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    Plasma concentrations of tulathromycin in Boer goats following administration of tulathromycin (2.5 mg/kg, SC) twice with a 7-day interval between doses. Data from 15 goats (represented by various graphic symbols) are indicated through the first dosing interval. One goat was euthanized 2 days after dose 1 and was excluded from this analysis. Remaining goats were euthanized on days 9, 12, 17, and 27 after dose 1 (days 2, 5, 10, and 20 after dose 2 [n = 3 at the first time point and 4 for remaining time points]).

  • View in gallery

    Elimination of tulathromycin (as determined via analysis of the hydrolytic tulathromycin fragment CP-60,300) from muscle (A), liver (B), kidney (C), fat (D), and lung (E) tissues of 16 Boer goats. See Figure 1 for remainder of key.

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Pharmacokinetics and tissue elimination of tulathromycin following subcutaneous administration in meat goats

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  • 1 Food Animal Residue Avoidance Databank, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606.
  • | 2 Food Animal Residue Avoidance Databank, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606.
  • | 3 Food Animal Residue Avoidance Databank, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606.
  • | 4 Food Animal Residue Avoidance Databank, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606.
  • | 5 Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 6 Food Animal Residue Avoidance Databank, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606.
  • | 7 Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

Abstract

Objective—To determine the tissue depletion profile of tulathromycin and determine an appropriate slaughter withdrawal interval in meat goats after multiple SC injections of the drug.

Animals—16 healthy Boer goats.

Procedures—All goats were administered tulathromycin (2.5 mg/kg, SC) twice, with a 7-day interval between doses. Blood samples were collected throughout the study, and goats were euthanized at 2, 5, 10, and 20 days after the second tulathromycin dose. Lung, liver, kidney, fat, and muscle tissues were collected. Concentrations of tulathromycin in plasma and the hydrolytic tulathromycin fragment CP-60,300 in tissue samples were determined with ultrahigh-pressure liquid chromatography–tandem mass spectrometry.

Results—The plasma profile of tulathromycin was biphasic. Absorption was very rapid, with maximum drug concentrations (1.00 ± 0.42 μg/mL and 2.09 ± 1.77 μg/mL following the first and second doses, respectively) detected within approximately 1 hour after injection. Plasma terminal elimination half-life of tulathromycin was 61.4 ± 14.1 hours after the second dose. Half-lives in tissue ranged from 2.4 days for muscle to 9.0 days for lung tissue; kidney tissue was used to determine the withdrawal interval for tulathromycin in goats because it is considered an edible tissue.

Conclusions and Clinical Relevance—On the basis of the tissue tolerance limit in cattle of 5 ppm (μg/g), the calculated withdrawal interval for tulathromycin would be 19 days following SC administration in goats. On the basis of the more stringent guidelines recommended by the FDA, the calculated meat withdrawal interval following tulathromycin administration in goats was 34 days.

Abstract

Objective—To determine the tissue depletion profile of tulathromycin and determine an appropriate slaughter withdrawal interval in meat goats after multiple SC injections of the drug.

Animals—16 healthy Boer goats.

Procedures—All goats were administered tulathromycin (2.5 mg/kg, SC) twice, with a 7-day interval between doses. Blood samples were collected throughout the study, and goats were euthanized at 2, 5, 10, and 20 days after the second tulathromycin dose. Lung, liver, kidney, fat, and muscle tissues were collected. Concentrations of tulathromycin in plasma and the hydrolytic tulathromycin fragment CP-60,300 in tissue samples were determined with ultrahigh-pressure liquid chromatography–tandem mass spectrometry.

Results—The plasma profile of tulathromycin was biphasic. Absorption was very rapid, with maximum drug concentrations (1.00 ± 0.42 μg/mL and 2.09 ± 1.77 μg/mL following the first and second doses, respectively) detected within approximately 1 hour after injection. Plasma terminal elimination half-life of tulathromycin was 61.4 ± 14.1 hours after the second dose. Half-lives in tissue ranged from 2.4 days for muscle to 9.0 days for lung tissue; kidney tissue was used to determine the withdrawal interval for tulathromycin in goats because it is considered an edible tissue.

Conclusions and Clinical Relevance—On the basis of the tissue tolerance limit in cattle of 5 ppm (μg/g), the calculated withdrawal interval for tulathromycin would be 19 days following SC administration in goats. On the basis of the more stringent guidelines recommended by the FDA, the calculated meat withdrawal interval following tulathromycin administration in goats was 34 days.

Proactively choosing treatment options for bacterial infections may have the potential to limit antimicrobial resistance, which is becoming increasingly important in food animal production medicine. Arguably, use of drugs that maintain therapeutic antimicrobial concentrations over an extended period of time following a single administration is one of the best ways that a veterinarian can combat the development of antimicrobial resistance, apart from stopping the use of all antimicrobials in food animal species.

The macrolide family of antimicrobial drugs is commonly used in food animal species, with erythromycin, tylosin, and tilmicosin currently approved for use in cattle in the United States. Some of these antimicrobials are used in an extralabel manner in goats, although tilmicosin may cause severe cardiovascular toxicity. Repeated administration of these products over several days is often needed to achieve a therapeutic effect.1 Prolonged exposure to antimicrobials is important for the treatment or prevention of several diseases in ruminants; however, single administration treatment is desirable for producers who wish to minimize animal handling and may potentially result in increased compliance.

Tulathromycin is a triamilide antimicrobial approved for the treatment of respiratory disease in cattle and swine. The drug has a long plasma elimination half-life in cattle of 90 hours,2,3 and therapeutic concentrations have been detected in lung tissue for 10 to 15 days after administration of a single dose.3,4 It has been recommended for use in goats for treatment of various diseases, including pneumonia and caseous lymphadenitis.5,6 Tulathromycin has been shown to be safe for use in goats,5,7 and data on pharmacokinetics of the drug in plasma have been published.8,9 However, pharmacokinetic data regarding the elimination of tulathromycin from tissues are lacking, and this information is necessary to determine appropriate slaughter withdrawal intervals. Given that plasma concentrations of macrolides are much lower than tissue concentrations,2 analysis of plasma alone is not sufficient to determine appropriate withdrawal intervals. The long half-life and pharmacodynamic profile of tulathromycin, which includes phagocytic transport to the site of infection resulting in high concentrations in tissue,3,10 emphasize the importance of a pharmacokinetic investigation in tissues. Therefore, the purpose of the study reported here was to characterize the plasma pharmacokinetic and tissue depletion profiles of tulathromycin in healthy meat goats after administration of multiple injections and to determine an appropriate slaughter withdrawal interval.

Materials and Methods

Animals—Sixteen healthy Boer goats (8 males and 8 females) weighing from 20 to 35 kg (mean, 26.3 ± 4.2 kg) were used in the study. The goats ranged in age from 5 to 7 months and were confirmed to be healthy on the basis of physical examination results. The goats used in this study were raised by the Teaching Animal Unit at the North Carolina State University College of Veterinary Medicine, where the study was performed. Goats were housed in small groups in stalls (4 goats/stall) and were allowed a 1-week acclimation period prior to beginning the study. They were fed a 14% protein diet throughout the trial composed of corn and soybean meal with salt, phosphate, selenium, and ammonium chloride. Coastal Bermuda grass hay and water were available ad libitum. The study was approved by the Institutional Animal Care and Use Committee at North Carolina State University.

Study design—All goats were weighed on the day before the study. On study day 1, all goats received an injection of tulathromycina (2.5 mg/kg, SC) in the neck; the total injection volume ranged from 0.5 to 0.9 mL/goat. Blood (10 mL/sample) was collected by jugular venipuncture into heparinized tubes at 0 (immediately prior to injection), 15, and 60 minutes as well as 4, 8, 24, 48, 72, 96, 120, 144, and 168 hours after injection. At 168 hours (end of day 7), all goats received a second SC injection of tulathromycin at 2.5 mg/kg. This was considered time 0 for dose 2. Blood was collected at 15 and 60 minutes following this injection and then at 24, 48, 72, and 96 hours. After 96 hours (264 hours after the first injection), blood was collected from goats remaining in the study every 48 hours. All blood samples were centrifuged immediately, and plasma was collected and frozen at −80°C until analyzed to determine tulathromycin concentrations. This dosing interval (2 injections 7 days apart) was chosen to most closely mimic what is commonly being done in veterinary practice.

All goats were monitored daily throughout the study, and the injection sites were examined each time blood was collected. To determine tissue concentrations of tulathromycin, groups of goats (n = 4/group) were euthanized by means of a pentobarbital overdose at different time points following the second injection. The first group was scheduled for euthanasia 2 days after the second dose (216 hours after initial injection), with other groups following on days 5 (288 hours), 10 (408 hours), and 20 (648 hours). Endpoints for this study were determined on the basis of pharmacokinetic modeling from a previous study8 of the drug in goat plasma. Immediately following euthanasia, samples of lung, liver, kidney, skeletal muscle, and mesenteric fat tissue were weighed and immediately frozen for analysis of tulathromycin concentrations.

Tulathromycin analysis—Plasma samples were analyzed with a UPLC tandem mass spectrometry detection assay as described.9 The LOQ was 2 ng/mL, and the upper LOQ was 500 ng/mL. Samples with tulathromycin concentrations > 500 ng/mL were diluted with control plasma (obtained from herdmate goats that were not included in this trial) and reanalyzed. The LOD was 0.7 ng/mL, and recovery was 98.3%.

Tulathromycin content in liver, kidney, muscle, and fat tissue samples was analyzed via a method described elsewhere.11 The same method was used for evaluation of lung tissue samples, except that an adjustment in the mobile phase was required. Briefly, tulathromycin residues were converted to the CP-60,300 fragment by acid-catalyzed hydrolysis with 2N hydrochloric acid solution at 60°C. The supernatant was passed through a columnb and eluted with a 95:5 mixture of acetonitrile and ammonium hydroxide. The eluate was evaporated to dryness at 50°C under a gentle stream of nitrogenc and reconstituted with the aqueous mobile phase. Quantification was performed with liquid chromatography–tandem mass spectrometry.

Samples (volume, 5 μL) were injected into a UPLC system.d The mobile phase was 0.02M ammonium acetate (pH, 4.0) with a mixture of formic acid and acetonitrile (77:23 for liver, kidney, muscle, and fat tissue; 81:19 for lung tissue) at a flow rate of 0.3 mL/min, and the columne was maintained at 35°C. The mass spectrometerf had a heated electrospray ionization source operated in the positive ion mode. Ions were monitored in the selective reaction monitoring mode for the CP-60,300 fragment and an internal standardg with transitions from 577.2 to 420.2 and 591.3 to 434.2, respectively. This method has been validated for evaluation of goat tissues.12

The retention time of CP-60,300 was approximately 1 minute. Inter- and intra-assay variations as measured by percentage relative SD in tissues were 4.8% and 12.7% for liver, 7.6% and 20.9% for kidney, 11.3% and 28.6% for muscle, and 4.8% and 10.7% for fat, respectively. Recoveries were 98.9% for liver, 97.7% for kidney, 89.9% for muscle, and 87.0% for fat. The LOQs and LODs for CP-60,300 in tissues were 0.69 and 0.24 μg/mL for muscle, 1.91 and 0.75 μg/mL for liver, 1.66 and 0.29 μg/mL for kidney, 0.61 and 0.14 μg/mL for fat, and 0.55 and 0.23 g/mL for lung, respectively.

Pharmacokinetic analysis—The profile over time of the plasma concentration of tulathromycin in the individual goats following each of the 2 doses was evaluated by noncompartmental analyses with software.h Noncompartmental parameters estimated from the data included T1/2λz, Cmax, Tmax, AUC0–tau, AUClast, AUC0–∞, and MTT. Given that only an extravascular route of drug administration was used in this study, MTT could not be used to estimate a mean absorption time because mean residence time could not be determined. In addition, only the apparent clearance and apparent volume of distribution during the terminal phase were calculated. To determine whether the pharmacokinetics differed significantly between doses of tulathromycin, a 2-tailed t test with a significance cutoff of P < 0.05 was used to compare the calculated noncompartmental analysis parameters. For comparison of AUC, the AUC0–∞ for dose 1 was compared with the AUC0–tau for dose 2.

For pharmacokinetic evaluation of tulathromycin in tissue samples, the mean tissue concentration versus time profile of CP-60,300 following the second dose of the drug was analyzed via noncompartmental analysis to determine the Cmax, Tmax, and T1/2λz. The analysis was performed with data from tissue samples that had CP-60,300 concentrations above the LOD. In addition, the tissue concentrations were used to estimate a withdrawal interval for tulathromycin in goats according to FDA guidelines12 with a target tolerance limit for CP-60,300 set to the tissue LOD. Data were evaluated for the tissue with the longest T1/2λz, adequate time points with measureable concentrations of CP-60,300, homogeneity of variance, and log-linearity of data versus time in the terminal portion of the concentration-time profile. After calculation of the slope and intercept in the terminal phase, the withdrawal interval was estimated from the upper limit of the 95% confidence interval for the 99th percentile of the terminal elimination rate.

Results

Animals—No adverse effects or other clinical abnormalities were observed in goats throughout the study. Following SC administration of tulathromycin in the neck, none of the goats developed swelling or irritation at the injection sites. Due to an identification number recording error, 1 goat was euthanized 2 days after the first tulathromycin dose instead of after the second tulathromycin dose. Although plasma data from this goat were not used, the tissue data were similar to those of the other 3 goats in this group and were included in the results. All other goats remained healthy during the study and were euthanized on the scheduled dates.

Pharmacokinetics—Overall, the plasma profile of tulathromycin following SC administration was biphasic (Figure 1). Pharmacokinetic parameters for the plasma concentrations of tulathromycin following the first and second doses were summarized (Table 1). An absorption phase was not detected in most goats because the Cmax was observed at the first blood sample collection time. There was no significant difference in any of the pharmacokinetic parameters between the first and second doses of tulathromycin.

Table 1—

Noncompartmental analysis parameters for tulathromycin in plasma of healthy Boer goats that received tulathromycin (2.5 mg/kg, SC) twice with a 7-day interval between doses.

ParameterDose 1 (n = 15)Dose 2 (n = 8)
Cmax (μg/mL)1.00 ± 0.422.09 ± 1.77
Tmax (h)0.60 ± 0.981.4 ± 2.7
T1/2λz (h)45.7 ± 17.661.4 ± 14.1
AUC0–tau (h•μg/mL)24.8 ± 6.923.4 ± 7.8
AUClast (h•μg/mL)24.8 ± 6.926.3 ± 9.1
AUC0–∞ (h•μg/mL)27.6 ± 8.827.1 ± 9.5
AUC0–∞ extrapolated (%)8.9 ± 6.93.0 ± 2.7
Vz/F (mL/kg)7,013 ± 2,1079,265 ± 3,590
CI/F (mL/h/kg)90.5 ± 29.292.0 ± 34.0
MTT (h)72.8 ± 22.083.0 ± 11.0

The time of injection was considered time 0 for each dose. Only goats that had blood samples collected for ≥ 168 hours after each dose were included in plasma analyses; 1 goat euthanized 2 days after dose 1 was excluded from dose 1 analysis, and another 7 goats euthanized on days 2 and 5 after dose 2 were excluded from dose 2 analysis. Arithmetic mean ± SD are reported for all parameters except half-life and apparent clearance, which are reported as harmonic mean ± pseudo-SD. The dosing interval (tau) was 168 hours.

AUC0–∞ extrapolated = Area under the curve extrapolated from time zero through infinity as a percentage of total AUC. Cl/F = Apparent clearance. Vz/F = Apparent volume of distribution during the terminal phase.

Figure 1—
Figure 1—

Plasma concentrations of tulathromycin in Boer goats following administration of tulathromycin (2.5 mg/kg, SC) twice with a 7-day interval between doses. Data from 15 goats (represented by various graphic symbols) are indicated through the first dosing interval. One goat was euthanized 2 days after dose 1 and was excluded from this analysis. Remaining goats were euthanized on days 9, 12, 17, and 27 after dose 1 (days 2, 5, 10, and 20 after dose 2 [n = 3 at the first time point and 4 for remaining time points]).

Citation: American Journal of Veterinary Research 73, 10; 10.2460/ajvr.73.10.1634

Maximum concentrations of tulathromycin (determined via analysis of the hydrolytic tulathromycin fragment CP-60,300) were detected later in tissues (Table 2; Figure 2) than in plasma (Table 1; Figure 1); the mean Tmax for all tissues was 2.6 days after dose 2, versus 0.60 and 1.4 hours in plasma following doses 1 and 2, respectively. In addition, the elimination of tulathromycin was slower in all tissues, compared with that in plasma. The T1/2λz of CP-60,300 ranged from 2.4 to 9 days in tissues, compared with mean values of 1.9 and 2.6 days for tulathromycin in plasma following doses 1 and 2, respectively.

Table 2—

Pharmacokinetics of tulathromycin (assessed via analysis of the hydrolytic tulathromycin fragment CP-60,300) in tissues of 16 healthy Boer goats that received tulathromycin (2.5 mg/kg, SC) twice with a 7-day interval between doses.

ParameterTissue
FatKidneyLiverLungMuscle
T1/2λz (d)6.6376.4457.0389.0482.389
Cmax (μg of CP-60,300/mL)0.38 ± 0.1062.528 ± 0.8183.548 ± 0.5793.275 ± 0.5251.093 ± 0.213
Tmax (d)22522
AUClast (d•μg of CP-60,300/mL)2.4826.039.631.23.42

The day of dose 2 was considered day 0 for time-dependent tissue variables. Data are reported as mean ± SD of the observed values for Cmax and the corresponding day (Tmax) or the noncompartmental analysis-estimated value of all 16 goats for T1/2λz and AUClast.

Figure 2—
Figure 2—

Elimination of tulathromycin (as determined via analysis of the hydrolytic tulathromycin fragment CP-60,300) from muscle (A), liver (B), kidney (C), fat (D), and lung (E) tissues of 16 Boer goats. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 73, 10; 10.2460/ajvr.73.10.1634

Although elimination of CP-60,300 was slowest in lung tissue on the basis of T1/2λz, kidney tissue was used to determine the withdrawal interval for tulathromycin in goats because it is considered an edible tissue. In addition, all kidney tissues had at least 3 time points in the terminal elimination phase with at least 4 samples having concentrations of CP-60,300 above the LOD, which met the FDA guidelines for minimum data requirements for estimating a withdrawal interval.13 Concentrations of CP-60,300 in each of the tissues and the number of samples above LOD were summarized (Table 3). The variance of kidney tissue concentrations of CP-60,300 at the different time points was homogeneous as evaluated by the Bartlett test for heterogeneity, the Levene test, and an F test; in addition, kidney tissue concentrations in the terminal phase were shown to be log-linear and thus suitable to use to estimate the withdrawal interval. Therefore, linear regression analysis of the natural log of kidney tissue concentrations during the terminal phase was performed to determine a slope and intercept to use for calculating the withdrawal interval. On the basis of tissue tolerance limits for tulathromycin in cattle (5 ppm [μg/g]) in the United States and the European Union, the withdrawal interval of tulathromycin in goats was calculated as 19 days. However, by applying more stringent calculations that set the tolerance limit to the LOD (0.29 ppm for our UPLC tandem mass spectrometry assay), the withdrawal interval was determined to be 34 days.

Table 3—

Mean ± SD tissue concentrations of CP-60,300 versus time used for pharmacokinetic analysis and for determination of the withdrawal interval after tulathromycin administration.

TissueTime (d)*Tissue concentration (μg/g)No. of samples above LOD
Fat20.380 ± 0.1064
50.280 ± 0.0264
100.165 ± 0.0352
200
Kidney22.53 ± 0.8184
52.34 ± 0.6214
101.08 ± 0.2064
200.445 ± 0.07424
Liver23.20 ± 0.7134
53.55 ± 0.5794
101.80 ± 0.5404
200.781
Lung23.28 ± 0.5254
52.21 ± 0.5194
101.43 ± 0.2724
200.692 ± 0.1844
Muscle21.09 ± 0.2134
50.458 ± 0.1494
100
200

Time after second injection (dose 2).

— = Not determined.

Discussion

Although tulathromycin is used in goats in an extralabel manner at present, it has been used by some veterinarians as an alternative for treatment of pneumonia associated with Mannheimia haemolytica, Pasteurella multocida, and Mycoplasma spp in goats.2,5 In addition, tulathromycin has been used for the treatment of caseous lymphadenitis.6 Goat production in the United States is increasing, according to the last agricultural census in 2007, having increased 24% from 2002 to 2007.14 During the same period, meat goat production increased 64%. There are approximately 3.2 million meat goats in the United States; consequently, it is vital that veterinarians have treatment options that offer good clinical efficacy. Extralabel use of certain drugs is permitted according to AMDUCA in food animal species as long as certain requirements are met.15 One of these requirements is that there is not already an approved drug labeled for the disease being treated in that species that would be clinically effective. In goats, ceftiofur sodiumi is approved for the treatment of respiratory disease caused by M haemolytica and P multocida and therefore should be the primary antimicrobial used for pneumonia. Another specific requirement is the determination of an appropriate withdrawal interval for the species in which the drug is being used. Extrapolation of pharmacokinetic data from other species may lead to erroneous calculation of withdrawal intervals and lead to violative drug residues in products for human consumption. Therefore, if tulathromycin is to be used in an extralabel manner in goats, it is important to determine appropriate withdrawal intervals to ensure that meat entering the food supply is safe.

In cattle, reported MIC90 of tulathromycin for the more common respiratory pathogens of cattle are as follows: M haemolytica, 2 μg/mL; P multocida, 1 μg/mL; Histophilus somni, 4 μg/mL; and Mycobacterium bovis, 1 μg/mL.2,16,17 A recent study18 in which bacterial isolates from goats with clinical pneumonia were investigated had very similar results. Using microbroth dilution to determine MIC values, investigators of that study18 evaluated 45 M haemolytica, 11 P multocida, and 11 Bibersteinia trehalosi isolates, and MIC90 concentrations were as follows: M haemolytica, 4 μg/mL; P multocida, 2 μg/mL; and Bibersteinia trehalose, 4 μg/mL). In the present study, concentrations of the hydrolytic tulathromycin fragment CP-60,300 detected in lung tissues were 3.3 ± 0.5 μg/mL, 2.2 ± 0.5 μg/mL, 1.4 ± 0.3 μg/mL, and 0.7 ± 0.2 μ/mL on days 2, 5, 10, and 20 after dose 2, respectively. It is likely that tulathromycin has the potential to be an effective treatment for respiratory disease in this species because concentrations in lung tissue in the present study were above the MICs reported18 for goats with clinical respiratory disease for a prolonged period. To maintain lung concentrations of tulathromycin > 2 μg/mL, results of the present study indicate the dosing interval in goats should be every 7 days when repeated treatments are needed.

Tulathromycin is also likely to be an effective treatment for caseous lymphadenitis in goats. In 1 study,6 both intralesional and SC administration of tulathromycin resulted in resolution of abscesses in most sheep and goats with caseous lymphadenitis. The proportion of goats that had resolved lesions 1 month after tulathromycin administration was not different, compared with traditional treatment (which consisted of opening, draining, and flushing the lesions along with SC administration of procaine penicillin) in that study.6 Although antimicrobial susceptibility data were not reported for that study,6 MIC90 concentrations of tulathromycin were ≤ 2.0 μg/mL for all of the 43 Corynebacterium pseudotuberculosis isolates that were cultured and were ≤ 1.0 μg/mL for 71% of those isolates.j Disk diffusion results indicated zones of inhibition ranging from 21 to 33 mm in diameter after 24 hours.j

In the present study, we used an analytic technique that measured concentrations of CP-60,300 in tissue samples of tulathromycin-treated goats. Measurement of CP-60,300 is the FDA-approved regulatory method and is designed to detect concentrations of any tulathromycin isoform. Consequently, this technique gives the most conservative assessment of drug residue concentrations in tissue samples. This assay has been validated for use in goats.12 Liver, kidney, fat, and muscle tissue were chosen for analysis because they represent edible tissues that could potentially enter the human food supply. In contrast, lung tissue is not considered an edible tissue; however, because tulathromycin is often used for the treatment of respiratory disease in goats, it is important to determine how long therapeutic concentrations might persist.

The pharmacokinetics of tulathromycin in the study reported here are similar to those found in previous studies8,9 of tulathromycin in goat plasma. Likewise, the drug depletion data collected in the present study confirm that the classic elimination profile of tulathromycin reported in cattle and swine,3,4,10 indicating that the drug is rapidly eliminated from the plasma and distributed to the tissue, also occurs in goats. For example, the mean plasma Tmax of tulathromycin in goats was 0.6 and 1.4 hours after doses 1 and 2, respectively, in stark contrast to the mean tissue Tmax of almost 3 days. However, in all tissues except the lungs, the T1/2λz values for goats in the present study (6.637, 6.445, 7.038, and 2.389 days for fat, kidney, liver, and muscle tissue, respectively) were shorter than those reported for cattle (8.6, 7.4, 15.2, and 7.1, for fat, kidney, liver, and muscle tissue, respectively),3 illustrating that the drug is eliminated from these tissues more quickly in goats than in cattle. Comparison with reported swine tissue data (T1/2λz values of 6.1 days for fat, 7.6 days for kidney, 8.6 days for liver, and 9.9 days for muscle tissue)10 revealed similar findings, with a slightly longer elimination profile in lung tissue for goats (T1/2λz, 9.048 days) than for swine (T1/2λz, 5.9 days).10

In the United States, the approved tolerance limit for tulathromycin in cattle is 5 ppm (μg/g) and in the European Union, the maximum residue concentration is 3 ppm for liver or kidney tissue. The maximum concentration of CP-60,300 detected in kidney tissue in the present study was 2.5 ppm at 2 days after the second injection of tulathromycin. According to the established safe concentrations described for this drug, the withdrawal interval for tulathromycin in goats was calculated to be 19 days. However, it is possible when a drug is used in an extralabel manner that the approved tolerance may not apply and any detectible tissue residue could result in a violation. Therefore, a more conservative withdrawal interval is often determined on the basis of the lower LOD. When the tolerance limit was set to 0.3 ppm (the lower LOD for tulathromycin in kidney tissue), analysis of the terminal regression line produced for this tissue indicated a withdrawal interval of 24 days for the 50th percentile. With use of the more stringent recommendations of the FDA,13 the withdrawal interval based on a tolerance of 0.3 ppm (the lower LOD) for the upper 95% confidence limit of the 99th percentile of the population would be 34 days.

Because of the stringent food safety standards set by the federal government, the use of tulathromycin in goats requires a much longer withdrawal interval (34 days) in comparison to the times established for cattle (18 days) and swine (5 days).19 Yet, practitioners can be confident that the conservative withdrawal interval established in the present study for goats on the basis of very rigorous standards will help ensure that the meat will be suitable for human consumption. Maintaining therapeutic drug concentrations well above the MIC is of utmost importance when treating bacterial diseases for veterinarians conscientious about limiting the growth of resistant organisms. For these reasons, tulathromycin has become an increasingly attractive choice for use in meat goats, emphasizing the importance of practitioner access to an accurate preslaughter withdrawal interval.

ABBREVIATIONS

AUC0–tau

Area under the curve from time zero through the dosing interval

AUClast

Area under the curve from time zero through the last measurable concentration

AUC0–∞

Area under the curve from time zero through infinity

Cmax

Observed maximum drug concentration

LOD

Limit of detection

LOQ

Limit of quantification

MIC

Minimum inhibitory concentration

MIC90

Minimum inhibitory concentration required to inhibit the growth of 90% of bacteria

MTT

Mean transit time

T1/2λz

Terminal elimination half-life

Tmax

Time of observed maximum drug concentration

UPLC

Ultrahigh-pressure liquid chromatography

a.

Draxxin, Pfizer Animal Health, New York, NY.

b.

OASIS MCX column, Waters Corp, Milford, Mass.

c.

N-Evap, Organomation Associates Inc, Berlin, Mass.

d.

Acquity UPLC system, Waters, Milford, Mass.

e.

Ace C8, 2.1 × 50 mm, 3 μm column, MacMod, Chadds Ford, Pa.

f.

Therm TSQ Quantum Discovery Max, Thermo Fisher Scientific, Waltham, Mass.

g.

Tulathromycin standards provided by Pfizer Animal Health, New York, NY.

h.

Phoenix, version 1.1, Pharsight Corp, Mountain View, Calif.

i.

Naxcel, Pfizer Animal Health, New York, NY.

j.

Washburn K, Texas A&M University, College Station, Tex: Personal communication, 2011.

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Contributor Notes

Supported in part by the National Research Support Project (NSRP-7—Minor Species Drug Program) of the USDA.

Jessica Romanet was supported by the Merial Veterinary Scholars summer research program.

Address correspondence to Dr. Smith (Geoffrey_Smith@ncsu.edu).