首页 | 本学科首页   官方微博 | 高级检索  
相似文献
 共查询到20条相似文献，搜索用时 31 毫秒
1.
The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vdss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (t1/2β) were determined for this selected group of drugs by using the empirically determined function Y=a Wb. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric correlation, or be inconclusive due to the lack of quality data or excessive variability due to the multi-laboratory origin of the FARAD data. The results of this study show that interspecies scaling is applicable to certain veterinary drugs. The experimental determination of the coefficients of the allometric equation for relevant pharmacokinetic parameters (clearance and volume of distribution) could be an important tool in estimating dose in species where the drug has never been studied. This could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally ‘well behaved’.  相似文献   

2.
The pharmacokinetics of thiamphenicol (TAP), a broad-spectrum antibiotic, was determined in male mice, rats, rabbits, dogs, pigs, sheep and calves. The relationship between the main pharmacokinetic parameters of TAP and body weight (W) was studied across these seven mammalian species, using double-logarithmic plots. The experimental values of volume of distribution (Vss), clearance (Cl) and elimination half-life (t(1/2)beta) were plotted, and extrapolated values were determined from corresponding allometric equations. These parameters were fitted to the following equations: Vss=0.98W0.92, Cl=15.80W0.76 and t(1/2)beta=0.94W0.20, and present good correlation (Vss: r2=0.997, P < 0.001; Cl: r2=0.976, P < 0.001, t(1/2)beta: r2=0.852, P < 0.005), that is expected of a drug eliminated primarily by renal glomerular filtration, with insignificant hepatic metabolism. For the t(1/2)beta, the extrapolated and observed values were similar. The extrapolated values of Cl were close to the experimental values, except for the mouse and pig mean percent error [(M.E.) equal to 62 and 119%, respectively], while the extrapolated and observed values for the Vss were very similar. The comparison between experimental and extrapolated values suggests that it could be possible to extrapolate, with good prediction, the kinetic parameters of this drug for mammalian species, using allometric scaling, except for the species that eliminate the drug by a combination of renal excretion and hepatic metabolism.  相似文献   

3.
Passerines (songbirds) and softbills (toucans and mynahs) are increasingly presented for veterinary care as pet owners and aviculturists recognize that successful medical and surgical treatment can be performed in these often tiny patients. Even with an increasing amount of pharmacokinetic data in birds, the use of extrapolated drug regimens continues to be a common practice for these species. The extrapolation, using allometric scaling from human, mammalian, and avian drugs to passeriformes and softbills, is complicated and limited. In this article, the choice of the therapeutic approach is discussed. Once the choice for a specific drug is made, tables help calculate the dose in milligrams per kilocalorie without using complicated formulas.  相似文献   

4.
Interspecies scaling is a useful tool for the prediction of pharmacokinetic parameters from animals to humans, and it is often used for estimating a first-time in human dose. The knowledge of pharmacokinetics in veterinary species is important for dosage selection, particularly in the treatment of large zoo animal species, such as elephants, giant cats and camels, for which pharmacokinetic data are scant. Therefore, the accuracy in clearance predictions in large animal species, with and without the use of correction factors (rule of exponents), and the impact of species selection in the prediction of clearance in large animal species was examined. Based upon this analysis, it was determined that there is a much larger risk of inaccuracies in the clearance estimates in large animal species when compared with that observed for humans. Unlike in humans, for large animal species, correction factors could not be applied because there was no trend between the exponents of simple allometry and the appropriate correction factor for improving our predictions. Nevertheless, we did see an indication that the exponents of simple allometry may alert us as to when the predicted clearance in the large animal may be underestimated or overpredicted. For example, if a large animal is included in the scaling, the predicted clearance in a large animal should be considered overestimated if the exponent of simple allometry is >1.3. Despite the potential for extrapolation error, the reality is that allometric scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect target animal safety, therapeutic response, or the accuracy of withdrawal time predictions.  相似文献   

5.
The purpose of this study was to examine the allometric analyses of marbofloxacin, moxifloxacin, danofloxacin and difloxacin using pharmacokinetic data from the literature. The parameters of interest (half-life, clearance and volume of distribution) were correlated across species as a function of body weight using an allometric approach (Y = aWb). Results of the allometric analysis indicated similarity between clearance and volume of distribution as they relate to body weight for all drugs. The elimination half-life was independent of body mass for all fluoroquinolones except moxifloxacin. Results of the analysis suggest that allometric scaling can be used as a tool for predicting pharmacokinetic parameters for fluoroquinolones.  相似文献   

6.
The objective of this study was to analyze the relationship between pharmacokinetic parameters and body weight (W) for orbifloxacin using reported pharmacokinetic data. The parameters of interest: clearance (Cl), volume of distribution at steady state (Vss) and elimination half-life were correlated across nine mammal species, including cattle, dog, rat, rabbit, goat, camel, horse, cat and sheep as a function of W using the conventional allometric equation Y = aW(b), where Y is the pharmacokinetic parameter, W is the body weight, a is the allometric coefficient (intercept) and b is the exponent that describes the relationship between the pharmacokinetic parameter and W. Our estimates (Cl=4.40 W(1.03); Vss=1.10W(1.05)) indicated that the increase in these parameters with W approximates a linear power relationship with slopes being very close to one. Overall, the results of this study indicated that it is possible to use allometry to predict pharmacokinetic variables of orbifloxacin based on W of mammal species.  相似文献   

7.
Interspecies scaling is a useful tool for the prediction of pharmacokinetic parameters from animals to humans, and it is often used for estimating a first-time in human dose. However, it is important to appreciate the mathematical underpinnings of this scaling procedure when using it to predict pharmacokinetic parameter values across animal species. When cautiously applied, allometry can be a tool for estimating clearance in veterinary species for the purpose of dosage selection. It is particularly valuable during the selection of dosages in large zoo animal species, such as elephants, large cats and camels, for which pharmacokinetic data are scant. In Part I, allometric predictions of clearance in large animal species were found to pose substantially greater risks of inaccuracies when compared with that observed for humans. In this report, we examine the factors influencing the accuracy of our clearance estimates from the perspective of the relationship between prediction error and such variables as the distribution of body weight values used in the regression analysis, the influence of a particular observation on the clearance estimate, and the 'goodness of fit' (R(2)) of the regression line. Ultimately, these considerations are used to generate recommendations regarding the data to be included in the allometric prediction of clearance in large animal species.  相似文献   

8.
The purpose of this study was to examine the allometric analysis of ciprofloxacin and enrofloxacin using pharmacokinetic data from the literature. The pharmacokinetic parameters used were half-life, clearance and volume of distribution. Relationships between body weight and the pharmacokinetic parameter were based on the empirical formula Y = aW(b), where Y is half-life, clearance or volume of distribution, W the body weight and a is an allometric coefficient (intercept) that is constant for a given drug. The exponential term b is a proportionality constant that describes the relationship between the pharmacokinetic parameter of interest and body weight. A total of 21 different species of animals were studied. Results of the allometric analyses indicated similarity between clearance and volume of distribution as they related to body weight for both drugs. Results of the current analyses indicate it is possible to use allometry to predict pharmacokinetic variables of enrofloxacin or ciprofloxacin based on body size of species. This could provide information on appropriate doses of ciprofloxacin and enrofloxacin for all species.  相似文献   

9.
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.  相似文献   

10.
Clinically normal koalas (n = 12) received a single dose of 10 mg/kg fluconazole orally (p.o.; n = 6) or intravenously (i.v.; n = 6). Serial plasma samples were collected over 24 h, and fluconazole concentrations were determined using a validated HPLC assay. A noncompartmental pharmacokinetic analysis was performed. Following i.v. administration, median (range) plasma clearance (CL) and steady‐state volume of distribution (Vss) were 0.31 (0.11–0.55) L/h/kg and 0.92 (0.38–1.40) L/kg, respectively. The elimination half‐life (t1/2) was much shorter than in many species (i.v.: median 2.25, range 0.98–6.51 h; p.o.: 4.69, range 2.47–8.01 h), and oral bioavailability was low and variable (median 0.53, range 0.20–0.97). Absorption rate‐limited disposition was evident. Plasma protein binding was 39.5 ± 3.5%. Although fluconazole volume of distribution (Varea) displayed an allometric relationship with other mammals, CL and t1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher (t1/2) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of fAUC/MIC pharmacodynamic targets, fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h.  相似文献   

11.
When body size varies greatly, drug disposition can best be described as an allometric function of body weight. Therefore, the allometry of standard metabolic rate (SMR; 3/4 power) and body surface area (BSA; 2/3 power) have been advocated as surrogate markers for the prediction of key pharmacokinetic parameters. The goal of the present study was to examine the allometric basis of pharmacokinetic scaling within a species, green iguanas. Enrofloxacin was administered intravenously to 20 green iguanas (322-3824 g), and noncompartmental analysis was used to calculate standard pharmacokinetic parameters, which were log(10) transformed and regressed against log(10) body weight. The slopes of significant regressions were compared with the values of unity, 3/4, and 2/3. The slope of enrofloxacin total body clearance (Cl) was also compared with the slopes relating SMR and renal Cl of (99m)Tc-diethylenetriamine penta-acetic acid ((99m)DTPA) to body weight in iguanas. Enrofloxacin Cl depended allometrically on body weight with the power of 0.32. The slope of enrofloxacin Cl was significantly less than those of SMR, Cl of (99m)DTPA, and the 2/3 value. Therefore, the relationship between enrofloxacin Cl and body weight does not directly depend on the allometry of BSA, SMR, or renal Cl of (99m)DTPA in iguanas.  相似文献   

12.
兽药最大残留限量(MRL)在不同动物间的外推最早是通过讨论不同有鳍鱼类间外推而提出的,后来延伸到反刍动物间、非反刍哺乳动物间、禽类间的外推等。2021年国际食品法典兽药残留委员会(CCRVDF)第25届会议讨论了兽药MRL在不同动物间的外推方法,国际食品法典委员会(CAC)第44届会议同意并采纳了这一方法。兽药MRL外推对世界各国尤其是发展中国家建立本国限量标准,保护公共健康和促进贸易有着十分重要的意义。本文就CAC关于兽药MRL在不同动物间外推的术语定义、方法和示例、限量标注等内容进行介绍,以期推动我国兽药MRL的科学制定。  相似文献   

13.
Interspecies scaling of pharmacokinetic (PK) parameters is commonplace in drug development. However, information about proportionality of pharmacodynamic (PD) parameters in different species is scarce. We investigated the feasibility of allometric scaling of PK and PD parameters of s(+)-ketoprofen (sKTP) using the literature data from several animal species. Two different indirect response models were proposed to characterize sKTP inhibitory effects on synthesis of thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2)). Using the traditional allometric approach, the obtained PK and PD parameters were plotted against body weights (BW) on a log-log scale. For all species, values of systemic clearance (Cl), distribution clearance (Cl(D)), central volume of distribution (V(c)), and volume of distribution at steady-state (V(ss)) were highly correlated (r(2) = 0.89-0.99) with BW. The PD parameters for inhibition of TXB(2) synthesis were poorly correlated with BW (r(2) = 0.25-0.54) while most of the parameters for inhibition of PGE(2) synthesis lacked any correlation (r(2) approximately 0.05). In conclusion, indirect response models adequately described the time course of sKTP inhibitory effects on synthesis of TXB(2) and PGE(2). Allometrical scaling showed PK parameters to change proportionally to BW, whereas PD parameters had limited ranges and were essentially weight independent.  相似文献   

14.
Comparative studies on some selected pharmacokinetic parameters for kanamycin in sheep, goats, rabbits, chickens and pigeons, and for apramycin in sheep, rabbits, chickens and pigeons were carried out after intravenous administration of the two drugs at a dose of 10 mg/kg. The results revealed that a two-compartment open model was most suitable for kanamycin, while for apramycin a one-compartment open model was usually optimal. The log distribution rate constant (alpha) of kanamycin was significantly correlated to the log of the body mass (r = 0.919, n = 5, p < 0.05). Interspecies differences in the apparent volume of distribution (Vda) of kanamycin were small. These differences were larger for apramycin, as were the variations in the area under the serum concentration-time curve (AUC) and in the total body clearance (ClB) of both kanamycin and apramycin, both having almost a threefold difference depending on the species but without any correlation to body mass. The values of the log half-life of kanamycin in the mammals in this study and also those from data in the literature revealed a significant correlation with log body mass between animal species according to the equation: t1/2 beta = 38.47W0.21 (r = 0.7648, n = 10, p < 0.05).  相似文献   

15.
In most species, large variations in body size necessitate dose adjustments based on an allometric function of body weight. Despite the substantial disparity in body size between miniature horses and light‐breed horses, there are no studies investigating appropriate dosing of any veterinary drug in miniature horses. The purpose of this study was to determine whether miniature horses should receive a different dosage of flunixin meglumine than that used typically in light‐breed horses. A standard dose of flunixin meglumine was administered intravenously to eight horses of each breed, and three‐compartmental analysis was used to compare pharmacokinetic parameters between breed groups. The total body clearance of flunixin was 0.97 ± 0.30 mL/min/kg in miniature horses and 1.04 ± 0.27 mL/min/kg in quarter horses. There were no significant differences between miniature horses and quarter horses in total body clearance, the terminal elimination rate, area under the plasma concentration versus time curve, apparent volume of distribution at steady‐state or the volume of the central compartment for flunixin (P > 0.05). Therefore, flunixin meglumine may be administered to miniature horses at the same dosage as is used in light‐breed horses.  相似文献   

16.
The pharmacokinetics of cefepime, a new fourth generation cephalosporin with enhanced antibacterial activity, was examined in neonatal foals and adult dogs. Cefepime was administered intravenously (i.v.) at a dose of 14 mg/kg to five neonatal foals and six adult dogs. Blood samples were collected in both groups of animals and plasma cefepime concentrations measured by reverse-phase high-performance liquid chromatography (HPLC). Cefepime concentrations in both groups of animals were described by a two-compartment pharmacokinetic model with elimination half-lives of 1.65 and 1.09 h for the foal and dog, respectively. We tested whether or not pharmacokinetic parameters for cefepime could be scaled across species using principles of allometry. The parameters of elimination half-life (t(1/2)beta), apparent volume of distribution (VDarea), and systemic clearance (CL) were scaled linearly to body weight on a double logarithmic plot with allometric exponents for body weight of 0.26, 1.08 and 0.72, respectively. This study further determined doses for cefepime, a potentially useful antibiotic for neonatal foals and dogs, from the pharmacokinetic values. An i.v. dose of cefepime estimated from this study for treating sensitive bacteria was 11 mg/kg every 8 h for neonatal foals and 40 mg/kg every 6 h for dogs.  相似文献   

17.
The allometric equations relating the half-life, the volume of distribution and the total body clearance of gentamicin, amikacin, tobramycin, kanamycin and apramycin to body weight for mammalian and mammalian + avian species were defined. Literature data were used as a source of comparative pharmacokinetic data. For all antibiotics examined half-life intercepts ranged from 0.49 to 1.66, slopes from 0.05 to 0.45, volume of distribution intercepts--0.13-0.75, slope-- 0.77-1.41, total body clearance intercepts--0.88-8.8 and slope--0.62-1.04. A better relationship between pharmacokinetic parameters and body weight was shown when all values were included in the allometric analysis. Different values of intercept and slope between birds and mammals were found in gentamicin and apramycin studies. In some cases, slopes and intercepts changed when all values of pharmacokinetic parameters were included. We conclude that small difference exist between pharmacokinetics of gentamicin, amikacin, tobramycin, kanamycin and apramycin. The allometric equations shown in our study provide a basis to estimate dose intervals for mammals and birds for which specific information is lacking.  相似文献   

18.
This study was carried out in 121 pigs to develop a population pharmacokinetic (PPK) model by oral (p.o.) administration of valnemulin at a single dose of 10 mg/kg. Serum biochemistry parameters of each pig were determined prior to drug administration. Three to five blood samples were collected at random time points, but uniformly distributed in the absorption, distribution, and elimination phases of drug disposition. Plasma concentrations of valnemulin were determined by high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS/MS). The concentration–time data were fitted to PPK models using nonlinear mixed effect modeling (NONMEM) with G77 FORTRAN compiler. NONMEM runs were executed using Wings for NONMEM. Fixed effects of weight, age, sex as well as biochemistry parameters, which may influence the PK of valnemulin, were investigated. The drug concentration–time data were adequately described by a one‐compartmental model with first‐order absorption. A random effect model of valnemulin revealed a pattern of log‐normal distribution, and it satisfactorily characterized the observed interindividual variability. The distribution of random residual errors, however, suggested an additive model for the initial phase (<12 h) followed by a combined model that consists of both proportional and additive features (≥12 h), so that the intra‐individual variability could be sufficiently characterized. Covariate analysis indicated that body weight had a conspicuous effect on valnemulin clearance (CL/F). The featured population PK values of Ka, V/F and CL/F were 0.292/h, 63.0 L and 41.3 L/h, respectively.  相似文献   

19.
ABSTRACT

Aims: To determine the pharmacokinetics and tissue depletion of 2?mg/kg marbofloxacin (MBX) in Bilgorajska geese (Anser anser domesticus) after I/V and oral administration, to calculate the daily dose from experimental data and to compare it with that calculated by allometric scaling.

Methods: Eight clinically normal female Bilgorajska geese were used in a three-phase study with a 3-week wash-out period between phases. In the first phase birds received I/V administration of 2?mg/kg MBX; the same dose was given orally in the second and third phases. Blood samples were collected between 0 minutes and 48 hours in the first and second phases, and samples of liver, kidney, lung, muscle and heart were collected following slaughter of birds between 6 and 48 hours in the third phase. Concentrations of MBX in plasma and tissues were analysed using HPLC. Two additional birds served as controls. The optimal dose was calculated based on a minimal inhibitory concentration (MIC) of 0.125 μg?mL using the observed clearance, or using clearance calculated by allometric scaling.

Results: Concentrations of MBX in plasma were detectable up to 24 hours following both I/V and oral administration. Mean oral bioavailability was 26.5 (SD 7.7)%. Concentrations of MBX in all tissues were highest at 6 hours and decreased constantly up to 34 hours. The mean optimal daily dose for oral administration of MBX, calculated using the observed clearance was 10.36 (SD 2.18) mg/kg, and using predicted clearance was 5.54 (SD 0.14) mg/kg. The preliminary withdrawal time for a maximum residue limit of 0.15?mg/kg calculated for muscle was 38.4 hours, heart 33.6 hours, kidney 48.3 hours, lung 47.7 hours and liver 49.3 hours.

Conclusion and Clinical Relevance: There was insufficient evidence to recommend MBX orally administered to geese at a daily dose of 2?mg?kg for treatment of bacteria with an MIC of 0.125?μg/mL. Further pharmacokinetic/pharmacodynamic studies in geese are recommended to determine the MBX dose regimen and its clinical efficacy in geese.  相似文献   

20.
The relationships between the half-lives during the elimination phase (t1/2 minutes) of ampicillin, amoxycillin, sulphadimidine and sulphacetamide and body mass (W, kg) between species of mammals and birds were examined using data from the authors' experiments and collected from the literature. Linear regression of the log half-lives of ampicillin, amoxycillin and sulphadimidine following intravenous injection on the log body mass for a variety of species of mammals and birds revealed significant correlations (r = 0.7709, n = 8, r = 0.7712, n = 8, r = 0.7749, n = 10). The interspecies relationships were described by the allometric equations t1/2 = 31.3 W0.16, t1/2 = 32.7 W0.12 and t1/2 = 129.2 W0.28, respectively. These equations may be of value for estimating dose intervals in species for which no relevant pharmacokinetic data are available.  相似文献   

设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号