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Introduction: The first commercially available target-controlled infusion pump, the "Diprifusor", employed a "Marsh" pharmacokinetic-pharmacodynamic parameter set, and this model (the Diprifusor-Marsh model) is also available in several of today's pumps. However, it is unsuited for effect-site, target-controlled infusions (Ce-TCI) because it assumes slow transfer between blood and the effect-site (ke0 = 0.26 min-1). We hypothesised that a faster ke0 of 1.21 min-1 (Adjusted-Marsh model) for Ce-TCI would result in hypnotic effects equivalent to that of the Schnider parameter set (Schnider model). Methods: We replicated a previously published study that demonstrated the Diprifusor-Marsh model's unsuitability for Ce-TCI. We randomised 40 unpremedicated young adults into two groups to receive Ce-TCI, employing either the Schnider model or the Adjusted-Marsh model. We infused propofol at 3 000 mg.hour-1, while running a pharmacokinetic simulation and recording the electroencephalographic bispectral index (BIS) electronically. At loss of consciousness (LOC), indicated by a syringe-drop, we converted the infusion to Ce-TCI, targeting the effect-site concentration (Ce) observed at LOC, for 20 minutes. We regarded a difference of 10 BIS-units as clinically important. Results: There were no statistically significant differences between the group medians regarding time-to-LOC, induction-dose, BIS at LOC and Ce-target. BIS decreased monotonically in both groups from a median of 78.5 at LOC to a steady-state median (25-27) at 15 minutes. The BIS of the Adjusted-Marsh model group closely followed the BIS of the Schnider model group. At steady state, the median BIS difference (95% CI) was -0.3 (-5.7 to 5.3), which was within the predefined interval for declaring equivalence. The Schnider model group's mean BIS at steady state did not differ from that of the previous study's Schnider model group. Conclusion: Reasons for the progressive BIS decrease to lower than expected values include delayed response-times by the BIS monitor, Ce overshoot explained by front-end kinetics, neural inertia and the choice of surrogate LOC indicator. We conclude that Ce-TCI using the Adjusted-Marsh parameter set results in equivalent hypnotic effects to those of the Schnider model, with the proviso that this may apply only to young adults of normal body habitus. [ABSTRACT FROM AUTHOR]

Introduction: The first commercially available target-controlled infusion pump, the "Diprifusor", employed a "Marsh" pharmacokinetic-pharmacodynamic parameter set, and this model (the Diprifusor-Marsh model) is also available in several of today's pumps. However, it is unsuited for effect-site, target-controlled infusions (Ce-TCI) because it assumes slow transfer between blood and the effect-site (ke0 = 0.26 min-1). We hypothesised that a faster ke0 of 1.21 min-1 (Adjusted-Marsh model) for Ce-TCI would result in hypnotic effects equivalent to that of the Schnider parameter set (Schnider model). Methods: We replicated a previously published study that demonstrated the Diprifusor-Marsh model's unsuitability for Ce-TCI. We randomised 40 unpremedicated young adults into two groups to receive Ce-TCI, employing either the Schnider model or the Adjusted-Marsh model. We infused propofol at 3 000 mg.hour-1, while running a pharmacokinetic simulation and recording the electroencephalographic bispectral index (BIS) electronically. At loss of consciousness (LOC), indicated by a syringe-drop, we converted the infusion to Ce-TCI, targeting the effect-site concentration (Ce) observed at LOC, for 20 minutes. We regarded a difference of 10 BIS-units as clinically important. Results: There were no statistically significant differences between the group medians regarding time-to-LOC, induction-dose, BIS at LOC and Ce-target. BIS decreased monotonically in both groups from a median of 78.5 at LOC to a steady-state median (25-27) at 15 minutes. The BIS of the Adjusted-Marsh model group closely followed the BIS of the Schnider model group. At steady state, the median BIS difference (95% CI) was -0.3 (-5.7 to 5.3), which was within the predefined interval for declaring equivalence. The Schnider model group's mean BIS at steady state did not differ from that of the previous study's Schnider model group. Conclusion: Reasons for the progressive BIS decrease to lower than expected values include delayed response-times by the BIS monitor, Ce overshoot explained by front-end kinetics, neural inertia and the choice of surrogate LOC indicator. We conclude that Ce-TCI using the Adjusted-Marsh parameter set results in equivalent hypnotic effects to those of the Schnider model, with the proviso that this may apply only to young adults of normal body habitus. [ABSTRACT FROM AUTHOR]

Introduction: The first commercially available target-controlled infusion pump, the "Diprifusor", employed a "Marsh" pharmacokinetic-pharmacodynamic parameter set, and this model (the Diprifusor-Marsh model) is also available in several of today's pumps. However, it is unsuited for effect-site, target-controlled infusions (Ce-TCI) because it assumes slow transfer between blood and the effect-site (ke0 = 0.26 min-1). We hypothesised that a faster ke0 of 1.21 min-1 (Adjusted-Marsh model) for Ce-TCI would result in hypnotic effects equivalent to that of the Schnider parameter set (Schnider model). Methods: We replicated a previously published study that demonstrated the Diprifusor-Marsh model's unsuitability for Ce-TCI. We randomised 40 unpremedicated young adults into two groups to receive Ce-TCI, employing either the Schnider model or the Adjusted-Marsh model. We infused propofol at 3 000 mg.hour-1, while running a pharmacokinetic simulation and recording the electroencephalographic bispectral index (BIS) electronically. At loss of consciousness (LOC), indicated by a syringe-drop, we converted the infusion to Ce-TCI, targeting the effect-site concentration (Ce) observed at LOC, for 20 minutes. We regarded a difference of 10 BIS-units as clinically important. Results: There were no statistically significant differences between the group medians regarding time-to-LOC, induction-dose, BIS at LOC and Ce-target. BIS decreased monotonically in both groups from a median of 78.5 at LOC to a steady-state median (25-27) at 15 minutes. The BIS of the Adjusted-Marsh model group closely followed the BIS of the Schnider model group. At steady state, the median BIS difference (95% CI) was -0.3 (-5.7 to 5.3), which was within the predefined interval for declaring equivalence. The Schnider model group's mean BIS at steady state did not differ from that of the previous study's Schnider model group. Conclusion: Reasons for the progressive BIS decrease to lower than expected values include delayed response-times by the BIS monitor, Ce overshoot explained by front-end kinetics, neural inertia and the choice of surrogate LOC indicator. We conclude that Ce-TCI using the Adjusted-Marsh parameter set results in equivalent hypnotic effects to those of the Schnider model, with the proviso that this may apply only to young adults of normal body habitus. [ABSTRACT FROM AUTHOR]

A transdermal formulation of the nonsteroidal anti‐inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single‐dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments. Plasma flunixin concentrations were determined using high‐pressure liquid chromatography with mass spectroscopy (HPLC‐MS). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (Tmax) was 2.81 hr, and the maximum drug concentration was 1.08 μg/ml. The mean terminal half‐life (T½) was determined to be 5.20 hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294 L/hr kg−1, and volume of distribution of fraction (Vz/F) absorbed was 2.20 L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses. [ABSTRACT FROM AUTHOR]

The objective of this study reported here was determine whether differences occurred in meloxicam pharmacokinetics between postpartum cows and mid‐lactation cows. Preliminary data from a separate study (P. J. Gorden, unpublished data) in postpartum cows demonstrated elevated plasma and milk concentration profiles compared to previously published data (Malreddy, Coetzee, KuKanich, & Gehring, ). Two different groups were enrolled, each with 10 cows. The treatment group (TRT) was postpartum cows treated with meloxicam, and the positive control (PC) group was cows in mid‐lactation treated with meloxicam. Plasma and milk meloxicam concentrations between the TRT and PC group were compared. Significant differences in meloxicam concentration in plasma were determined at all time points from 8 hr to 120 hr post‐treatment. In milk, there was a treatment (p = .003), time (p < .001), and treatment by time interaction (p < .001). Significant differences in milk meloxicam concentration were determined at all time points from 8 hr to 96 hr post‐treatment, except for the 16‐hr time point. The time needed for meloxicam to no longer be detected in milk of the TRT group was longer compared to the PC group, indicating that a longer milk withdrawal is needed. These data suggest higher bioavailability as the underlying mechanism. Further research is needed to determine the mechanisms underlying differences this outcome. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine if concentrations of chlortetracycline could be detected in fetal plasma or tissues after administering an oral dose of chlortetracycline (CTC; 500 mg/head/day) reported to be effective in controlling Campylobacter spp. abortions. Five pregnant ewes were administered 250 mg/head twice a day (total dose 500 mg/hd/d) for 7 days. On the beginning of day 7, intravenous catheters were surgically implanted or inserted into the fetus and dam. Plasma samples were collected from the ewe and fetus at various time points before and up to 36 hr after the last dose of CTC. All ewes were then sacrificed, and tissues were harvested from the fetus for drug analysis. Concentrations of CTC in maternal plasma were consistent with our previous study and below the minimum inhibitory concentration of Campylobacter abortion isolates. Concentrations of CTC were below the limit of detection in three of five fetal plasma samples and all of the placenta, amniotic fluid, and fetal stomach contents. Low concentrations were detectable in fetal kidney and liver, suggesting that CTC reaches the fetus, although at a variable and low ratio when compared to maternal concentrations. [ABSTRACT FROM AUTHOR]

Malreddy, P. R., Coetzee, J. F., KuKanich, B., Gehring, R. Pharmacokinetics and milk secretion of gabapentin and meloxicam co-administered orally in Holstein-Friesian cows. J. vet. Pharmacol. Therap. 36, 14-20. Management of neuropathic pain in dairy cattle could be achieved by combination therapy of gabapentin, a GABA analog and meloxicam, an nonsteroidal anti-inflammatory drug. This study was designed to determine specifically the depletion of these drugs into milk. Six animals received meloxicam at 1 mg/kg and gabapentin at 10 mg/kg, while another group ( n = 6) received meloxicam at 1 mg/kg and gabapentin at 20 mg/kg. Plasma and milk drug concentrations were determined over 7 days postadministration by HPLC/MS followed by noncompartmental pharmacokinetic analyses. The mean (±SD) plasma Cmax and Tmax for meloxicam (2.89 ± 0.48 μg/mL and 11.33 ± 4.12 h) were not much different from gabapentin at 10 mg/kg (2.87 ± 0.2 μg/mL and 8 ± 0 h). The mean (±SD) milk Cmax for meloxicam (0.41 ± 80.16 μg/mL) was comparable to gabapentin at 10 mg/kg (0.63 ± 0.13 μg/mL and 12 ± 6.69 h). The mean plasma and milk Cmax for gabapentin at 20 mg/kg P.O. were almost double the values at 10 mg/kg. The mean (±SD) milk to plasma ratio for meloxicam (0.14 ± 0.04) was lower than for gabapentin (0.23 ± 0.06). The results of this study suggest that milk from treated cows will have low drug residue concentration soon after plasma drug concentrations have fallen below effective levels. [ABSTRACT FROM AUTHOR]

Mosher, R. A., Coetzee, J. F., Cull, C. A., Gehring, R., KuKanich, B. Pharmacokinetics of oral meloxicam in ruminant and preruminant calves. J. vet. Pharmacol. Therap. 35, 373-381. The pharmacokinetics of oral meloxicam has been studied in ruminant, but not preruminant calves. Oral meloxicam was administered at 0.5 mg/kg to six ruminant calves via gavage (RG); to six preruminant calves via gavage (PRG); and to six preruminant calves via suckling in milk replacer (PRF). Plasma drug concentrations, determined over 120-h postadministration, were analyzed by compartmental and noncompartmental methods. The rate of drug absorption was faster ( P < 0.01) in PRF (0.237 ± 0.0478/h) than RG calves (0.0815 ± 0.0188/h), while absorption in PRG calves (0.153 ± 0.128/h) was not different from other groups. Cmax was lower ( P = 0.03) in PRF (1.27 ± 0.430 μg/mL) than in PRG calves (2.20 ± 0.467 μg/mL), while Cmax of RG calves (1.95 ± 0.955 μg/mL) was not different from other groups. V/ F was higher in PRF calves (365 ± 57 mL/kg) than either PRG (177 ± 63 mL/kg, P < 0.01) or RG (232 ± 83 mL/kg, P = 0.01) calves. These observations were likely due to differences in bioavailability, physiological maturity, and timing of the drug delivery into different compartments of the ruminant gastrointestinal tract. Results suggest that an adjustment in meloxicam dose may be necessary when administered with milk replacer. [ABSTRACT FROM AUTHOR]

Reinbold, J. B., Coetzee, J. F., Gehring, R., Havel, J. A., Hollis, L. C., Olson, K. C., Apley, M. D. Plasma pharmacokinetics of oral chlortetracycline in group fed, ruminating, Holstein steers in a feedlot setting. J. vet. Pharmacol. Therap. 33, 76–83. Chlortetracycline HCl (CTC) has impacted profitable livestock production since 1945. However, pharmacokinetic parameters for CTC in ruminating cattle are unavailable in peer-reviewed literature. A total of 18 steers were randomized to 4.4, 11, or 22 mg/kg/day p.o. CTC treatment groups ( n = 6). Chlortetracycline treatment was offered as one-half of the daily dose b.i.d. (160 total doses/group) for 80 days. Blood samples were collected at selected time points throughout an 83-day study and analyzed with a solid phase extraction technique and novel ultrahigh performance liquid chromatography-mass spectroscopy/mass spectroscopy analytical method. Noncompartmental analysis (NCA) determined individual pharmacokinetic parameters by treatment group with coefficient of variation (CV %) estimates. A one-compartment open model with first order absorption and elimination, where absorption rate constant was equal to elimination rate constant, was fitted using nonlinear mixed effects modeling (NLMEM). NLMEM determined the primary pharmacokinetic parameters: volume of distribution (V/F, 40.9 L/kg) and rate constant (k, 0.0478 h−1), and the secondary parameters: dose-normalized area under the curve (AUC/D, 0.29 h·μg/L), clearance (Cl/F, 1.8 L/kg/h), elimination half-life ( t1/2, 16.2 h), Cmax/Dose (4.5 ng/mL), and time of Cmax ( Tmax, 23.3 h) with improved CV estimates over NCA. Dose linearity was confirmed byanova of parameters derived from NCA by treatment group. Further studies are necessary for determining absolute bioavailability and pharmacokinetic–pharmacodynamic relationships of CTC in group fed, ruminating cattle. [ABSTRACT FROM AUTHOR]

We present an uncommon case of limited dorsal myeloschisis in a 3-month-old infant requiring repair guided by intraoperative neuromonitoring (IONM) and therefore avoidance of volatile anaesthetic agents. The case presented challenges in positioning, airway management, a lack of age appropriate pharmacokinetic models in target-controlled infusion (TCI) syringe pumps and unavailability of remifentanil, considered to be an essential drug in this setting. We overcame these challenges using manually controlled infusions of propofol and alfentanil guided by pharmacokinetic simulation software (Stelsim). [ABSTRACT FROM AUTHOR]

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3–4 weeks, were administered fentanyl citrate at a single dose of 5.0 μg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half‐life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr−1 kg−1, volume of distribution at steady‐state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half‐life, volume of distribution at steady‐state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg−1 hr−1. Fentanyl citrate administered i.v. at 5.0 μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half‐life or systemic clearance and have significant impact on dosage regimen selection in clinical practice. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of intramuscularly administered ceftiofur crystalline-free acid ( CCFA) were determined in pigs that were clinically healthy ( n = 8), vaccinated with a Porcine reproductive and respiratory syndrome modified live virus ( PRRS MLV) ( n = 10), challenged with wild-type porcine reproductive and respiratory syndrome virus ( PRRSv) VR-2385 ( n = 10), or vaccinated with PRRS MLV and later challenged with wild-type PRRSv VR-2385 ( n = 10). Animals were given a single dose of CCFA intramuscularly at 5 mg/kg body weight. Blood was collected at 0 (pretreatment), 0.25, 0.5, 1, 6, 12, 24, 48, 96, 144, 192, and 240 h postinjection. Plasma was analyzed using liquid chromatography-mass spectrometry. Plasma concentration-time curves for each group were evaluated with noncompartmental modeling. When compared to control animals, those receiving the PRRSv wild-type challenge only had a lower AUC0-last, higher Cl/F, and higher Vz/F. The PRRSv wild-type challenge only group had the longest T1/2 λ. The Cmax did not differ among all four treatments. Control animals had no statistically significant differences from animals vaccinated with PRRS MLV alone or animals vaccinated with PRRS MLV and later challenged with wild-type PRRSv. Our results suggest that PRRSv wild-type infection has the potential to alter CCFA pharmacokinetics and PRRS MLV vaccination may attenuate those changes. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the plasma pharmacokinetics of ketamine and its active metabolite norketamine administered intravenously at a dose of 0.1 mg/kg together with xylazine (0.05 mg/kg) to control the pain associated with castration in calves. A two-compartment model with an additional metabolite compartment linked to the central compartment was used to simultaneously describe the time-concentration profiles of both ketamine and its major metabolite norketamine. Parameter values estimated from the time-concentration profiles observed in this study were volume of the central compartment (Vc = 132.82 ± 68.23 mL/kg), distribution clearance (CLD = 15.49 ± 2.56 mL/min/kg), volume of the peripheral compartment (VT = 257.05 ± 41.65 mL/kg), ketamine clearance by the formation of the norketamine metabolite (CL2M = 8.56 ± 7.37 mL/kg/min) and ketamine clearance by other routes (CLo = 16.41 ± 3.42 mL/kg/min). Previously published data from rats suggest that the metabolite norketamine contributes to the analgesic effect of ketamine, with a potency that is one-third of the parent drug. An understanding of the time-concentration relationships and the disposition of the parent drug and its metabolite is therefore important for a better understanding of the analgesic potential of ketamine in cattle. [ABSTRACT FROM AUTHOR]

The purpose of the study was to compare the pharmacokinetics of amikacin administered i.v., to Greyhound and Beagle dogs and determine amikacin pharmacokinetics administered subcutaneously to Greyhounds. Amikacin was administered i.v. at 10 mg/kg to six healthy Greyhounds and six healthy Beagles. The Greyhounds also received amikacin, 10 mg/kg s.c. Plasma was sampled at predetermined time points and amikacin concentrations determined by a fluorescence polarization immunoassay (FPIA). The volume of distribution was significantly smaller in Greyhounds (mean = 176.5 mL/kg) compared to Beagles (234.0 mL/kg). The C0 and AUC were significantly larger in Greyhounds (86.03 μg/mL and 79.97 h·μg/mL) compared to Beagles (69.97 μg/mL and 50.04 h·μg/mL). The plasma clearance was significantly lower in Greyhounds (2.08 mL/min/kg) compared to Beagles (3.33 mL/min/kg). The fraction of the dose absorbed after s.c. administration to Greyhounds was 0.91, the mean absorption time was 0.87 h, and the mean maximum plasma concentration was 27.40 μg/mL at 0.64 h. Significant differences in the pharmacokinetics of amikacin in Greyhounds indicate it should be administered at a lower dose compared to Beagles. The dose in Greyhounds to achieve a Cmax: AUC ≥ 8 for bacteria (with an MIC ≤ 4 μg/mL) is 12 mg/kg q24 h compared to 22 mg/kg q24 in Beagles. [ABSTRACT FROM AUTHOR]

A cross-over study design was used to determine the pharmacokinetics of ampicillin in swine. Each of eight pigs was subjected to all of the following three treatments: (1) intramuscular (i.m.) injection of 17.6 mg/kg of ampicillin trihydrate; (2) injection of a mean dose of 17.6 mg/kg of ampicillin trihydrate using a needle-free (NF) injection device; and (3) intravenous injection of 17.6 mg/kg of sodium ampicillin administered as a bolus. Ampicillin trihydrate administered by NF injection in this study was not statistically different from i.m. injection as measured by AUC0−∞, MRT, MAT, or Cmax. However, the 90% confidence limits about the difference in NF to i.m. mean Cmax and AUC0−∞ values, expressed relative to the i.m. treatment mean, exceeded the traditional bioequivalence limits of ±20%. In part, failure to demonstrate bioequivalence was attributable to small study size and the large within-subject variability associated with this drug. Therefore the power of this study was not sufficient to definitively prove or disprove bioequivalence and additional studies to describe appropriate dosage regimens for ampicillin trihydrate when administered by NF injection to pigs are warranted. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British × Continental beef calves aged 4 to 6 months and weighing 297-392 kg received 0.5 mg/kg meloxicam per os once daily for 4 days. Plasma meloxicam concentrations were determined in 8 calves over 6 days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n = 3/timepoint), and 19 days (n = 4) after final administration. Meloxicam concentrations were determined in plasma ( LOQ= 0.025 μg/ mL) and muscle, liver, kidney, and fat samples ( LOQ = 2 ng/g) after extraction using validated LC- MS- MS methods. The mean (± SD) Cmax, Cmin, and Caverage plasma meloxicam concentrations were 4.52 ± 0.87 μg/mL, 2.95 ± 0.77 μg/mL, and 3.84 ± 0.81 μg/ mL, respectively. Mean (± SD) tissue meloxicam concentrations were highest in liver (226.67 ± 118.16 ng/g) and kidney samples (52.73 ± 39.01 ng/g) at 5 days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15 days after treatment. These findings suggest that tissue from meloxicam-treated calves will have low residue concentrations by 21 days after repeated oral administration. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare the pharmacokinetics of meloxicam in mature swine after intravenous (i.v.) and oral (p.o.) administration. Six mature sows (mean bodyweight ± standard deviation = 217.3 ± 65.68 kg) were administered an i.v. or p.o. dose of meloxicam at a target dose of 0.5 mg/kg in a cross-over design. Plasma samples collected up to 48 h postadministration were analyzed by high-pressure liquid chromatography and mass spectrometry ( HPLC- MS) followed by noncompartmental pharmacokinetic analysis. Mean peak plasma concentration ( CMAX) after p.o. administration was 1070 ng/mL (645-1749 ng/mL). TMAX was recorded at 2.40 h (0.50-12.00 h) after p.o. administration. Half-life (T½ λz) for i.v. and p.o. administration was 6.15 h (4.39-7.79 h) and 6.83 h (5.18-9.63 h), respectively. The bioavailability (F) for p.o. administration was 87% (39-351%). The results of this study suggest that meloxicam is well absorbed after oral administration. [ABSTRACT FROM AUTHOR]

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: Cmax 14.76 ± 3.72 ng/mL and area under the curve (AUC0-∞) 358.77 ± 76.26 ng·h/mL. Median (range) Tmax was 3 h (1-12 h). Alpha-hydroxyalprazolam concentrations were detected in each horse, although concentrations were low (Cmax 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. [ABSTRACT FROM AUTHOR]

The objectives of this study were to determine plasma concentrations and pharmacokinetic parameters of feed-grade chlortetracycline (CTC) in sheep after oral administration of 80 or 500 mg/head daily, divided into two equal doses given at 12-h intervals for 8 days. These are the approved, and commonly used but unapproved, feed additive doses, respectively, in the United States for the prevention of ovine infectious abortion. Blood samples were collected just prior to dosing at 0, 12, 24, 72, 96, and 192 h, as well as 4, 8, 12, 24, and 36 h after the last dose, and noncompartmental pharmacokinetic analysis was performed to estimate elimination half-life and area under the plasma concentration-time curve (AUC). Mean observed maximum CTC concentrations ( Cmax) were 20.0 ng/mL (80 mg dose) and 101 ng/mL (500 mg dose). Mean apparent elimination half-life was 18 h (80 mg dose) and 20 h (500 mg dose). Although published data do not exist to estimate plasma CTC concentrations necessary for the prevention of ovine infectious abortion, concentrations reached in our study suggest that either the FDA-approved and FDA-unapproved dosages are not high enough or that the pharmacodynamic parameter relating preventive dose to pathogen minimum inhibitory concentrations is yet to be determined. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the pharmacokinetics of intravenous and oral firocoxib in 10 healthy preweaned calves. Firocoxib (0.5 mg/kg) was initially administered i.v. to calves, and following a 14-day washout period, animals received firocoxib orally prior to cautery dehorning. Firocoxib concentrations were determined by liquid chromatography-tandem mass spectrometry. Changes in hematology and plasma chemistry were determined using automated methods. Computer software was used to estimate pharmacokinetic parameters best described with a two-compartment model for i.v. administration and a one-compartment model for p.o. administration. Following i.v. dosing, the geometric mean (range) T1/2K10 and T1/2β were 6.7 (4.6-9.7) and 37.2 (23.5-160.4) h, respectively, Vss was 3.10 (2.10-7.22) L/kg, and CL was 121.7 (100.1-156.7) mL/h/kg. Following oral administration, geometric mean (range) Cmax was 127.9 (102.5-151.3) ng/mL, Tmax was 4.0 (2.6-5.6) h, and T1/2K10 was 18.8 (14.2-25.5) h. Bioavailability of oral firocoxib was calculated using the AUC derived from both study populations to be 98.4% (83.1-117.6%). No adverse clinical effects were evident following firocoxib administration. Pharmacokinetic analysis of i.v. and p.o. firocoxib indicates high bioavailability and a prolonged terminal half-life in preweaned calves. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the pharmacokinetics and effect of nalbuphine administered intravenously to calves immediately prior to surgical castration. Ten healthy calves were randomly assigned to two treatments ( n = 5): (i) 0.9% sodium chloride ( CONT) placebo, (ii) nalbuphine hydrochloride ( NAL) (0.4 mg/kg). Blood samples collected over 10 h postcastration were analyzed for nalbuphine and cortisol concentrations. Additionally, heart rate, respiratory rate, rectal temperature, and step count was compared between groups using a random-effects mixed model. Changes in behavior and attitude were assessed using a six-point ordinal scoring system and compared using chi-square analysis. Plasma NAL concentrations were only detectable for 3 h postadministration (T½ = 0.68 h; Range: 0.53-0.79 h). There was no effect of NAL treatment prior to castration on cortisol concentrations ( P = 0.99), heart rate ( P = 0.73), respiratory rate ( P = 0.59), rectal temperature ( P = 0.22), and step count ( P = 0.08) but fewer calves showed signs of head shaking, kicking, and tail flicking in the NAL group compared with the CONT group ( P = 0.036). Therefore, we conclude that a single intravenous injection of nalbuphine at 0.4 mg/kg reduced some pain-related behaviors but did not significantly eliminate the physiological signs of distress in calves after surgical castration. [ABSTRACT FROM AUTHOR]

The article focuses on dose scaling in anaesthesia for the morbidly obese. Topics discussed include impact of linear dosing according to total body weight results in overdosing the obese and underdosing small children, the study "Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model" by LI Cortinez and others and use of using dual-energy X-ray absorptiometry for measurement of fat-free mass. Also discusses the allometric scaling as an alternate method.

Approved analgesic compounds in cattle are not currently available in the United States due to the lack of validated pain assessment methods and marker residue depletion studies. In this study, we compared the pharmacokinetic parameters and effect of preemptive analgesics administered to calves subjected to dehorning with local anesthesia. Holstein steers were randomly assigned to receive one of the following treatments per os ( PO) or intravenously ( IV) ( n = 8/group): meloxicam (1 mg/kg PO), gabapentin (15 mg/kg PO), meloxicam (1 mg/kg), and gabapentin (15 mg/kg) PO, flunixin (2.2 mg/kg IV), or a placebo. Plasma drug, haptoglobin, substance P ( SP) concentrations, serum cortisol concentrations, ocular thermography, mechanical nociceptive threshold ( MNT), and average daily gain ( ADG) were evaluated. Data were analyzed using mixed-effects models and noncompartmental pharmacokinetic analysis. Meloxicam, gabapentin, and meloxicam with gabapentin at the present doses did not reduce cortisol concentrations. Analgesic-treated calves had significantly lower plasma SP concentrations and improved ADG compared with controls. Flunixin calves had reduced circulating cortisol compared with controls. Meloxicam-treated calves showed an increase in MNT at two horn bud sites compared with the other treatments. Analgesics improved ADG and reduced biomarkers of pain, but effects differed by compound and route of administration. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the pharmacokinetics of intravenous flunixin (2.2 mg/kg b.w.), oral meloxicam (1 mg/kg b.w.), oral gabapentin (15 mg/kg b.w.) alone or co-administrated with meloxicam as well as the effects of these compounds on prostaglandin E2 (PGE2) synthesis in calves subjected to surgical dehorning. Plasma samples collected up to 24 h after drug administration were analyzed by liquid chromatography/mass spectrometry, whereas blood PGE2 levels were measured by immunoenzymatic assay. In plasma, the terminal half-live of flunixin, meloxicam and gabapentin were 6.0 h (range, 3.4-11.0 h), 16.7 h (range, 13.7-21.3 h) and 15.3 h (range, 11-32.9 h), respectively. The co-administration of single doses of gabapentin and meloxicam did not seem to affect the pharmacokinetic profile of the two drugs except for gabapentin that reached significantly (P < 0.05) higher maximum serum concentration (Cmax) when co-administered with meloxicam, than when administered alone. At 5, 360 and 720 min after dehorning, a significant (P < 0.01) decrease in PGE2 concentration was observed in flunixin-treated animals compared with control calves. Moreover, circulating log PGE2 concentrations were inversely proportional to log flunixin concentrations (R2 = 0.75; P < 0.0001). None of the other drugs significantly affected blood PGE2 levels. Further assessment of oral meloxicam and gabapentin in established pain models is required to formulate science based analgesic recommendations to enhance animal well-being after dehorning. [ABSTRACT FROM AUTHOR]

The objectives of this study were to determine plasma concentrations and pharmacokinetic parameters of tulathromycin after a single subcutaneous administration in the cervical region in sheep using the cattle labeled dose of 2.5 mg/kg. Six adult healthy ewes were administered tulathromycin on day 0. Blood samples were collected just prior to dosing and at selected time points for 360 h. Plasma samples were analyzed to determine tulathromycin concentrations, and noncompartmental analysis was performed for pharmacokinetic parameters. The mean maximum plasma concentration was 3598 ng/ mL, the mean time to maximum concentration was 1.6 h, and the apparent elimination half-life ranged from 68.1 to 233.1 h (mean 118 h). When comparing our results to goats and cattle, it appears sheep are more similar to cattle in regard to the concentrations observed and pharmacokinetic parameters. In summary, the pharmacokinetics of tulathromycin in sheep appear to be similar enough to those in goats and cattle to recommend similar dosing (2.5 mg/kg SC), assuming that the target pathogens have similar inhibitory concentrations. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the changes in the pharmacokinetics of meloxicam in goat kids who were castrated following the administration of xylazine. Six goat kids were used for the study. The study was performed in two periods according to a longitudinal study, with a 15‐day washout period between periods. In the first period (Control group), 1 mg/kg meloxicam was administered by i.v. route to kids. In the second period (Castration group), the kids were sedated with 0.3 mg/kg xylazine and castration was performed following meloxicam administration. Plasma meloxicam concentration was analyzed using HPLC‐UV, and pharmacokinetic parameters were calculated by noncompartmental model. In the control group following the administration of meloxicam, mean elimination half‐life (t1/2ʎz), area under the concentration–time curve (AUC0−∞), total body clearance (ClT), and volume of distribution at steady‐state (Vdss) were 13.50 ± 0.62 hr, 41.10 ± 2.86 hr µg/ml, 24.43 ± 1.75 ml hr−1 kg−1, and 0.45 ± 0.03 L/kg, respectively. In the castration group, the t1/2ʎz of meloxicam prolonged, AUC0−∞ increased, and ClT and Vdss decreased. In conclusion, the excretion of meloxicam from the body slowed and the t1/2ʎz was prolonged in the castrated goat kids following xylazine administration. However, there is a need to determine the pharmacodynamics of meloxicam in castrated goat kids. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the pharmacokinetics of robenacoxib (RX), a COX‐2 selective non‐steroidal anti‐inflammatory drug, in goats after single intravenous (IV), subcutaneous (SC) and oral (PO) administrations. 5‐month‐old healthy female goats (n = 8) were used. The animals were subjected to a three‐phase, two‐dose (2 mg/kg IV, 4 mg/kg SC, PO) unblinded, parallel study design, with a four‐month washout period between the IV and SC treatment, and a one‐week period between the SC and PO treatment. Blood was drawn from the jugular vein in heparinized vacutainer tubes at 0, 0.085 (for IV only), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10 and 24 h. Plasma RX concentrations were measured using HPLC coupled to a UV multiple wavelength detector, and the data were pharmacokinetically analysed using ThothPro™ 4.3 software in a non‐compartmental approach. Following IV administration, terminal elimination half‐life, volume of distribution and total clearance were 0.32 h, 0.24 L/kg and 0.52 L/h/kg, respectively. For SC and PO, the mean peak plasma concentrations were 2.34 and 3.34 μg/mL at 1.50 and 0.50 h, respectively. The t1/2λz was significantly different between the IV and the extravascular (EV) administrations (0.32 h IV vs 1.37 h SC and 1.63 h PO), suggesting the occurrence of a flip‐flop phenomenon. The significant difference in Vd values between IV (0.24 L/kg) and EV (0.95 L/kg SC and 1.71 L/kg; corrected for F %) routes might have also triggered the t1/2λz difference. The absolute average SC and PO bioavailability were high (98% and 91%, respectively). In conclusion, the IV administration of RX might not be suitable for goats, due to its short t1/2λz. The EV routes, however, appear to be convenient for the drug's occasional use. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of meloxicam was studied in 1‐, 6‐, and 12‐month‐old sheep following a single intravenous (i.v.) dose of 1 mg/kg. The experiments were carried out when the Romanov sheep were 1 month old (7.93 ± 0.91 kg), 6 months old (27.47 ± 4.91 kg), and 12 months old (37.10 ± 3.64 kg). Meloxicam concentration in plasma was determined by high‐performance liquid chromatography and the data collected were evaluated by non‐compartmental kinetic analysis. Meloxicam was detected in the plasma up to 72 h following i.v. administration in all age groups. The volume of distribution at steady state (Vdss) and total body clearance (ClT) were significantly higher in 1‐month‐old (304.87 mL/kg and 16.57 mL/h/kg) than in 12‐month‐old (193.43 mL/kg and 10.50 mL/h/kg) sheep. The area under the concentration–time curve from 0 to 72 h value of meloxicam was lower in 1‐month‐old (58.51 h*μg/mL) compared to 12‐month‐old (92.59 h*μg/mL) sheep. There was no difference in t1/2ʎz value in different age groups. The body extraction ratio values for meloxicam ranged from 0.0186 to 0.0719 after i.v. administration in all age groups. Meloxicam showed an increase in plasma concentration and a decrease in Vdss and ClT in 12‐month‐old compared to 1‐month‐old sheep. Compared to 1‐month‐old and 12‐month‐old sheep, there was no difference in these parameters in 6‐month‐old sheep. Because the age of sheep has an influence on the pharmacokinetics of meloxicam, dosage apparently may need to be adjusted for age. [ABSTRACT FROM AUTHOR]

Florfenicol was administered to five heifers intramuscularly at a dose rate of 20 mg/kg bwt and following wash‐out period, subcutaneously at a dose rate of 40 mg/kg bwt. Blood plasma samples were collected from heifers before injection of florfenicol and up to 120 h after intramuscular (IM) injection and up to 264 h after subcutaneous (SC) injection. Florfenicol concentrations in plasma were measured by high‐performance liquid chromatography with mass‐spectrometric detection. Pharmacokinetics of florfenicol was estimated using non‐compartment analysis. Mean maximum plasma concentration, area under the concentration–time curve and elimination half‐life for florfenicol were 3.2 μg/ml, 101.5 μg × h/ml and 24.5 h, respectively, after IM injection at 20 mg/kg bwt, and 2.7 μg/ml, 194.5 μg × h/ml and 103.8 h, respectively, after SC injection at 40 mg/kg bwt. The obtained results indicated that both administration routes provided comparable bioavailability, whereas SC route was attributed with lower peak levels and markedly slower absorption of florfenicol from injection site. Both administration routes provided plasma florfenicol levels which are expected to be effective against prevalent infectious agents of cattle. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the effects of food and manufacturer on the oral bioavailability of fluconazole in dogs. We hypothesized feeding would decrease fluconazole bioavailability and large variability between manufacturers would occur. Six healthy purpose‐bred dogs aged 2–3 years, weighing 9.5–13.7 kg, were enrolled. Each dog was administered a 100 mg fluconazole tablet from three FDA approved manufacturers (1‐Glenmark, 2‐Citron, 3‐Harris) in a randomized crossover block study, fasted for 12 h (fasted) or 15 min after feeding (fed); each dog had 6 treatments. Blood was collected for 72 h after dosing with a 10‐day washout between treatments. Fluconazole plasma concentrations were determined with mass spectrometry. Overall variability in dose‐normalized drug exposure (AUC/dose) was large (range 1.9–2.9x) within each treatment, while the overall range across all treatments was 3.3‐fold. The inter‐dog variability in the terminal half‐life was also large, 3.1‐fold. The mean fed relative oral bioavailability was lower (82%–90%) compared to fasted for each formulation. Due to the large variability, the formulations were not bioequivalent. These data suggest the variability in the half‐life was a major contributor to the large variability in fluconazole pharmacokinetics in dogs, while the feeding status and manufacturer were minor contributors. [ABSTRACT FROM AUTHOR]

Effective rabbit analgesia is challenging, and there are few studies available on the newer COX‐2 selective NSAIDs, such as robenacoxib. This study aimed to establish the pharmacokinetics of oral and subcutaneous robenacoxib, describe its inhibitory actions on COX enzymes, and develop dosing, using six healthy New Zealand white rabbits. Pharmacokinetics were determined from plasma concentrations after oral administration of robenacoxib (0.83–0.96 mg/kg) and also after subcutaneous administration (2 mg/kg). The inhibitory actions of robenacoxib were evaluated by measuring plasma concentrations of thromboxane B2 (TBX2) and prostaglandin E2 (PGE2) as surrogate markers of cyclooxygenase enzyme isoform inhibition. The mean maximum concentration for oral and subcutaneous administration was 0.23 μg/ml and 5.82 μg/ml, respectively. Oral robenacoxib administration did not demonstrate a significant difference between any time point for PGE2 or TBX2, though subcutaneous administration did for both. There was no significant difference in PGE2 or TBX2 concentrations at any time point when comparing subcutaneous versus oral routes. Although the results support that plasma robenacoxib exceeds the therapeutic levels compared to dogs and cats, there was little significance in the difference in the changes associated with COX‐1 and COX‐2 inhibition. Further studies are warranted to determine appropriate dosing, safety, and efficacy in rabbits. [ABSTRACT FROM AUTHOR]

Ketoprofen is registered in many countries for injectable administration in cattle. Because it is soluble in a wide range of excipients, development of a novel transdermal (TD) ketoprofen formulation was pursued to provide a convenient and pain‐free route of administration in cattle. One hundred and six excipient combinations were screened using in vitro techniques (Franz diffusion cells), with a 20%(w/v) ketoprofen formulation dissolved in a combination of 45%:45%(v/v) ethanol and isopropyl myristate (IPM) and 10%(v/v) eucalyptus oil achieving maximal penetration of ketoprofen through bovine skin. A bioavailability study was then conducted using a randomized cross‐over design (n = 12), including IV, IM (both 3 mg/kg) and TD (10 mg/kg) ketoprofen formulations administered with a one‐week washout period between administrations. The IV and IM formulation pharmacokinetic results were as expected. The CMAX, Tmax and AUC0‐Last were significantly higher (arithmetic mean ± SD) after TD administration (20.0 ± 6.5 μg/ml, 115 ± 17 min and 3940 ± 1324 μg*min/ml, respectively), compared to IM (11.0 ± 4.0 μg/ml, 74 ± 43 min and 2376 ± 738 μg*min/ml, respectively), although there were no significant differences for T½β. However, dose corrected values CMAX and AUCinf were significantly higher for IM compared to TD. The arithmetic mean bioavailability (F) of the transdermal formulation was 50%. The plasma concentration of the TD formulation at a dose of 10 mg/kg was similar to the IM formulation at 3 mg/kg by 30 min post‐dosing with an arithmetic mean ± SD of 7.97 ± 4.38 vs. 8.02 ± 3.55 μg/ml, respectively. The TD formulation was generally well tolerated by cattle, although some local irritation along the site of application was noted after 12 h of exposure during the bioavailability study. Results indicate that this novel TD formulation provides a substantial improvement in administration convenience, may improve animal welfare and end‐user safety through needle‐free administration, and achieves similar plasma pharmacokinetics to the IM product when administered at 10 mg/kg. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the pharmacokinetics (PK) of robenacoxib (RX), a COX‐2 selective non‐steroidal anti‐inflammatory drug, in sheep after single subcutaneous (SC), oral (PO), and intravenous (IV) administration. Five healthy female sheep underwent a three‐phase parallel study design with a washout period of 4 weeks, in which sheep received a 4 mg/kg SC dose in phase 1, a 4 mg/kg PO administration in phase 2, and a 2 mg/kg IV administration in phase 3. Plasma RX concentrations were measured over a 48 h period for each treatment using HPLC coupled to a UV multiple wavelength detector, and the PK parameters were estimated using a non‐compartmental method. Following IV administration, terminal elimination half‐life, volume of distribution at steady state, and total clearance were 2.64 h, 0.077 L/kg, and 0.056 L/h kg, respectively. The mean peak plasma concentrations following SC and PO administrations were 7.04 and 3.01 μg/mL, respectively. The mean bioavailability following SC and PO administrations were 45.98% and 16.58%, respectively. The SC route may be proposed for use in sheep. However, the multi‐dose and pharmacodynamic studies are necessary to establish more accurately its safety and efficacy in sheep. [ABSTRACT FROM AUTHOR]

This study performed population‐pharmacokinetic/pharmacodynamic (pop‐PK/PD) modeling of ketoprofen and flunixin in piglets undergoing routine castration and tail‐docking, utilizing previously published data. Six‐day‐old male piglets (8/group) received either ketoprofen (3.0 mg/kg) or flunixin (2.2 mg/kg) intramuscularly. Two hours post‐dose, piglets were castrated and tail docked. Inhibitory indirect response models were developed utilizing plasma cortisol or interstitial fluid prostaglandin E2 (PGE2) concentration data. Plasma IC50 for ketoprofen utilizing PGE2 as a biomarker was 1.2 μg/ml, and ED50 for was 5.83 mg/kg. The ED50 calculated using cortisol was 4.36 mg/kg; however, the IC50 was high, at 2.56 μg/ml. A large degree of inter‐individual variability (124.08%) was also associated with the cortisol IC50 following ketoprofen administration. IC50 for flunixin utilizing cortisol as a biomarker was 0.06 μg/ml, and ED50 was 0.51 mg/kg. The results show that the currently marketed doses of ketoprofen (3.0 mg/kg) and flunixin (2.2 mg/kg) correspond to drug responses of 33.97% (ketoprofen‐PGE2), 40.75% (ketoprofen‐cortisol), and 81.05% (flunixin‐cortisol) of the maximal possible responses. Given this information, flunixin may be the best NSAID to use in mitigating castration and tail‐docking pain at the current label dose. [ABSTRACT FROM AUTHOR]

Violative chemical residues in edible tissues from food-producing animals are of global public health concern. Great efforts have been made to develop physiologically based pharmacokinetic (PBPK) models for estimating withdrawal intervals (WDIs) for extralabel prescribed drugs in food animals. Existing models are insufficient to address the food safety concern as these models are either limited to 1 specific drug or difficult to be used by non-modelers. This study aimed to develop a user-friendly generic PBPK platform that can predict tissue residues and estimate WDIs for multiple drugs including flunixin, florfenicol, and penicillin G in cattle and swine. Mechanism-based in silico methods were used to predict tissue/plasma partition coefficients and the models were calibrated and evaluated with pharmacokinetic data from Food Animal Residue Avoidance Databank (FARAD). Results showed that model predictions were, in general, within a 2-fold factor of experimental data for all 3 drugs in both species. Following extralabel administration and respective U.S. FDA-approved tolerances, predicted WDIs for both cattle and swine were close to or slightly longer than FDA-approved label withdrawal times (eg, predicted 8, 28, and 7 days vs labeled 4, 28, and 4 days for flunixin, florfenicol, and penicillin G in cattle, respectively). The final model was converted to a web-based interactive generic PBPK platform. This PBPK platform serves as a user-friendly quantitative tool for real-time predictions of WDIs for flunixin, florfenicol, and penicillin G following FDA-approved label or extralabel use in both cattle and swine, and provides a basis for extrapolating to other drugs and species. [ABSTRACT FROM AUTHOR]

The impact of probiotics on difloxacin disposition in Mycoplasma gallisepticum-infected chickens after intravenous and oral administration (10 mg/kg) and its tissue residues after oral administration (10 mg/kg for 5 days) was studied. Difloxacin concentrations were estimated by the high-performance liquid chromatography method. Following intravenous administration of difloxacin, the volume of distribution in probiotic-pretreated Mycoplasma gallisepticum-infected chickens (4.05 ± 0.07) was less than that in non-treated birds (4.16 ± 0.07 mg/µg/mL). The t1/2β of difloxacin in probiotic-pretreated Mycoplasma gallisepticum-infected chickens (4.75 ± 0.09 hours) was significantly longer than that in the non-treated ones (4.55 ± 0.05 hours). The total body clearance of the drug from the plasma of probiotic-pretreated Mycoplasma gallisepticum-infected chickens (0.64 ± 0.00 mg/(µg/mL)/h) was less than that in non-treated ones (0.69 ± 0.01 mg/(µg/mL)/h). The area under the curve extrapolated to last plasma concentration0-t (15.20 ± 0.08 µg/mL/h) and the mean residence time (6.33 ± 0.11 hours) values in probiotic-pretreated Mycoplasma gallisepticum-infected chickens were larger than those in non-treated ones (14.13 ± 0.22 ig/mL/h and 6.02 ± 0.06 hours). The drug was rapidly absorbed orally in probiotic-pretreated Mycoplasma gallisepticum-infected chickens compared to non-treated ones (t1/2ab 1.47 ± 0.02 vs. 1.53 ± 0.05 hours). The peak serum concentration of difloxacin in probiotic-pretreated Mycoplasma gallisepticum-infected chickens was higher than that in non-treated ones (1.46 ± 0.07 vs. 1.18 ± 0.07 µg/mL) and was achieved at shorter time to peak concentration (2.59 ± 0.01 vs. 2.74 ± 0.05 hours). Residue levels of difloxacin were lower in probiotic-pretreated Mycoplasma gallisepticum-infected chickens than in non-treated ones in all examined tissues. [ABSTRACT FROM AUTHOR]

Cats and kittens in animal shelters and catteries regularly suffer from severe gastrointestinal coccidiosis, which can be fatal, and there are no drugs labeled for feline coccidiosis in the United States. Ponazuril, a triazine‐class drug, is increasingly used at a dose of 50 mg/kg/d, orally, for three to five days in shelter environments for coccidiosis. A single oral dose of ponazuril paste 15% (Marquis®; Merial) at 50 mg/kg was administered to six healthy adult cats. Sample analysis was completed via high‐performance liquid chromatography. Plasma concentrations peaked at 7.49 ± 2.06 µg/ml at 14.67 ± 7.45 hr post‐administration. This study shows that ponazuril achieved a plasma concentration that inhibits growth of similar organisms after a single oral dose in cats. Further studies are necessary to optimize dosing for the treatment of clinical coccidiosis in cats. [ABSTRACT FROM AUTHOR]

A flow‐limited physiologically based pharmacokinetic (PBPK) model consisting of seven compartments was established for orbifloxacin in crucian carp to predict drug concentrations after intravenous or intramuscular injections. Physiological and anatomical parameters, including tissue weights and blood flow through different tissues, were obtained from previous literature. The tissue/plasma partition coefficients for orbifloxacin were calculated using the area method or parameter optimization. In addition, their values were 0.9326, 1.1204, 1.1644, 1.3514, and 2.0057 in the liver, skin, muscle, kidney, and the rest of the body compartment, respectively. Based on the current PBPK model, orbifloxacin concentrations were predicted and compared with those previously reported for further validation. In addition, the mean absolute percentage error (MAPE) values were also calculated, with values ranging from 10.21% in plasma to 42.37% in kidneys, indicating acceptable predictions for all tissues and plasma. A local sensitivity analysis was performed, which showed that the parameters related to elimination and distribution were most influential on orbifloxacin concentrations in muscle. This model was finally used to predict plasma and tissue concentrations after multiple intramuscular dosing. The current PBPK model provided a valuable tool for predicting the tissue residues of orbifloxacin in crucian carp following intramuscular injection. [ABSTRACT FROM AUTHOR]

The pharmacokinetics and bioavailability of meloxicam were investigated after single intravascular (IV), intramuscular (IM), and oral dose of 1 mg/kg in rainbow trout broodstock at 11 ± 1.2°C. A total of 36 healthy rainbow trout (Oncorhynchus mykiss) broodstock weighing 1.40 ± 0.26 kg was used for the investigation. Plasma concentrations of meloxicam were measured with high‐performance liquid chromatography‐ultraviolet detection, and pharmacokinetic parameters were calculated by non‐compartmental analysis. The elimination half‐life for IV, IM, and oral routes was 3.63, 4.55, and 2.95 h, respectively. The IV route for meloxicam showed the total clearance of 0.05 L/h/kg and volume of distribution at a steady state of 0.20 L/kg. The peak plasma concentration was 2.97 μg/ml for the IM route and 0.84 μg/ml for the oral route. The bioavailability was 78.45% for the IM route and 21.48% for the oral route. Meloxicam following IM and oral administration displayed short t1/2ʎz. The short t1/2ʎz could be an advantage for the short‐term use in acute conditions. The IM route with the good bioavailability can be preferred for the treatment of various conditions. However, developing new oral formulations with the good bioavailability for meloxicam is necessary to minimize stress and trauma through minimal handling in rainbow trout broodstock. [ABSTRACT FROM AUTHOR]

Alpacas residing in the region endemic for Coccidioides spp. are susceptible to serious, disseminated coccidioidomycosis that may result in death. There is currently no oral antifungal dose recommendation for this species. We used a steady‐state study design to assess the pharmacokinetics of oral generic fluconazole in alpacas dosed q 24 h for 14 days. Cohorts of 2–3 animals received fluconazole from 6 to 15 mg/kg/day, and pharmacokinetic analysis was performed after each group of animals in order to make dose adjustments for the next group. The final three animals were used as confirmation of our dose recommendation. The median Tmax was 7 h, and the median Cmax was 1.25 µg/ml per mg/kg dose. The mean dose‐normalized 24‐h AUC was 41.7 µg h/ml per mg/kg dose (CV = 72%). Based on these results, we recommend alpacas receive a starting dose of oral fluconazole at 10–15 mg/kg/day based on the fluconazole AUC in humans (313–625 µg h/ml). Testing to ascertain putative therapeutic plasma concentrations and monitoring of serum transaminases should be performed. [ABSTRACT FROM AUTHOR]