon parrot. Pharmacokinetic parameters, including serum half-life (t1/2) and apparent volume of distribution (Vd) were calculated from the OTC concentration-time curves for each species and route of administration. Significant differences (P less than 0.05) were found in the t1/2 and Vd parameters between species and routes of administration. Dosage regimens to maintain minimum OTC concentration of 5 micrograms/ml of serum were calculated from the t 1/2 and Vd values obtained, using steady-state pharmacokinetics. In the pheasant, the calculated mean IV dose was 23 mg/kg of body weight every 6 hours, whereas the mean IM dose was 43 mg/kg every 24 hours. The mean IM dose was 16 mg/kg every 24 hours for the owl and 58 mg/kg every 24 hours for the parrot. The small volumes required for treatment, the long-dosing interval obtainable, and the broad spectrum of antimicrobial activity of the long-acting OTC preparation studied offered major advantages over other antibiotics commonly used in treating avian species.  相似文献   

20.
The giant river shrimp (Macrobrachium rosenbergii), a native species of Thailand, is either exported for commercial purposes or supplied to meet the local requirements in Thailand. Limited pharmacokinetic information of the major antibiotic, oxytetracycline (OTC), is available for this freshwater shrimp. The purpose of the present study was to investigate the muscle tissue kinetics of OTC in M. rosenbergii following either intramuscular (i.m.) or oral (p.o.) administration at two dosages of 11 and 22 mg/kg body weight (b.w.). The concentration of OTC in shrimp tissues was measured using high‐performance liquid chromatography (HPLC) equipped with a fluorescence detector. Muscle tissue concentrations were below the detection limit (LOD, 0.1 μg/g) after 96 and 120 h, following i.m. and p.o. administration, respectively. Peak muscle concentrations (Cmax) were 3.47 and 1.73 μg/g after i.m. and p.o. administration at a single dose of 11 mg/kg b.w. whereas they were 6.03 and 2.51 μg/g at a single dose of 22 mg/kg b.w., respectively. A noncompartment model was developed to describe the pharmacokinetics of OTC in the giant freshwater shrimp. The terminal half‐lives of OTC were 28.68 and 28.09 h after i.m. and p.o. administration at a single dose of 11 mg/kg b.w., but 29.95 and 27.03 h at a single dose of 22 mg/kg b.w., respectively. The relative bioavailability was 82.32 and 64.67% following i.m. and p.o. administration, respectively. Based on the pharmacokinetic data, i.m. and p.o. administration with OTC at a dose of 11 mg/kg b.w. would be appropriate for use in giant freshwater shrimp farming. To avoid the OTC residue in shrimp muscle, it should take at least seven half‐lives (8 days) to wash out the drug from the muscle of M. rosenbergii.  相似文献   

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