Pharmacokinetics of tulathromycin in plasma and milk samples after a single subcutaneous injection in lactating goats (Capra hircus)

Eight adult female dairy goats received one subcutaneous administration of tulathromycin at a dosage of 2.5 mg/kg body weight. Blood and milk samples were assayed for tulathromycin and the common fragment of tulathromycin, respectively, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of tulathromycin was analyzed by a noncompartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single‐dose administration of tulathromycin were as follows: C_max (121.54 ± 19.01 ng/mL); T_max (12 ± 12–24 h); area under the curve AUC_0→∞ (8324.54 ± 1706.56 ng·h/mL); terminal‐phase rate constant λz (0.01 ± 0.002 h⁻¹); and terminal‐phase rate constant half‐life t_1/2λz (67.20 h; harmonic). Mean milk pharmacokinetic parameters (±SD) following 45 days of sampling were as follows: C_max (1594 ± 379.23 ng/mL); T_max (12 ± 12–36 h); AUC_0→∞ (72,250.51 ± 18,909.57 ng·h/mL); λz (0.005 ± 0.001 h⁻¹); and t_1/2λz (155.28 h; harmonic). All goats had injection‐site reactions that diminished in size over time. The conclusions from this study were that tulathromycin residues are detectable in milk samples from adult goats for at least 45 days following subcutaneous administration, this therapeutic option should be reserved for cases where other treatment options have failed, and goat milk should be withheld from the human food chain for at least 45 days following tulathromycin administration.     

Injectable eprinomectin for cattle: Tick efficacy and pharmacokinetics

The aims of the present study were to evaluate the pharmacokinetic profile and efficacy of eprinomectin (EPM) against Rhipicephalus microplus in cattle of a new injectable form of EPM (Voss Performa®). The product was administered subcutaneously at a dose of 200 μg EPM/kg, in a single dose. The efficacy of EPM against R. microplus in cattle was evaluated through field and stall tests. Studies were performed to estimate the pharmacokinetic parameters of EPM with the purpose of better understanding the kinetics of the formulation. The formulation was effective in controlling R. microplus in both naturally and artificially infested cattle, providing efficacy greater than 95%. The results of pharmacokinetic study were C_max of 47.15 ± 22.20 ng/ml, T_max of 1.33 ± 0.492 days, T_1/2 of 2.96 ± 1.212 days, AUC_0–t of 228.08 ± 57.30 ng day ml⁻¹, and AUC_0-∞ of 240.50 ± 58.44 ng day ml⁻¹. Therefore, the new injectable EPM formulation becomes an important alternative for the control of cattle tick in Brazil.     

Pharmacological assessment of netobimin as a potential anthelmintic for use in horses: Plasma disposition, faecal excretion and efficacy

This study aimed to determine the plasma disposition and faecal excretion of netobimin (NTB) and its respective metabolites as well as the efficacy against strongyles in horses following oral administration. Netobimin (10 mg/kg) was administered orally to 8 horses. Blood and faecal samples were collected from 1 to 120 h post-treatment and analysed by high performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of ABZSO enantiomers produced was also determined. Faecal strongyle egg counts (EPG) were performed by a modified McMaster’s technique before and after the treatment. Neither NTB nor ABZ were present and only albendazole sulphoxide (ABZSO) and sulphone metabolites (ABZSO₂) were detected in the plasma samples. Maximum plasma concentration of ABZSO (0.53 ± 0.14 μg/ml) and ABZSO₂ (0.36 ± 0.09 μg/ml) were observed at (t_max) 10.50 and 19.50 h, respectively following administration of NTB. The area under the curve (AUC) of the two metabolites was similar to each other. Netobimin was not detected, and ABZ was predominant in faecal samples. The maximum plasma concentration (C_max) of (−)ABZSO was significantly higher than (+)ABZSO, but the area under the curves (AUCs) of the enantiomer were not significantly different each other in plasma samples. The enantiomers of ABZSO were close to racemate in the faecal samples analyzed. Netobimin reduced the EPG by 100%, 100%, 77%, 80% and 75% 2, 4, 6, 8 and 10 weeks post-treatment, respectively. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver which are responsible for sulphoxidation and sulphonation of ABZ. Considering the pharmacokinetic and efficacy parameters NTB could be used as an anthelmintic in horses.     

Phosphorus excretion by mares post-lactation

Across the equine literature, estimates of true P digestibility range from −23% to 79%. This large range cannot be explained by differences in P intake or phytate-P intake alone. However, differences in endogenous P secretion into the GI tract may explain the variation. In horses, excess absorbed P is not excreted in the urine but is re-secreted into the GI tract, increasing faecal P and leading to estimates of low P digestibility. Thus, accurate estimates of P digestibility can only be obtained if absorbed P is retained in the horse. The objective of this study was to examine P digestibility in post-lactational mares and control mares that were fed similar amounts of P. It was hypothesized that post-lactational mares would have greater P retention and higher apparent P digestibility than control mares. Prior to the study, four lactating and four non-lactating mares were fed a diet that provided 100% of the control mares’ P requirement, but only 55% of the lactating mares’ P requirement. During the study, both groups were fed P at the rate recommended for non-lactating mares. Post-lactational mares did not retain more P than control mares but tended to excrete more P than control mares (p = .082), presumably due to differences in endogenous P secretion into the GI tract. Metabolic changes occurring during mammary gland involution may have contributed to the increase in P excretion. However, faecal P excretion exceeded P intake in both groups (p = .08) and both groups lost weight during the study. Tissue mobilization during weight loss may have influenced P secretion into the GI tract.     

Assessment of the long‐acting ivermectin formulation in sheep: Further insight into potential pharmacokinetic interactions

The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long‐acting (LA) formulation to sheep and its impact on potential drug‐drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 μg/kg) and as LA formulation at 630 μg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long‐lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated C_max and AUC_0‐t values of the IVM‐LA formulation were 1.47‐ and 3.35‐fold higher compared with IVM 1% formulation, respectively. The T_1/2ab and T_max collected after administration of the LA formulation were 2‐ and 3.5‐fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7‐fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post‐administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug‐drug interactions is a further contribution to the field.     

Plasma disposition and faecal excretion of eprinomectin following topical and subcutaneous administration in non-lactating dairy cattle

AIMS: To investigate the plasma disposition and faecal excretion of eprinomectin (EPM) in non-lactating dairy cattle following topical and S/C administration.

METHODS: Holstein dairy cows, 3.5–5 years-old, were selected 20–25 days after being dried off and were randomly allocated to receive EPM either topically (n=5) or S/C (n=5) at dose rates of 0.5 and 0.2?mg/kg bodyweight, respectively. Heparinised blood and faecal samples were collected at various times between 1 hour and 30 days after treatment, and were analysed for concentrations of EPM using high performance liquid chromatography with a fluorescence detector.

RESULTS: The maximum concentration of EPM in plasma (C_max) and the time to reach C_max were both greater after S/C administration (59.70 (SD 12.90) ng/mL and 1.30 (SD 0.27) days, respectively) than after topical administration (20.73 (SD 4.04) ng/mL and 4.40 (SD 0.89) days, respectively) (p<0.001). In addition, S/C administration resulted in greater plasma availability (area under the curve; AUC), and a shorter terminal half-life and mean residence time (295.9 (SD 61.47) ng.day/mL; 2.95 (SD 0.74) days and 4.69 (SD 1.01) days, respectively) compared with topical administration (168.2 (SD15.67) ng.day/mL; 4.63 (SD 0.32) days, and 8.23 (SD 0.57) days, respectively) (p<0.01). EPM was detected in faeces between 0.80 (SD 0.45) and 13.6 (SD 4.16) days following S/C administration, and between 1 (SD 0.5) and 20.0 (SD 3.54) days following topical administration. Subcutaneous administration resulted in greater faecal excretion than topical administration, expressed as AUC adjusted for dose (1188.9 (SD 491.64) vs. 311.5 (SD 46.90) ng.day/g; p<0.05). Maximum concentration in faeces was also higher following S/C than topical administration (223.0 (SD 63.96) vs. 99.47 (SD 43.24) ng/g; p<0.01).

CONCLUSIONS: Subcutaneous administration of EPM generated higher plasma concentrations and greater plasma availability compared with topical administration in non-lactating cattle. Although the S/C route provides higher faecal concentrations, the longer faecal persistence of EPM following topical administration may result in more persistent efficacy preventing establishment of incoming nematode larvae in cattle.     

Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows

Sellers, G., Lin, H. C., G. Riddell, M. G., Ravis, W. R., Lin, Y. J., Duran, S. H., Givens, M.D. Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows. J. vet. Pharmacol. Therap. 33 , 480–484. The purpose of this study was to evaluate the pharmacokinetics of ketamine in mature Holstein cows following administration of a single intravenous (i.v.) dose. Plasma and milk concentrations were determined using a high‐performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following i.v. administration, plasma T_max was 0.083 h and plasma C_max was 18 135 ± 22 720 ng/mL. Plasma AUC was 4484 ± 1,398 ng·h/mL. Plasma t_½β was 1.80 ± 0.50 h and mean residence time was 0.794 ± 0.318 h with total body clearance of 1.29 ± 0.70 L/h/kg. The mean plasma steady‐state volume of distribution was calculated as 0.990 ± 0.530 L/kg and volume of distribution based on area was calculated as 3.23 ± 1.51 L/kg. The last measurable time for ketamine detection in plasma was 8.0 h with a mean concentration of 24.9 ± 11.8 ng/mL. Milk T_max was detected at 0.67 ± 0.26 h with C_max of 2495 ± 904 ng/mL. Milk AUC till the last time was 6593 ± 2617 ng·h/mL with mean AUC milk to AUC plasma ratio of 1.99 ± 2.15. The last measurable time that ketamine was detected in milk was 44 ± 10.0 h with a mean concentration of 16.0 ± 9.0 ng/mL.     

Pharmacokinetics of enrofloxacin and danofloxacin in premature calves

The aim of this study was to determine the pharmacokinetics/pharmacodynamics of enrofloxacin (ENR) and danofloxacin (DNX) following intravenous (IV) and intramuscular (IM) administrations in premature calves. The study was performed on twenty‐four calves that were determined to be premature by anamnesis and general clinical examination. Premature calves were randomly divided into four groups (six premature calves/group) according to a parallel pharmacokinetic (PK) design as follows: ENR‐IV (10 mg/kg, IV), ENR‐IM (10 mg/kg, IM), DNX‐IV (8 mg/kg, IV), and DNX‐IM (8 mg/kg, IM). Plasma samples were collected for the determination of tested drugs by high‐pressure liquid chromatography with UV detector and analyzed by noncompartmental methods. Mean PK parameters of ENR and DNX following IV administration were as follows: elimination half‐life (t_1/2λz) 11.16 and 17.47 hr, area under the plasma concentration–time curve (AUC_0‐48) 139.75 and 38.90 hr*µg/ml, and volume of distribution at steady‐state 1.06 and 4.45 L/kg, respectively. Total body clearance of ENR and DNX was 0.07 and 0.18 L hr^?1 kg^?1, respectively. The PK parameters of ENR and DNX following IM injection were t_1/2λz 21.10 and 28.41 hr, AUC_0‐48 164.34 and 48.32 hr*µg/ml, respectively. The bioavailability (F) of ENR and DNX was determined to be 118% and 124%, respectively. The mean AUC_0‐48CPR/AUC_0‐48ENR ratio was 0.20 and 0.16 after IV and IM administration, respectively, in premature calves. The results showed that ENR (10 mg/kg) and DNX (8 mg/kg) following IV and IM administration produced sufficient plasma concentration for AUC_0‐24/minimum inhibitory concentration (MIC) and maximum concentration (C_max)/MIC ratios for susceptible bacteria, with the MIC₉₀ of 0.5 and 0.03 μg/ml, respectively. These findings may be helpful in planning the dosage regimen for ENR and DNX, but there is a need for further study in naturally infected premature calves.     

Plasma and synovial fluid pharmacokinetics of cefquinome following the administration of multiple doses in horses

The plasma and synovial fluid pharmacokinetics and safety of cefquinome, a 2‐amino‐5‐thiazolyl cephalosporin, were determined after multiple intravenous administrations in sixteen healthy horses. Cefquinome was administered to each horse through a slow i.v. injection over 20 min at 1, 2, 4, and 6 mg/kg (n = 4 horses per dose) every 12 h for 7 days (a total of 13 injections). Serial blood and synovial fluid samples were collected during the 12 h after the administration of the first and last doses and were analyzed by a high‐performance liquid chromatography assay. The data were evaluated using noncompartmental pharmacokinetic analyses. The estimated plasma pharmacokinetic parameters were compared with the hypothetical minimum inhibitory concentration (MIC) values (0.125–2 μg/mL). The plasma and synovial fluid concentrations and area under the concentration–time curves (AUC) of cefquinome showed a dose‐dependent increase. After a first dose of cefquinome, the ranges for the mean plasma half‐life values (2.30–2.41 h), the mean residence time (1.77–2.25 h), the systemic clearance (158–241 mL/h/kg), and the volume of distribution at steady‐state (355–431 mL/kg) were consistent across dose levels and similar to those observed after multiple doses. Cefquinome did not accumulate after multiple doses. Cefquinome penetrated the synovial fluid with AUC_{synovial fluid}/AUC_plasma ratios ranging from 0.57 to 1.37 after first and thirteenth doses, respectively. Cefquinome is well tolerated, with no adverse effects. The percentage of time for which the plasma concentrations were above the MIC was >45% for bacteria, with MIC values of ≤0.25, ≤0.5, and ≤1 μg/mL after the administration of 1, 2, and 4 or 6 mg/kg doses of CFQ at 12‐h intervals, respectively. Further studies are needed to determine the optimal dosage regimes in critically ill patients.     

Pharmacokinetics and physiologic effects of alprazolam after a single oral dose in healthy mares

The objective of this study was to evaluate the pharmacokinetic properties and physiologic effects of a single oral dose of alprazolam in horses. Seven adult female horses received an oral administration of alprazolam at a dosage of 0.04 mg/kg body weight. Blood samples were collected at various time points and assayed for alprazolam and its metabolite, α‐hydroxyalprazolam, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of alprazolam was analyzed by a one‐compartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single‐dose administration of alprazolam were as follows: C_max 14.76 ± 3.72 ng/mL and area under the curve (AUC_0–∞) 358.77 ± 76.26 ng·h/mL. Median (range) T_max was 3 h (1–12 h). Alpha‐hydroxyalprazolam concentrations were detected in each horse, although concentrations were low (C_max 1.36 ± 0.28 ng/mL). Repeat physical examinations and assessment of the degree of sedation and ataxia were performed every 12 h to evaluate for adverse effects. Oral alprazolam tablets were absorbed in adult horses and no clinically relevant adverse events were observed. Further evaluation of repeated dosing and safety of administration of alprazolam to horses is warranted.     

Pharmacokinetics of tulathromycin after subcutaneous injection in North American bison (Bison bison)

Tulathromycin is approved for the treatment of respiratory disease in cattle and swine. It is intended for long‐acting, single‐dose injection therapy (Draxxin), making it particularly desirable for use in bison due to the difficulty in handling and ease of creating stress in these animals. The pharmacokinetic properties of tulathromycin in bison were investigated. Ten wood bison received a single 2.5 mg/kg subcutaneous injection of Draxxin. Serum concentrations were measured by liquid chromatography–mass spectrometry (LC‐MS) detection. Tulathromycin demonstrated early maximal serum concentrations, extensive distribution, and slow elimination characteristics. The mean maximum serum concentration (C_max) was 195 ng/mL at 1.04 h (t_max) postinjection. The mean area under the serum concentration–time curve, extrapolated to infinity (AUC_0–inf), was 9341 ng·h/mL. The mean apparent volume of distribution (V_d/F) and clearance (Cls/F) was 111 L/kg and 0.4 L/h/kg, respectively, and the mean half‐life (t_1/2) was 214 h (8.9 days). Compared to values for cattle, C_max and AUC_0–inf were lower in bison, while the V_d/F was larger and the t_1/2 longer. Tissue distribution and clinical efficacy studies in bison are needed to confirm the purported extensive distribution of tulathromycin into lung tissue and to determine whether a 2.5 mg/kg subcutaneous dosage is adequate for bison.     

Pharmacokinetics and perioperative efficacy of intravenous ketorolac in dogs

Ketorolac (KET) is a nonsteroidal anti‐inflammatory drug approved for the use in humans that possesses a potent analgesic activity, comparable to morphine, and could represent a useful tool to control acute pain also in animals. The clinical efficacy and pharmacokinetic profile of intravenous (IV) ketorolac tromethamine (0.5 mg/kg) were studied in 15 dogs undergoing gonadectomy. Intra‐operative cardiorespiratory variables were monitored, and post‐operative pain was assessed using a subjective pain score (0–24) in all dogs, whereas the pharmacokinetic profile of the drug was determined in 10 animals. During surgery, mean minimal alveolar concentration of isoflurane was 1.69 ± 0.11%, and normocapnia and spontaneous ventilation were maintained in all animals. During pain assessment, no significant differences between males and females were found, and in no case rescue analgesia was necessary. No adverse effects were reported. Serum samples were purified by solid‐phase extraction and analysed by HPLC with UV‐Vis detection. A large variability was observed in serum concentrations. The kinetics of ketorolac was described by a noncompartmental analysis. The elimination half‐life (t_½λz) and Cl_B were 10.95 ± 7.06 h and 92.66 ± 84.49 mL/h/kg, respectively, and V_dss and V_z were 1030.09 ± 620.50 mL/kg and 1512.25 ± 799.13 mL/kg, respectively. AUC_(0→last) and MRT_(0→last) were 6.08 ± 3.28 h × μg/mL and 5.59 ± 2.12 h, respectively. The results indicate that ketorolac possess good post‐operative analgesic effects until about 6 h after administration in dogs undergoing moderately painful surgery.     

Pharmacokinetics of toltrazuril and its metabolites in pregnant and nonpregnant ewes and determination of their concentrations in milk,allantoic fluid,and newborn plasma

The objectives of this study were to determine the pharmacokinetics of toltrazuril and its metabolites in pregnant and nonpregnant ewes following a single oral dose and to determine the plasma concentrations of these compounds in milk, allantoic fluid, and newborn plasma. Eighteen healthy ewes were randomly divided into three groups (n = 6 each): pregnant ewes at 12–13 weeks of gestation (group A), nonpregnant ewes (group B), and pregnant ewes at 1–2 weeks before expected lambing date (group C). Ewes in all groups received a single oral dose of toltrazuril at 20 mg/kg body weight. In groups A and B, blood samples were collected at 1, 3, 5, 7, 9, 12, 15, 18 hr, every 6 hr to day 3, every 12 hr to day 7 and thereafter every 24 hr to day 14 post-toltrazuril administration. In group C, parturition was induced 24–36 hr after toltrazuril administration then milk, allantoic fluid, and newborn plasma samples were collected immediately after birth. Drug metabolites were assayed using ultra high-performance liquid chromatography–ultraviolet detection method (UHPLC-UV). The maximum concentration (C_max), area under the plasma concentration-time curve (AUC_0–t), AUC to 24 and 48 hr (AUC_0–24), and (AUC_0–48) were significantly higher in pregnant ewes. Longer apparent half-life (T_1/2), significantly higher apparent volume of distribution (Vd/F) and total clearance (Cl/F) were observed in nonpregnant ewes. The time to maximum plasma concentration (T_max), mean residence time (MRT) and elimination rate constant (K_el) were similar in both groups. The AUC_0–24 and AUC_0–48 were significantly higher in nonpregnant ewes. The AUC_0–t was significantly higher in pregnant ones. The ratio of plasma toltrazuril concentrations in ewes and toltrazuril concentrations in newborn lambs' plasma, allantoic fluid, and milk were 68%, 2.3%, and 5.3%, respectively. Results of this study showed that toltrazuril is well absorbed after a single oral dose in ewes with widespread distribution in different body tissues.     

Pharmacokinetics of tildipirosin in pig tonsils

The penetration of antimicrobials in pig tonsils is hardly known. The objective of the study was to quantify the tildipirosin (TD) penetration in tonsils. Animals were randomly divided into six groups (control, T1, T2 (1), T2(5), T2(10), and T2(15)) of eight animals. T1 and T2 groups received a dose of 2 and 4 mg of TD/kg bw in one shot (Zuprevo^® MSD Animal Health), respectively, and the control group received 2 mL of saline solution. The animals were sacrificed by intravenous administration of pentobarbital sodium 24 h after finishing the treatment for the control, T1, and T2(1) groups, whereas animals of T2(5), T2(10), and T2(15) groups were sacrificed at 5, 10, and 15 days, post‐treatment, respectively. Tonsils and blood samples were taken at necropsy to obtain plasma, and the tildipirosin concentration was determined by high‐performance liquid chromatography with tandem mass spectrometry detection. The concentration in plasma was always significantly lower than in tonsil. Average TD tonsil concentrations increased significantly in a dose‐dependent manner, and the tonsil TD vs. plasma TD concentration ratio was approximately 75 for the doses of 2 and 4 mg of TD/kg bw at 24 h post‐treatment. Moreover, the maximum concentration of tildipirosin in tonsil was observed at 1 day postadministration, and this concentration decreased gradually from this day until 15 days postadministration for the dose of 4 mg of TD/kg bw. Finally, the ratio AUC_tonsil/AUC_plasma was 97.9, and the T_{1/2 (h)} was clearly higher in tonsil than in plasma.     

Breed-related plasma disposition of ivermectin following subcutaneous administration in Kilis and Damascus goats

Many factors related with drug and animals affect the plasma disposition of endectocides including ivermectin (IVM). The aim of the present study was to investigate the breed differences in pharmacokinetics of IVM in goats following subcutaneous administration. Two different goat breeds (Kilis and Damascus goats) were allocated into two treatment groups with respect to breed. The injectable formulation of IVM was administered subcutaneously at a dose rate of 0.2 mg/kg bodyweight. Blood samples were collected before treatment and at various times between 1 h and 40 days after treatment and the plasma samples were analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The results indicated that the plasma disposition of IVM was substantially affected by breed differences following subcutaneous administration in goats. The last detectable plasma concentration (t_last) of IVM was significantly later in Kilis goats (38.33 days) compared with Damascus goats (22.50 days). Although, there were no significant differences on C_max (10.83 ng/ml vs. 10.15 ng/ml) and t_max (2.75 days vs. 2.33 days) values; the area under the concentration–time curve-AUC (110.26 ng.d/ml vs. 73.38 ng.d/ml) the terminal half-life-t_1/2λz (5.65 days vs. 3.81 days) and the mean plasma residence time-MRT (9.31 days vs. 6.35 days) were significantly different in Kilis goats compared with Damascus goats, respectively. The breed-related difference observed on the plasma disposition of IVM between Kilis and Damascus goats could be attributable to different excretion pattern or specific anatomical and/or physiological characteristics such as body fat composition of each breed.     

Pharmacokinetics and dynamics of mycophenolate mofetil after single‐dose oral administration in juvenile dachshunds

Mycophenolate mofetil (MMF) is recommended as an alternative/complementary immunosuppressant. Pharmacokinetic and dynamic effects of MMF are unknown in young‐aged dogs. We investigated the pharmacokinetics and pharmacodynamics of single oral dose MMF metabolite, mycophenolic acid (MPA), in healthy juvenile dogs purpose‐bred for the tripeptidyl peptidase 1 gene (TPP1) mutation. The dogs were heterozygous for the mutation (nonaffected carriers). Six dogs received 13 mg/kg oral MMF and two placebo. Pharmacokinetic parameters derived from plasma MPA were evaluated. Whole‐blood mitogen‐stimulated T‐cell proliferation was determined using a flow cytometric assay. Plasma MPA C_max (mean ± SD, 9.33 ± 7.04 μg/ml) occurred at <1 hr. The AUC_0–∞ (mean ± SD, 12.84±6.62 hr*μg/ml), MRT_inf (mean ± SD, 11.09 ± 9.63 min), T1/2 (harmonic mean ± PseudoSD 5.50 ± 3.80 min), and k/d (mean ± SD, 0.002 ± 0.001 1/min). Significant differences could not be detected between % inhibition of proliferating CD5+ T lymphocytes at any time point (p = .380). No relationship was observed between MPA concentration and % inhibition of proliferating CD5+ T lymphocytes (R = .148, p = .324). Pharmacodynamics do not support the use of MMF in juvenile dogs at the administered dose based on existing therapeutic targets.     

The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits

The aim of this study was to determine the effect of Escherichia coli lipopolysaccharide (LPS)‐induced acute phase response (APR) on the pharmaco‐kinetics and biotransformation of florfenicol (FFC) in rabbits. Six rabbits (3.0 ± 0.08 kg body weight (bw)) were distributed through a crossover design with 4 weeks of washout period. Pairs of rabbits similar in bw and sex were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of E. coli LPS at intervals of 6 h, and Group 2 (control) was treated with an equivalent volume of saline solution (SS) at the same intervals and frequency of Group 1. At 24 h after the first injection of LPS or SS, an intravenous bolus of 20 mg/kg bw of FFC was administered. Blood samples were collected from the auricular vein before drug administration and at different times between 0.05 and 24.0 h after treatment. FFC and florfenicol‐amine (FFC‐a) were extracted from the plasma, and their concentrations were determined by high‐performance liquid chromatography. A noncompartmental pharmacokinetic model was used for data analysis, and data were compared using the paired Student t‐test. The mean values of AUC_0–∞ in the endotoxaemic rabbits (26.3 ± 2.7 μg·h/mL) were significantly higher (P < 0.05) than values observed in healthy rabbits (17.2 ± 0.97 μg·h/mL). The total mean plasma clearance (CL_T) decreased from 1228 ± 107.5 mL·h/kg in the control group to 806.4 ± 91.4 mL·h/kg in the LPS‐treated rabbits. A significant increase (P < 0.05) in the half‐life of elimination was observed in the endotoxaemic rabbits (5.59 ± 1.14 h) compared to the values observed in healthy animals (3.44 ± 0.57 h). In conclusion, the administration of repeated doses of 1 μg/kg E. coli LPS induced an APR in rabbits, producing significant modifications in plasma concentrations of FFC leading to increases in the AUC, terminal half‐life and mean residence time (MRT), but a significant decrease in CL_T of the drug. As a consequence of the APR induced by LPS, there was a reduction in the metabolic conversion of FFC to their metabolite FFC‐a in the liver, suggesting that the mediators released during the APR induced significant inhibitory effects on the hepatic drug‐metabolizing enzymes.     

Pharmacokinetics of vitacoxib in rabbits after intravenous and oral administration

This study describes the pharmacokinetics of vitacoxib in healthy rabbits following administration of 10 mg/kg intravenous (i.v.) and 10 mg/kg oral. Twelve New Zealand white rabbits were randomly allocated to two equally sized treatment groups. Blood samples were collected at predetermined times from 0 to 36 hr after treatment. Plasma drug concentrations were determined using UPLC‐MS/MS. Pharmacokinetic analysis was completed using noncompartmental methods via WinNonlin^? 6.4 software. The mean concentration area under curve (AUC_last) for vitacoxib was determined to be 11.0 ± 4.37 μg hr/ml for i.v. administration and 2.82 ± 0.98 μg hr/ml for oral administration. The elimination half‐life (T_1/2λz) was 6.30 ± 2.44 and 6.30 ± 1.19 hr for the i.v. and oral route, respectively. The C_max (maximum plasma concentration) and T_max (time to reach the observed maximum (peak) concentration at steady‐state) following oral application were 189 ± 83.1 ng/ml and 6.58 ± 3.41 hr, respectively. Mean residence time (MRT_last) following i.v. injection was 6.91 ± 3.22 and 11.7 ± 2.12 hr after oral administration. The mean bioavailability of oral administration was calculated to be 25.6%. No adverse effects were observed in any rabbit. Further studies characterizing the pharmacodynamics of vitacoxib are required to develop a formulation of vitacoxib for rabbits.     

Induced Lactation with a Dopamine Antagonist in Mares: Different Responses between Ovariectomized and Intact Mares

The aim of this study was to compare the effects of treatment with repeated injections of sulpiride (a dopamine D₂ antagonist) on prolactin secretion and induced lactation in ovariectomized and intact adult mares and to verify if this induction was possible at the beginning and at the end of the birth season. Two experiments were carried out in September [experiment (expt) 1], and in March (expt 2), in France (48°N). In expt 1, three groups of five mares were tested: intact‐control, intact‐treated and ovariectomized‐treated mares. In expt 2, mares previously subjected to artificial photoperiod were assigned in two groups: four intact‐control and five intact‐treated mares. The cyclicity of intact mares was previously synchronized with PGF_2α injections, then all the mares were in the follicular phase at the beginning of treatment. Sulpiride was intramuscularly injected (0.5 mg/kg of BW), twice a day. Mares were milked at 7:30, 11:45, 16:00 and 20:15 hours. Blood samples were collected every day during the treatment for progesterone, total oestrogen and prolactin assays. In the two experiments, only treated intact mares produced milk, with a large inter‐animal variability. Prolactin increase after sulpiride treatment was not so great in the ovariectomized‐treated mares as in the intact‐treated mares. The total correlations between prolactin, progesterone, oestrogen plasma concentrations and daily milk production were significant (0.57, 0.25, 0.17 respectively). This induction of lactation can be performed during the entire birth season in intact mares, but not in ovariectomized mares, indicating that steroids are necessary for this induction in mares treated by dopamine D2 antagonist.     

Effect of using Acacia mearnsii tannin extract as a feed additive on nutritional variables and productive performance in dairy cows grazing a temperate pasture

This study was carried out to evaluate the impact of including Acacia mearnsii tannin extract (TA) as a feed additive on nutrition and productive performance of dairy cows grazing a high‐quality temperate pasture and receiving supplementation with a concentrate feedstuff. Fourteen multiparous Holstein cows were assigned to either of the following treatments: concentrate without or with 20 g TA/kg dry matter (DM). Concentrate intake accounted for 32% of the total DM intake. Tannin addition increased the herbage DM intake by 22% (p < .05). There was no effect of TA inclusion on milk yield, milk composition, milk nitrogen (N) excretion, milk and plasma urea‐N concentration, urinary excretion of total N, urea‐N, and purine derivatives. However, TA inclusion increased the N intake and retention, total N excretion in manure, fecal N to urine N ratio, and decreased the dietary N efficiency for milk production and the percentage of ingested N excreted in urine (p < .05). In conclusion, supplementing dairy cows grazing a high‐quality temperate pasture with a concentrate containing 20 g TA/kg DM showed the potential of decreasing the proportion of ingested N excreted in urine without affecting the productive performance.