• View in gallery
    Figure 1—

    Mean ± SD plasma concentration of enrofloxacin over time in 6 American black vultures (Coragyps atratus) after IV administration of a single dose of enrofloxacin (5 mg/kg).

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    Figure 2—

    Values for enrofloxacin Cl (gray bars) and the extraction ratio (black bars) for 6 American black vultures and avian species reported in other studies.10,14–30 The extraction ratio was obtained by use of an equation proposed in another study.12

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    Figure 3—

    Results for allometric scaling of Cl (A) and Vdss (B) for enrofloxacin in 6 American black vultures and avian species reported in other studies.10,14–30 BW = Body weight.

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Evaluation of allometric scaling as a tool for extrapolation of the enrofloxacin dose in American black vultures (Coragyps atratus)

Samanta Waxman1Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Chorroarin 280, 1427 Buenos Aires, Argentina.

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Ana P. Prados1Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Chorroarin 280, 1427 Buenos Aires, Argentina.

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José J. De Lucas2Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, 1425 Buenos Aires, Argentina.
3Departamento de Farmacología y Toxicología, Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria, s/n. 28040 Madrid, Spain.

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Guillermo Wiemeyer4Ecoparque, R. de la India 3000, 1425 Buenos Aires, Argentina.
5The Peregrine Fund, 5668 W Flying Hawk Ln, Boise, ID 83709.
6Fundación Caburé-í, Sucre 2842, 1428 Buenos Aires, Argentina.

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Laura Torres-Bianchini4Ecoparque, R. de la India 3000, 1425 Buenos Aires, Argentina.

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Manuel I. San Andres2Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, 1425 Buenos Aires, Argentina.
3Departamento de Farmacología y Toxicología, Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria, s/n. 28040 Madrid, Spain.

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Casilda Rodríguez2Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, 1425 Buenos Aires, Argentina.
3Departamento de Farmacología y Toxicología, Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria, s/n. 28040 Madrid, Spain.
1Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Chorroarin 280, 1427 Buenos Aires, Argentina.
2Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, 1425 Buenos Aires, Argentina.
3Departamento de Farmacología y Toxicología, Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria, s/n. 28040 Madrid, Spain.
4Ecoparque, R. de la India 3000, 1425 Buenos Aires, Argentina.
5The Peregrine Fund, 5668 W Flying Hawk Ln, Boise, ID 83709.
6Fundación Caburé-í, Sucre 2842, 1428 Buenos Aires, Argentina.

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Abstract

OBJECTIVE

To determine the pharmacokinetics of enrofloxacin after IV administration in American black vultures (Coragyps atratus), to compare clearance of enrofloxacin in American black vultures with clearance of this fluoroquinolone in other avian species, and to evaluate whether allometric scaling is an appropriate tool for dose extrapolation in avian species.

ANIMALS

6 healthy adult American black vultures.

PROCEDURES

Enrofloxacin concentrations were quantified by use of high-performance liquid chromatography. Pharmacokinetics of enrofloxacin was determined in American black vultures after IV administration. Pharmacokinetic parameters for 12 avian species obtained from 24 pharmacokinetic studies were used. Allometric analysis of enrofloxacin pharmacokinetic parameters was performed.

RESULTS

Volume of distribution at steady state for enrofloxacin was 3.47 L/kg, clearance was 0.147 L/h·kg, and elimination half-life was 18.3 hours. Comparisons among avian species revealed that American black vultures had the lowest extraction ratio for enrofloxacin (1.04%). Only the volume of distribution at steady state and clearance had a good allometric fit. Goodness of fit was improved when ratites were not included in the analysis.

CONCLUSIONS AND CLINICAL RELEVANCE

Results suggested that the use of allometric scaling for the prediction of volume of distribution at steady state could provide a suitable method for extrapolation of enrofloxacin doses among avian species; however, allometric scaling could not be used to adequately predict the clearance of enrofloxacin.

Abstract

OBJECTIVE

To determine the pharmacokinetics of enrofloxacin after IV administration in American black vultures (Coragyps atratus), to compare clearance of enrofloxacin in American black vultures with clearance of this fluoroquinolone in other avian species, and to evaluate whether allometric scaling is an appropriate tool for dose extrapolation in avian species.

ANIMALS

6 healthy adult American black vultures.

PROCEDURES

Enrofloxacin concentrations were quantified by use of high-performance liquid chromatography. Pharmacokinetics of enrofloxacin was determined in American black vultures after IV administration. Pharmacokinetic parameters for 12 avian species obtained from 24 pharmacokinetic studies were used. Allometric analysis of enrofloxacin pharmacokinetic parameters was performed.

RESULTS

Volume of distribution at steady state for enrofloxacin was 3.47 L/kg, clearance was 0.147 L/h·kg, and elimination half-life was 18.3 hours. Comparisons among avian species revealed that American black vultures had the lowest extraction ratio for enrofloxacin (1.04%). Only the volume of distribution at steady state and clearance had a good allometric fit. Goodness of fit was improved when ratites were not included in the analysis.

CONCLUSIONS AND CLINICAL RELEVANCE

Results suggested that the use of allometric scaling for the prediction of volume of distribution at steady state could provide a suitable method for extrapolation of enrofloxacin doses among avian species; however, allometric scaling could not be used to adequately predict the clearance of enrofloxacin.

In veterinary medicine, the treatment of wild birds is challenging because of the scarcity of scientific information with which to determine dosing regimens. Veterinarians involved in wildlife conservation sometimes use allometric scaling as a tool to make decisions on treatments for species in which few data are available. Frequently, allometric scaling is applied to estimate drug doses when pharmacokinetic data for the target species are not available. Special consideration must be given when a particular pharmacokinetic behavior is described for a specific species (eg, obligate scavengers). This could be important because slow drug elimination in species of the Gyps genus has been reported.1–3

The American black vulture (Coragyps atratus) is a New World vulture belonging to the order Cathartiforme. Its distribution includes the southern United States and South America, and it is classified as least concern in the red list of threatened species.4 Although this vulture species has genetic differences from members of the Gyps genus, the carrion-feeding lifestyle of vultures and the morphological convergence between Gyps spp and American black vultures,5,6 which also can involve shared physiologic characteristics, could be reflected in similar pharmacokinetic behavior of drugs.

Enrofloxacin is one of the most widely used fluoroquinolones in veterinary medicine. Because of its pharmacokinetic profile and spectrum of activity, enrofloxacin is an antimicrobial agent frequently administered to avian species in rehabilitation centers. It is commonly used to treat bacteremia or septicemia and infections of the soft tissues, skin, bones and joints, urinary tract, respiratory tract, and reproductive tract.7,8 Although enrofloxacin has been extensively evaluated in avian species, no pharmacokinetic studies have been performed with scavengers; therefore, the dose of enrofloxacin for black vultures is currently obtained by extrapolation from data for other bird species.9

The objectives of the study reported here were to evaluate the pharmacokinetic behavior of enrofloxacin after IV administration in black vultures, to compare (by means of the physiologic interpretation of Cl) the elimination of enrofloxacin with Cl for enrofloxacin in other avian species, and to evaluate whether allometric scaling is an appropriate tool for extrapolation of the dose of enrofloxacin in American black vultures. We hypothesized that allometric scaling would be a useful tool for extrapolation of drug doses in avian species.

Materials and Methods

Animals

Six healthy adult American black vultures housed in captivity at the Buenos Aires Zoological Garden were used in the study. Vultures were fed in a manner appropriate for the species. Body weight of the vultures ranged from 1.8 to 2.2 kg. Vultures were considered healthy on the basis of results of a complete physical examination, routine consumption of daily meals, maintenance of body weight, and results of hematologic tests. No drugs were administered to the vultures for at least 2 months before the start of the study. The study was performed at the Buenos Aires Zoological Garden, and it was approved by the Institutional Animal Care and Use Committee of the Veterinary Sciences School of the Universidad de Buenos Aires.

Experimental procedures

A 24-gauge catheter was placed in an ulnar vein of each vulture. A single dose (5 mg/kg) of a 5% injectable solution of enrofloxacina was administered IV. Blood samples (0.6 mL) were collected by use of a 27-gauge catheter placed in a medial tarsal vein. Blood samples were obtained immediately before (time 0) and 5, 15, and 35 minutes and 1, 2, 4, 6, 8, 11, 24, 29, 34, and 48 hours after enrofloxacin administration. Samples were immediately placed in tubes containing heparin.

Drug assay

Analytic standards of ofloxacin, enrofloxacin, and ciprofloxacin were purchased.b Sample processing and drug detection methods for enrofloxacin and ciprofloxacin were adapted from a method described elsewhere.10 Ofloxacin was used as an internal standard.

Enrofloxacin was quantified with a high-performance liquid chromatography system.c Extracted samples were injected into an ion-pairing C18 reverse-phase column (5 μm; 150 × 4.6 mm). Limit of quantification was 0.025 μg/mL for enrofloxacin and 0.050 μg/mL for ciprofloxacin; calibration curves were linear (R2 > 0.99) up to concentrations of 5 μg/mL. Intraday precision was < 8%, and interday precision was < 12%. Accuracy ranged from 82% to 120% and from 88% to 113% for enrofloxacin and ciprofloxacin, respectively.

Pharmacokinetic analysis

Plasma concentrations of enrofloxacin were evaluated by use of compartmental and noncompartmental analysis with a software package.d Data were used for additional computations.

Physiologic interpretation of Cl and dose calculation

Cardiac output of various species for which the pharmacokinetics of enrofloxacin was known was estimated by use of the allometric equation proposed in another study11 for the physiologic interpretation of body Cl in birds: CO = 290.7 × BW0.69, where CO is cardiac output in milliliters per minute and BW is body weight in kilograms.

The minimal physiologic model for total body Cl12 was applied. Considering the entire body as a system of drug reservoir, the extraction ratio was estimated as the percentage of drug cleared by the entire body during a single passage through the various organs that contributed to body Cl; the extraction ratio was calculated as Cl/CO, where CO is the previously determined cardiac output.

Because the MIC, MBC, and MPC for isolates cultured from black vultures were not known, MIC, MBC, and MPC values for Escherichia coli isolates cultured from chickens13 were used for extrapolation of the optimal dose of enrofloxacin for American black vultures. The optimal dose was calculated by use of the following equation: dose = ([AUC/MIC] × Cl × MIC)/(F × 24 hours), where F is bioavailability, which was assigned a value of 1. Values for MIC in the equation were replaced by values for MBC or MPC to calculate optimal doses for bactericidal action or resistance prevention, respectively. The optimal dose was calculated by use of the Cl determined for the pharmacokinetic analysis and also by use of the Cl predicted with allometric scaling.

Allometric computation

A simple allometric analysis of enrofloxacin pharmacokinetics was performed with pharmacokinetic data obtained for American black vultures in the present study and data obtained after IV administration in other avian species.10,14–30 Allometric analysis was performed for t½β, Vdss, Cl, MRT, and AUC weighted by dose (ie, AUC/dose). For allometric scaling, each parameter and the body weight were logarithmically transformed and fitted by use of least squares linear regression analysis to the following equation: log10 y = log10 a + (b × log10 BW), where y is a pharmacokinetic parameter (Cl, Vdss, t½β, MRT, and AUC/dose), a is the y-axis intercept, b is the slope, and BW is body weight.

Allometric scaling involved the use of data for up to 13 avian species. Allometric scaling was performed with the inclusion or exclusion of pharmacokinetic data obtained for American black vultures (13 or 12 avian species, respectively), with the exclusion of data obtained for ostriches and greater rheas (11 avian species), and with the exclusion of data obtained for American black vultures, ostriches, and greater rheas (10 avian species). Only when a good fit was found were the allometric equations obtained from those linear regressions used to predict pharmacokinetic parameters.

The predicted Vdss and Cl for American black vultures (value for BW in the equation was 2.0 kg) were obtained by use of allometric equations that included data for all avian species (n = 13), all avian species except for American black vultures (12), all avian species except for ostriches and greater rheas (11), and all avian species except for American black vultures, ostriches, and greater rheas (10). The 95% prediction interval and accuracy of the predicted values were calculated.

Statistical analysis

The analysis was performed with statistical software.e Normality of data was assessed with the Shapiro-Wilk test. Correlation analysis and least squares linear regression were performed. Goodness of fit was measured by use of R2 and the SD of residuals. An F test was used to evaluate the null hypothesis that the overall slope was 0, and the Wald-Wolfowitz runs test was used to determine whether fit of the data differed significantly from a straight line. Values were considered significant at P < 0.05.

Results

Mean plasma concentration-time curve and pharmacokinetic parameters obtained after IV administration were determined (Figure 1; Table 1). The Cl of enrofloxacin was 0.147 L/h·kg, Vdss was 3.47 L/kg, and t½β was 18.3 hours. Very low plasma enrofloxacin concentrations were detected, and only 1 sample from each of 2 vultures had a concentration greater than the limit of quantification. Because of the sparse number of points available for evaluation, pharmacokinetic analysis was not performed.

Figure 1—
Figure 1—

Mean ± SD plasma concentration of enrofloxacin over time in 6 American black vultures (Coragyps atratus) after IV administration of a single dose of enrofloxacin (5 mg/kg).

Citation: American Journal of Veterinary Research 80, 8; 10.2460/ajvr.80.8.727

Table 1—

Pharmacokinetic parameters obtained for 6 American black vultures (Coragyps atratus) after IV administration of enrofloxacin (5 mg/kg).

AnalysisParameterArithmetic MeanMedianGeometric meanSDRange*
CompartmentaC0 (μg/mL)3.093.093.090.180.42
 α (h−1)0.5520.5980.5480.0740.167
 β (h−1)0.0380.0400.0380.0040.010
 AUC0-∞ (μg·h/mL)34.935.534.55.914.3
 t½α (h)1.31.21.30.20.4
 t½β (h)18.317.318.12.45.8
 Vdc (L/kg)1.621.621.620.090.22
 Cl (L/h·kg)0.1470.1410.1450.0260.060
 Vdss (L/kg)3.473.443.450.451.09
NoncompartmentalAUC0-last (μg·h/mL)33.134.132.93.39.5
 AUC0-∞ (μg·h/mL)41.042.140.93.79.6
 t½λ (h)16.716.716.71.13.1
 Vdz (L/kg)3.143.083.110.361.05
 Cl (L/h·kg)0.130.120.130.010.03
 MRT0-last (h)16.416.216.30.82.1
 MRT0-∞ (h)24.624.224.51.84.8
 tlast (h)48.048.048.00.00.0
 Clast (μg/mL)0.330.330.330.040.09

The range was calculated as the maximum value minus the minimum value.

Value reported is the harmonic mean.

α = Distribution rate constant. AUC0-∞ = AUC from time zero to infinity. AUC0-last = AUC from time zero to the last quantifiable concentration. β = Elimination rate constant. C0 = Plasma concentration at time 0. Clast = Last quantifiable concentration. MRT0-∞ = MRT from time zero to infinity. MRT0_last = MRT from time zero to the last quantifiable concentration. tlast = Time of last quantifiable concentration. t½a = Distribution half-life. tl/2λ, = Terminal half-life. Vdc = Volume of distribution of the central compartment. Vdz = Volume of distribution based on the terminal phase.

The estimated cardiac output, extraction ratio, and extrapolated dose were calculated for the 6 American black vultures of the present study and avian species reported in other studies10,14–30 (Figure 2; Table 2). The extraction ratio for American black vultures was 1.04%. The allometric equation was used to fit data for all avian species (including vultures; 13 avian species), data that excluded vultures (12 avian species), data that included vultures but excluded ostriches and greater rheas (11 avian species), and data that excluded vultures, ostriches, and greater rheas (10 avian species). Allometric relationships between body weight and pharmacokinetic parameters for the American black vultures of the present study and avian species reported in other studies10,14–30 were evaluated (Figure 3; Tables 3 and 4). Only data for Vdss and, to a lesser extent, Cl had a good fit. When all 13 species were considered for the allometric calculation, high variability (94%) in the Vdss of enrofloxacin among species was explained by interspecies variation in body weight. Also, 69% of the variability in Cl could be attributed to differences in body weight. Slopes for both equations were significantly different from 0, but they did not differ significantly from a straight line.

Figure 2—
Figure 2—

Values for enrofloxacin Cl (gray bars) and the extraction ratio (black bars) for 6 American black vultures and avian species reported in other studies.10,14–30 The extraction ratio was obtained by use of an equation proposed in another study.12

Citation: American Journal of Veterinary Research 80, 8; 10.2460/ajvr.80.8.727

Figure 3—
Figure 3—

Results for allometric scaling of Cl (A) and Vdss (B) for enrofloxacin in 6 American black vultures and avian species reported in other studies.10,14–30 BW = Body weight.

Citation: American Journal of Veterinary Research 80, 8; 10.2460/ajvr.80.8.727

Table 2—

Values for American black vultures and various avian species administered enrofloxacin.

      Extrapolated dose 
Avian speciesBody weight (kg)Dose (mg·kg)CO (L/h·kg)Cl (L/h·kg)Extraction ratio (%)*MICMBCMPCReference
African penguin3.601511.730.1821.550.231.379130
Chicken0.651019.930.6183.100.774.6430926
Chicken2.70512.820.1981.540.251.499921
Chicken2.70512.820.1791.400.221.348921
Chicken2.952.512.470.6675.350.835.0033322
Chicken2.98512.430.2502.010.311.8812517
Chicken0.951017.720.3501.970.442.6317528
Chicken1.681014.850.1300.880.160.986514
Chicken1.701014.800.1481.000.191.117414
Chicken1.821014.490.1320.910.170.996614
Chicken2.501013.130.2902.210.362.1814515
 Mean chicken 2.04
Duck1.091016.980.8905.241.116.6844529
Emu25.502.26.390.3605.630.452.7018025
Greater rhea2.971512.453.95031.744.9429.631,97519
Houbara bustard1.291016.120.3432.130.432.5717216
Ostrich43.5055.424.56084.205.7034.202,28018
Pheasant0.951017.720.6003.390.754.5030027
Quail0.201028.641.5205.311.9011.4076023
Quail0.201028.641.4004.891.7510.5070027
 Mean quail5.10
Red-tailed hawk1.251516.280.2401.470.301.8012024
Southern crested caracara1.33515.970.2401.500.301.8012010
Turkey6.952.59.560.5025.250.633.7725122
Turkey7.00109.540.4084.280.513.0620420
 Mean turkey4.76
American black vulture2.001014.070.1471.040.181.1073NA

The extrapolated dose of enrofloxacin was determined for microorganisms with an MIC of 0.01 μg/mL, an MBC of 0.06 μg/mL, and an MPC of 4 μg/mL.

For the extraction ratio, values > 35% were considered high, values of approximately 15% were considered medium, and values < 5% were considered low.

— = Not determined. CO = Cardiac output. NA = Not applicable; represents results for the 6 American black vultures of the study reported here.

Table 3—

Values for pharmacokinetic parameters of enrofloxacin after IV administration to various avian species.

Avian speciesBody weight (kg)*Cl (L/h·kg)Vdss (L/kg)t½β (h)MRT (h)AUC/dose (g·h/mL)Reference
African penguin3.600.1823.0013.6716.505.5030
Chicken0.650.6183.905.566.381.6226
Chicken2.700.1981.986.9910.245.3521
Chicken2.700.1791.777.529.965.9121
Chicken2.950.6674.555.546.991.6222
Chicken2.980.2502.9210.9612.504.3417
Chicken0.950.3502.224.756.722.8528
Chicken1.680.1302.404.162.7614
Chicken1.700.1482.433.652.5714
Chicken1.820.1322.484.342.8114
Chicken2.500.2902.7710.299.653.4515
Duck1.090.8902.076.472.262.3629
Emu25.500.3601.623.334.403.7525
Greater rhea2.973.9505.012.661.230.2419
Houbara bustard1.290.3432.985.638.132.9816
Ostrich43.504.5603.400.780.700.1918
Pheasant0.950.6003.704.601.8127
Quail0.201.5205.362.453.530.6623
Quail0.201.4004.602.300.7127
Red-tailed hawk1.300.2402.3019.409.584.1524
Southern crested caracara1.330.2402.097.817.974.3810
Turkey6.950.5024.066.058.322.0922
Turkey7.000.4083.576.648.962.5920
American black vulture2.000.1473.4718.2924.588.20NA

Value reported is mean body weight. When the mean body weight was not included in the report, the value midway between the minimum and maximum value was used as an estimate.

See Table 2 for remainder of key.

Table 4—

Parameters determined for variables by use of allometric analysis of data for various avian species.

No. of avian species*ParameterClVdsst½βMRTAUC/dose
13a0.463.176.776.722.35
 bt1.157 (0.232)0.939 (0.070)−0.233 (0.174)−0.227 (0.216)−0.172 (0.241)
 R20.6930.9430.1410.1000.044
 SDr0.4960.1490.3720.4510.515
 P valued     
 F test< 0.001< 0.0010.2070.3170.491
  Wald-Wolfowitz runs test0.1520.1210.5000.2790.236
12a0.523.136.085.772.07
 b1.145 (0.229)0.940 (0.073)−0.22 (0.165)−0.207 (0.202)−0.158 (0.236)
 R20.7140.9430.1530.1050.043
 SDr0.4880.1550.3530.4210.503
 P valued     
 F test< 0.001< 0.0010.2090.3320.518
  Wald-Wolfowitz runs test0.1970.1750.6520.3330.279
11a0.433.096.747.072.53
 b0.746 (0.168)0.860 (0.075)0.053 (0.179)0.106 (0.191)0.279 (0.150)
 R20.6860.9350.0010.0370.278
 SDr0.2840.1280.3030.3170.253
 P valued     
 F test0.002< 0.0010.7750.5930.096
  Wald-Wolfowitz runs test0.0240.1100.8330.0480.024
10a0.473.036.146.212.30
 b0.750 (0.156)0.859 (0.077)0.049 (0.166)0.107 (0.164)0.275 (0.128)
 R20.7430.9390.0110.0580.364
 SDr0.2640.1310.2810.2720.217
 P valued     
 F test0.001< 0.0010.7770.5340.065
  Wald-Wolfowitz runs test0.0400.6430.8810.1070.048

Allometric analysis was performed with data for all avian species (including vultures; 13 avian species), data that excluded vultures (12 avian species), data that included vultures but excluded ostriches and greater rheas (11 avian species), and data that excluded vultures, ostriches, and greater rheas (10 avian species).

Value reported is the mean (SE).

Values were considered significant at P < 0.05.

a = The y-axis intercept. b = Slope. SDr = SD of residuals.

Predicted Vdss and Cl for American black vultures (value for body weight = 2.0 kg) were obtained by use of allometric equations that accounted for data from all birds (13 avian species), excluded data for vultures (12 avian species), included data for vultures but excluded data for ostriches and greater rheas (11 avian species), and excluded data for vultures, ostriches, and greater rheas (10 avian species). The 95% confidence interval and accuracy of predicted values were determined (Table 5).

Table 5—

Predicted values for Vdss and Cl of enrofloxacin obtained by use of allometric equations with data for various avian species.

 No. of avian species*
Variable13121110
 Cl (L/h·kg) Predicted
Mean (SD)0.521 (0.215)0.583 (0.245)0.352 (0.107)0.386 (0.111)
95% Cl0.348 to 0.7790.391 to 0.8820.261 to 0.4750.291 to 0.513
Accuracy (%) 95% CI254 137 to 430297 166 to 500140 78 to 223162 98 to 249
 Vdss (L/kg) Predicted
Mean (SD) 95% CI3.02 (0.37) 2.67 to 3.412.98 (0.38) 2.63 to 3.392.77 (0.38) 2.42 to 3.172.71 (0.39) 2.35 to 3.12
Accuracy (%) 95% CI−13 −2 to −23−14 −2 to −24−20 −9 to −30−22 −10 to −32

For the allometric analysis, body weight of the 6 American black vultures used in the equation was 2.0 kg. 95% CI = 95% confidence interval.

Value measured for the 6 American black vultures of the present study was 0.47 L/h·kg.

Value measured for the 6 American black vultures of the present study was 43.47 L/kg.

See Table 4 for remainder of key.

Discussion

In the study reported here, the pharmacokinetic behavior of enrofloxacin after IV administration to American black vultures was determined. Enrofloxacin had a high Vdss and low Cl after IV administration to black vultures, which resulted in a prolonged t½β. The value of t½β obtained in the present study is exceeded only by the value (19.4 hours) reported after administration (15 mg/kg, IV) to red-tailed hawks (Buteo jamaicensis).24

American black vultures had the lowest Cl for enrofloxacin, compared with Cl for other avian species (Table 2). However, it is extremely important to determine whether a given plasma Cl obtained in a study is really low. To perform a physiologic interpretation of plasma Cl, a minimal physiologic model for total body Cl12 was applied. Because liver and kidney blood flows represent approximately half of the cardiac output, the overall extraction ratio should be considered high for values > 35%, medium for values of approximately 15%, and low for values < 5%. By use of these breakpoints, the enrofloxacin extraction ratio calculated for American black vultures of the present study (1.04%) was in the low extraction group, and it was the lowest value of all birds that were evaluated. Ducks, quails, turkeys, and emus had values slightly > 5%. Emus have slow Cl, similar to that for houbara bustards; however, the percentage of extraction is higher in emus. The ratites (ie, ostriches and greater rheas) had the highest extraction and Cl values of all birds, although the predicted cardiac output was the lowest of the analyzed species. Ostriches had the highest Cl. This could be related to special pharmacokinetic behavior in ostriches, which has been reported for other drugs.31 It also could have been attributable to an allometrically underestimated cardiac output because it has been determined that the heart weight of ostriches is higher than the allometrically calculated heart weight.32 In that study,32 a heart weight-to-body weight ratio of 1.08 was reported for ostriches, which is as high as the ratio in many birds that weigh < 50 g. The value for ostriches is an outlier because according to the authors of the aforementioned study,32 it is related to the fact these birds are extraordinarily powerful runners. Despite the fact quail had the highest cardiac output (29 L/h·kg), this avian species had an extraction ratio of 5.1%.

In veterinary medicine, the treatment of wild birds is challenging because of the scarcity of available scientific information on which to base therapeutic dosing regimens. Frequently, allometric scaling is applied to estimate drug doses when pharmacokinetic data are not available. Dose extrapolation by use of basal metabolic rate ratios provides relatively lower doses for large birds and higher doses for small birds. The enrofloxacin dose predicted for American black vultures by use of the dose approved for chickens (10 mg/kg) and by applying an equation previously used to estimate a specific minimum energy cost33 (specific minimum energy cost = 78 × BW−0.25) or by use of the metabolic value for Coragyps spp (76.99 kcal/d·kg)34 would be 11 or 13 mg/kg, respectively.

The aforementioned metabolic scaling approach takes into consideration the fact that body metabolic rate can be used for almost any drug and any species; however, this is a simplistic view of the relationship between basal metabolic rate and drug pharmacokinetics. Another allometric approach would be to use scaling of pharmacokinetic parameters across animal species. Volume of distribution and Cl are pivotal parameters that are necessary to estimate loading and maintenance doses, respectively.

Although the use of allometric scaling to extrapolate doses would not be appropriate when a drug undergoes extensive metabolism, allometric analysis for enrofloxacin has been performed in various studies.35–38 However, to our knowledge, allometric analysis of enrofloxacin in avian species has been evaluated in only 1 study.38 The use of allometric scaling could be appropriate for extrapolating enrofloxacin pharmacokinetics in mammals, which would facilitate selection of an appropriate dose for avian species.35

In the allometric analysis for the present study, the best fit was obtained for Vdss and a good fit was achieved for Cl, with extremely high or high positive correlations.39 Investigators of another study38 performed allometric scaling with data for mammalian and avian species. Only 3 avian species (chickens, turkeys, and houbara bustards) were included in that study,38 and results similar to those described for the study reported here were found. However, higher R2 values were obtained in the present study for Vdss and Cl. When the values reported for mammalian species of that study38 were analyzed, slope was 0.75 and 0.78 for Cl and Vdss, respectively. In a study36 that involved the use of data for 16 vertebrate species (most of which were mammalian), lower values were obtained for goodness of fit; however, the allometric behavior of the pharmacokinetic parameters was similar among species. The pharmacokinetic parameters of mammals that reportedly correlate with body weight are Cl, t½β, and volume of distribution (exponents of 0.82, 0.06, and 0.90, respectively).35 In the study reported here, a negligible correlation was detected between body weight and t½β, MRT, and AUC/dose.

When Vdss was subjected to allometric analysis, goodness of fit and the predicted Vdss obtained with all 4 allometric analyses were similar. However, when allometric analysis of Cl was performed, goodness of fit was improved, and the predicted Cl for American black vultures was closer to the measured values when ratites were not included in the analysis. Similar to pharmacokinetic behavior of other drugs,31,40 enrofloxacin has a unexpected pharmacokinetic behavior in ostriches and greater rheas. A high Cl was found for these species, and the higher residual values for these species conformed to a straight line. In 1 study,31 authors reported that ostriches had more rapid elimination. Those authors believed that this contradicted the allometric relationship with body weight; therefore, a good correlation was not detected in that study. In the study reported here, use of allometric scaling that did not take into account data for ratites (ostriches and greater rheas) resulted in a predicted Cl for American black vultures of 0.352 L/h·kg; Table 5), which was closer to the measured value obtained for the present study but with a narrower 95% confidence interval (0.261 to 0.475 L/h·kg) and slightly higher accuracy. Although the inclusion of large animals in allometric scaling can substantially improve the prediction of enrofloxacin Cl in large mammalian species,37 the same is apparently not true for enrofloxacin Cl in birds. On the other hand, the exclusion of data from the ratites did not modify the goodness of fit for the Vdss estimation, which was considered adequate in all cases.

The maintenance dose calculated by use of an equation proposed in another study12 and with an MIC of 0.01 μg/mL would be 0.18 mg/kg/d if the Cl for the present study were used. If the predicted Cl (obtained by use of the equation that included data for 12 avian species [all avian species except American black vultures]) were to be used, the dose would be 0.73 mg/kg/d, which would be 300% as great as the dose obtained by use of the measured Cl for the present study. Analysis of results for the study reported here suggested that application of allometric principles for the prediction of Vdss could provide a suitable method for extrapolation of the enrofloxacin loading dose among avian species; however, the prediction of Cl would not be adequate, and therefore, the maintenance dose calculated with predicted Cl values would not be appropriate. Regardless, extreme caution should be taken when allometric approaches are used for extrapolation of drug doses for clinical cases. The mathematical assumptions as well as the limitations of this method should be considered.33

The slow elimination of certain drugs in Gyps vultures could be related to toxicosis issues.1–3,41 We believe slow elimination of drugs could be evident in other obligate scavengers belonging to the New World vultures (eg, Coragyps atratus) because extremely slow elimination was detected in the study reported here. Extreme caution should be used when the maintenance dose is extrapolated from data for other avian species (even those of the same family or extrapolated by use of allometric scaling) because of the important differences reported for the present study. Findings for the study reported here could be the starting point for more accurate extrapolation of drug doses for vultures, which reportedly have issues with drug elimination.1–3

If a maintenance dose were to be calculated with the equation proposed by other authors12 and an MIC value reported in another study,13 we suggest that for most of the species included in the comparisons in the present study, a recommended dose of 5 mg/kg could be adequate to achieve clinical success, except for avian species with a high extraction ratio. However, the dose obtained for the various species by use of MPC values could be an indication of the inability of these dosing regimens to completely eradicate pathogenic microorganisms and could result in the emergence of resistant bacteria.42 Therefore, analysis of results for the study reported here suggested that administration of enrofloxacin (5 mg/kg, IV) to American black vultures could have a therapeutic effect, although it would not prevent the emergence of resistant bacteria. Nevertheless, these results should be interpreted with extreme caution because the pharmacodynamic parameters were calculated for E coli isolates obtained from chickens,13 a species in which the selection pressure is probably high as a result of the intensive use of this class of antimicrobial. Further studies are necessary to evaluate the pharmacokinetic and pharmacodynamic behavior of enrofloxacin in American black vultures and the influence of infectious disease on the pharmacokinetics of this drug.

In the present study, American black vultures had the slowest elimination for enrofloxacin for all species evaluated. Analysis of the results suggested that the use of allometric principles can provide a suitable method for extrapolation of the enrofloxacin loading dose among avian species; however, allometric scaling could not be used to adequately predict the maintenance dose of enrofloxacin.

Acknowledgments

Supported as part of a UBACyT Project, Secretaría de Ciencia y Técnica, Universidad de Buenos Aires. Funding sources did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.

The authors declare that there were no conflicts of interest. None of the authors had any financial or personal relationships that could have inappropriately influenced or biased the content of the paper.

The authors thank Dr. M. A. Rivolta for providing permission to work at the Buenos Aires Zoological Garden, Mariano Diaz, Mar Sanz, and Carmen Muñoz Serrano for technical assistance, and Santiago Cano for assistance with the statistical analysis.

ABBREVIATIONS

AUC

Area under the plasma concentration-time curve

Cl

Clearance

MBC

Minimum bactericidal concentration

MIC

Minimum inhibitory concentration

MPC

Mutant prevention concentration

MRT

Mean residence time

t½β

Elimination half-life

Vdss

Volume of distribution at steady state

Footnotes

a.

Baytril 5%, Bayer Hispania SL, Barcelona, Spain.

b.

Sigma-Aldrich Corp, Madrid, Spain.

c.

Spectra-Physics System, Madrid, Spain.

d.

PCnonlin, version 4.0, SCI Software, Statistical Consultants Inc, Lexington, Ky.

e.

Prism, version 4.00, GraphPad Software, La Jolla, Calif.

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Contributor Notes

Dr. Prados's present address is Animal Clinic of Sierra de los Padres, Sierra de los Padres, 7601, Buenos Aires, Argentina.

Dr. Torres-Bianchinni's present address is Ministerio de Salud y Desarrollo Social, Av 9 de Julio, 1925 Buenos Aires, Argentina.

Address correspondence to Dr. Rodríguez (rodfermc@vet.ucm.es).