Pharmacokinetics and lung tissue concentrations of tulathromycin, a new triamilide antibiotic, in cattle

The pharmacokinetics of the new triamilide antibiotic tulathromycin was investigated in two cattle studies. Following a single subcutaneous injection, the drug was rapidly absorbed and bioavailability was excellent. High and persistent levels of the drug in lung tissue were observed as well. These attributes are advantageous for an antimicrobial drug indicated for the treatment of bacterial and mycoplasmal respiratory diseases in cattle.     

Pharmacokinetics and lung tissue concentrations of tulathromycin in swine

The absolute bioavailability and lung tissue distribution of the triamilide antimicrobial, tulathromycin, were investigated in swine. Fifty-six pigs received 2.5 mg/kg of tulathromycin 10% formulation by either intramuscular (i.m.) or intravenous (i.v.) route in two studies: study A (10 pigs, i.m. and 10 pigs, i.v.) and study B (36 pigs, i.m.). After i.m. administration the mean maximum plasma concentration (C(max)) was 616 ng/mL, which was reached by 0.25 h postinjection (t(max)). The mean apparent elimination half-life (t(1/2)) in plasma was 75.6 h. After i.v. injection plasma clearance (Cl) was 181 mL/kg.h, the volume of distribution at steady-state (V(ss)) was 13.2 L/kg and the elimination t(1/2) was 67.5 h. The systemic bioavailability following i.m. administration was >87% and the ratio of lung drug concentration for i.m. vs. i.v. injection was > or =0.96. Following i.m. administration, a mean tulathromycin concentration of 2840 ng/g was detected in lung tissue at 12 h postdosing. The mean lung C(max) of 3470 ng/g was reached by 24 h postdose (t(max)). Mean lung drug concentrations after 6 and 10 days were 1700 and 1240 ng/g, respectively. The AUC(inf) was 61.4 times greater for the lung than for plasma. The apparent elimination t(1/2) for tulathromycin in the lung was 142 h (6 days). Following i.m. administration to pigs at 2.5 mg/kg body weight, tulathromycin was rapidly absorbed and highly bioavailable. The high distribution to lung and slow elimination following a single dose of tulathromycin, are desirable pharmacokinetic attributes for an antimicrobial drug indicated for the treatment of respiratory disease in swine.     

Pharmacokinetics of tildipirosin in bovine plasma,lung tissue,and bronchial fluid (from live,nonanesthetized cattle)

Menge, M., Rose, M., Bohland, C., Zschiesche, E., Kilp, S., Metz, W., Allan, M., Röpke, R., Nürnberger, M. Pharmacokinetics of tildipirosin in bovine plasma, lung tissue, and bronchial fluid (from live, nonanesthetized cattle). J. vet. Pharmacol. Therap.  35 , 550–559. The pharmacokinetics of tildipirosin (Zuprevo^® 180 mg/mL solution for injection for cattle), a novel 16‐membered macrolide for treatment, control, and prevention of bovine respiratory disease, were investigated in studies collecting blood plasma, lung tissue, and in vivo samples of bronchial fluid (BF) from cattle. After single subcutaneous (s.c.) injection at 4 mg/kg body weight, maximum plasma concentration (C_max) was 0.7 μg/mL. T_max was 23 min. Mean residence time from the time of dosing to the time of last measurable concentration (MRT_last) and terminal half‐life (T_1/2) was 6 and 9 days, respectively. A strong dose–response relationship with no significant sex effect was shown for both C_max and area under the plasma concentration–time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUC_last) over the range of doses up to 6 mg/kg. Absolute bioavailability was 78.9%. The volume of distribution based on the terminal phase (V_z) was 49.4 L/kg, and the plasma clearance was 144 mL/h/kg. The time–concentration profile of tildipirosin in BF and lung far exceeded those in blood plasma. In lung, tildipirosin concentrations reached 9.2 μg/g at 4 h, peaked at 14.8 μg/g at day 1, and slowly declined to 2.0 μg/g at day 28. In BF, the concentration of tildipirosin reached 1.5 and 3.0 μg/g at 4 and 10 h, maintained a plateau of about 3.5 μg/g between day 1 and 3, and slowly declined to 1.0 at day 21. T_1/2 in lung and BF was approximately 10 and 11 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination.     

Pharmacokinetics of gamithromycin after intravenous and subcutaneous administration in pigs

The aim of this study was to investigate the pharmacokinetic properties of gamithromycin in pigs after an intravenous (i.v.) or subcutaneous (s.c.) bolus injection of 6 mg/kg body weight. The plasma concentrations of gamithromycin were determined using a validated high-performance liquid chromatography–tandem mass spectrometry method, and the pharmacokinetics were noncompartmentally analysed.     

Pharmacokinetics and pharmacodynamics of gamithromycin in pulmonary epithelial lining fluid in naturally occurring bovine respiratory disease in multisource commingled feedlot cattle

The objectives of this study were to determine (i) whether an association exists between individual pharmacokinetic parameters and treatment outcome when feeder cattle were diagnosed with bovine respiratory disease (BRD) and treated with gamithromycin (Zactran^®) at the label dose and (ii) whether there was a stronger association between treatment outcome and gamithromycin concentration in plasma or in the pulmonary epithelial lining fluid (PELF) effect compartment. The study design was a prospective, blinded, randomized clinical trial utilizing three groups of 60 (362–592 lb) steers/bulls randomly allocated within origin to sham injection or gamithromycin mass medication. Cattle were evaluated daily for signs of BRD by a veterinarian blinded to treatment. Animals meeting the BRD case definition were enrolled and allocated to a sample collection scheme consisting of samples for bacterial isolation (bronchoalveolar lavage fluid and nasopharyngeal swabs) and gamithromycin concentration determination (PELF and plasma). Gamithromycin susceptibility of M. haemolytica (n = 287) and P. multocida (n = 257) were determined using broth microdilution with frozen panels containing gamithromycin at concentrations from 0.03 to 16 μg/mL. A two‐compartment plasma pharmacokinetic model with an additional compartment for gamithromycin in PELF was developed using rich data sets from published and unpublished studies. The sparse data from our study were then fit to this model using nonlinear mixed effects modeling to estimate individual parameter values. The resulting parameter estimates were used to simulate full time–concentration profiles for each animal in this study. These profiles were analyzed using noncompartmental methods so that PK/PD indices (AUC₂₄/MIC, AUC_∞/MIC, C_MAX/MIC) could be calculated for plasma and PELF (also T>MIC) for each individual. The calculated PK/PD indices were indicative that for both M. haemolytica and P. multocida a higher drug exposure in terms of concentration, and duration of exposure relative to the MIC of the target pathogen, was favorable to a successful case outcome. A significant association was found between treatment success and PELF AUC_0–24/MIC for P. multocida. The calves in this study demonstrated an increased clearance and volume of distribution in plasma as compared to the healthy calves in two previously published reports. Ultimately, the findings from this study indicate that higher PK/PD indices were predictive of positive treatment outcomes.     

Pharmacokinetics and pulmonary distribution of gamithromycin after intravenous administration in foals

The long‐acting azalide antibiotic gamithromycin is marketed for intramuscular treatment of bovine and swine infections. Off‐label use in foals leads to severe local lesions likely caused by hyperosmolality of the injected solution. We provide evidence from a pharmacokinetic study in 10 warm‐blooded healthy foals for intravenous bolus injection of gamithromycin diluted in distilled water to be a safe and well tolerated alternative. By intravenous dosing, markedly higher plasma exposure and better penetration into bronchoalveolar lavage cells but lower distribution into epithelial lining fluid are achieved as after intramuscular or subcutaneous administration. Intravenously injected gamithromycin was tolerated without any adverse drug reactions. The protocols for treatment of equine pulmonary infections caused by Rhodococcus equi should be revised accordingly.     

Metabolite concentrations in plasma following treatment of cattle with five anthelmintics

Plasma concentrations of anthelmintics and their metabolites were determined after cattle were treated at recommended dose rates and routes of administration. Fenbendazole, oxfendazole, febantel, albendazole and thiabendazole were given orally and oxfendazole was also administered with an intraruminal injector. After fenbendazole, oxfendazole and febantel were administered, fenbendazole, oxfendazole and fenbendazole sulphone were all detected in plasma in each case. However, there were marked differences between the three anthelmintics in the peak concentrations and areas under the plasma concentration/time curve (AUC) of these three metabolites. Intraruminal administration of oxfendazole produced higher AUC for fenbendazole and fenbendazole sulphone than did oral administration. Albendazole sulphoxide and sulphone were detected in cattle plasma after albendazole administration but no parent drug was present. These metabolites disappeared more rapidly in cattle than has been reported for sheep. Only 5(6)hydroxythiabendazole was detected in cattle plasma after thiabendazole treatment.     

Pharmacokinetics and tissue concentrations of firocoxib in sows following oral administration

The objectives of this study were to describe the pharmacokinetics of firocoxib following oral (PO) dosing and intravenous (IV) injection in sows. Seven healthy sows were administered 0.5 mg firocoxib/kg IV. Following a 23-d washout period, sows were administered firocoxib at 4.0 mg firocoxib/kg PO. Blood samples were collected at predetermined times for 72 hr after IV and 120 hr after PO administration. Plasma firocoxib concentration was measured using UPLC-MS/MS, and pharmacokinetic analysis was performed using noncompartmental procedures. Tissue firocoxib concentrations were determined at 5, 10 (n = 2/time point), and 21 d (n = 3) after PO administration. The geometric mean half-life following IV and PO administration was 16.6 and 22.5 hr, respectively. A mean peak plasma concentration (Cmax) of 0.06 µg/ml was recorded at 7.41 hr (T_max) after oral administration. Mean oral bioavailability was determined to be 70.3%. No signs of NSAID toxicity were observed on macroscopic and microscopic investigation. Firocoxib was detected in the skin with subcutaneous fat (0.02 µg/g) of one of three sows at 21 days postadministration. Additional work to establish appropriate meat withhold intervals in sows is required. Firocoxib was readily absorbed following PO administration. Further work is needed to better understand the analgesic effects for sows and piglets nursing sows administered firocoxib.     

The comparison of thiobarbituric acid reactive substances (TBARS) concentrations in plasma and serum from dairy cattle

The aim of this study was to compare thiobarbituric acid reactive substances (TBARS) concentrations in serum, plasma with heparin (heparin plasma), and plasma with ethylenediaminetetraacetic acid disodium salt (EDTA plasma) as anticoagulants from dairy cattle. Serum, heparin plasma, and EDTA plasma TBARS were not sufficiently strongly correlated to allow accurate prediction of one set of values from the other. Heparin plasma TBARS concentrations were found to be lower, and were affected by the duration of mixing during the assay process. The results suggest that it is necessary to differentiate TBARS concentrations between different sample types such as serum, heparin plasma, and EDTA plasma. For measurements of TBARS concentrations in cattle, EDTA plasma samples may be more suitable than the other samples.     

Blood plasma and tissue concentrations of vitamin E in beef cattle as influenced by supplementation of various tocopherol compounds

Twenty-four crossbred beef cows were used to investigate the concentration of alpha-tocopherol in plasma and tissues following oral administration of four tocopherol sources. Animals were allotted to the following treatments: DL-alpha-tocopherol, D-alpha-tocopherol, DL-tocopheryl acetate and D-alpha-tocopheryl acetate. Animals received a daily oral dose of 1,000 IU of the respective tocopherol treatment for 28 d and then were slaughtered. Blood samples were collected on d 0, 1, 7, 14 and 28 for tocopherol concentration assays, and samples from 10 different tissues were collected from slaughtered cows. Identification of alpha-tocopherol in tissues was confirmed by HPLC retention times and by comparison of mass spectra with that of alpha-tocopherol standards. The D-alpha-tocopherol and its acetate ester increased plasma tocopherol concentration faster than the racemic products, the greatest response occurring with D-alpha-tocopherol. Across all treatments, the highest alpha-tocopherol concentrations were noted in the adrenal gland and liver, the lowest in muscle and thyroid tissue. Tissue analyses confirmed that in adrenal gland, kidney, liver and lung, alpha-tocopherol concentrations were higher following D-alpha than DL-alpha-tocopherol supplementation.     

Clinical and experimental modifications of plasma iron and zinc concentrations in cattle

Plasma iron and zinc concentrations were studied in pyrexic cattle or in cattle experimentally infected with infectious bovine rhinotracheitis virus or Escherichia coli endotoxin. Plasma iron and zinc levels tended to decline in the animals given endotoxin and in the pyrexic cattle, but the plasma iron level was only modified after experimental infectious bovine rhinotracheitis infection. These changes were not always related to pyrexia. Plasma iron and zinc concentrations taken together may be used as an indicator of infection.     

Relationships between postnatal plasma oxytocin concentrations and social behaviors in cattle

We examined the associations between natural individual variations in basal oxytocin (OXT) in postnatal cattle and social behavioral traits. At 1, 2 and 6 weeks of age, the basal OXT exhibited individual variability in 20 Holstein heifer calves. Cluster analysis of mean OXT for these time periods obtained two subgroups: high OXT (HOXT; n = 9) and low OXT (LOXT; n = 11). Social behaviors were observed for 2 days at week 6 after introduction into a four‐peer group, and at 10–14 months of age (10 months) immediately and 1 week, 1 month and 5 months after introduction into 11–15 heifers. At week 6, the main effect of the OXT groups was not significant for all social behaviors. At 10 months, there tended to be interactions between the OXT groups and time periods with respect to the frequency of escape behaviors. LOXT heifers exhibited more escape behaviors than HOXT heifers on the first day of the second sociality tests. At 10 months, HOXT heifers exhibited both attacking and affiliative behavior for peers more than LOXT heifers during 5 months after the second social introduction. This suggests that postnatal OXT concentrations may have long‐lasting effects on individual differences among social behavioral traits in cattle.     

Time-dependent changes in plasma concentrations of 3-methylindole and blood concentrations of 3-methyleneindolenine-adduct in feedlot cattle

OBJECTIVE: To describe time-dependent changes in plasma concentrations of 3-methylindole (3MI) and blood concentrations of 3-methyleneindolenine (3MEIN)-adduct in feedlot cattle. ANIMALS: 64 yearling steers. PROCEDURES: Steers were assigned to 2 groups (32 steers/group). During the first 8 weeks, blood samples were collected from group 1 before the morning ration was fed, whereas samples from group 2 were collected 2 to 3 hours after the ration was fed. Blood samples were collected from all steers approximately 4 times/wk for 3 weeks and 3 times/wk for the subsequent 5 weeks. Samples were collected at the same time for all steers for an additional 10 weeks. Plasma samples were analyzed for 3MI concentrations. Blood samples collected from cattle in group 2 during the first 8 weeks were analyzed for 3MEIN-adduct concentrations. RESULTS: Mean blood concentration of 3MEIN-adduct increased to a maximum value on day 33 (0.80 U/microg of protein) and then decreased to a minimum on day 54 0.40 U/microg of protein). Plasma 3MI concentrations initially decreased and remained low until after day 54. Group-1 cattle had lower plasma 3MI concentrations, compared with concentrations for group-2 cattle. Blood 3MEIN-adduct concentrations and plasma 3MI concentrations were not associated with deleterious effects on weight gains. CONCLUSIONS AND CLINICAL RELEVANCE: Blood 3MEIN-adduct concentrations peaked during the period of greatest risk for development of bovine respiratory disease complex. Conversely, plasma 3MI concentrations decreased during the same period. Animal-to-animal variation in metabolic capacity to convert 3MI to 3MEIN may be of more importance than differences in plasma 3MI concentration.     

Pharmacokinetics and tissue concentrations of azithromycin in ball pythons (Python regius)

OBJECTIVE: To determine pharmacokinetics and tissue concentrations of azithromycin in ball pythons (Python regius) after IV or oral administration of a single dose. ANIMALS: 2 male and 5 female ball pythons. PROCEDURES: Using a crossover design, each snake was given a single dose of azithromycin (10 mg/kg) IV. After a 4-week washout period, each snake was given a single dose of azithromycin (10 mg/kg) orally. Blood samples were collected prior to dose administration and 1, 3, 6, 12, 24, 48, 72, and 96 hours after azithromycin administration. Azithromycin was quantitated by use of liquid chromatography-mass spectrometry. RESULTS: After IV administration, azithromycin had an apparent volume of distribution of 5.69 L/kg and a plasma clearance of 0.19 L/h/kg. Harmonic means for the terminal half-life were 17 hours following IV administration and 51 hours following oral administration. Mean residence times were 37 and 94 hours following IV and oral administration, respectively. Following oral administration, azithromycin had a peak plasma concentration (Cmax) of 1.04 microg/mL, a time to Cmax of 8.4 hours, and a prolonged mean absorption time of 57 hours. Mean oral bioavailability was 77%. Tissue concentrations ranged from 4 to 140 times the corresponding plasma concentration at 24 and 72 hours after azithromycin administration. CONCLUSIONS AND CLINICAL RELEVANCE: Azithromycin is well absorbed and tolerated by ball pythons. On the basis of plasma pharmacokinetics and tissue concentration data, we suggest an azithromycin dosage in ball pythons of 10 mg/kg, orally, every 2 to 7 days, depending upon the site of infection and susceptibil ity of the infective organism.     

Pharmacokinetics, bioavailability, and in vitro antibacterial activity of rifampin in the horse

The pharmacokinetics and bioavailability of rifampin were determined after IV (10 mg/kg of body weight) and intragastric (20 mg/kg of body weight) administration to 6 healthy, adult horses. After IV administration, the disposition kinetics of rifampin were best described by a 2-compartment open model. A rapid distribution phase was followed by a slower elimination phase, with a half-life (t1/2[beta]) of 7.27 +/- 1.11 hours. The mean body clearance was 1.49 +/- 0.41 ml/min.kg, and the mean volume of distribution was 932 +/- 292 ml/kg, indicating that rifampin was widely distributed in the body. After intragastric administration of rifampin in aqueous suspension, a brief lag period (0.31 +/- 0.09 hour) was followed by rapid, but incomplete, absorption (t1/2[a] = 0.51 +/- 0.32 hour) and slow elimination (t1/2[d] = 11.50 +/- 1.55 hours). The mean bioavailability (fractional absorption) of the administered dose during the first 24 hours was 53.94 +/- 18.90%, and we estimated that 70.0 +/- 23.6% of the drug would eventually be absorbed. The mean peak plasma rifampin concentration was 13.25 +/- 2.70 micrograms/ml at 2.5 +/- 1.6 hours after dosing. All 6 horses had plasma rifampin concentrations greater than 2 micrograms/ml by 45 minutes after dosing; concentrations greater than 3 micrograms/ml persisted for at least 24 hours. Mean plasma rifampin concentrations at 12 and 24 hours after dosing were 6.86 +/- 1.69 micrograms/ml and 3.83 +/- 0.87 micrograms/ml, respectively. We tested 162 isolates of 16 bacterial species cultured from clinically ill horses for susceptibility to rifampin.(ABSTRACT TRUNCATED AT 250 WORDS)