Disposition of levetiracetam in healthy adult horses.

Nine horses received 20 mg/kg of intravenous (LEVIV ); 30 mg/kg of intragastric, crushed immediate release (LEVCIR ); and 30 mg/kg of intragastric, crushed extended release (LEVCER ) levetiracetam, in a three-way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEVCIR and LEVCER were 50.72 ± 10.60 and 53.58 ± 15.94 µg/ml, respectively. The y-intercept for IV administration was 64.54 ± 24.99 µg/ml. The terminal half-life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEVCIR , LEVCER, and LEVIV , respectively. Volume of distribution at steady-state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg-1  hr-1 . Bioavailability was 96 ± 10, and 98 ± 13% for LEVCIR and LEVCER , respectively. A single dose of Levetiracetam (LEV) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.

Pharmacokinetics of tramadol and its major metabolites in alpacas following intravenous and oral administration.

Tramadol, a centrally acting opioid analgesic with monamine reuptake inhibition, was administered to six alpacas (43-71 kg) randomly assigned to two treatment groups, using an open, single-dose, two-period, randomized cross-over design at a dose of 3.4-4.4 mg/kg intravenously (i.v.) and, after a washout period, 11 mg/kg orally. Serum samples were collected and stored at -80°C until assayed by HPLC. Pharmacokinetic parameters were calculated. The mean half-lives (t(1/2)) i.v. were 0.85±0.463 and 0.520±0.256 h orally. The Cp(0) i.v. was 2467±540 ng/mL, and the C(max) was 1202±1319 ng/mL orally. T(max) occurred at 0.111±0.068 h orally. The area under the curve (AUC(0-∞)) i.v. was 895±189 and 373±217 ng*h/mL orally. The volume of distribution (V(d[area])) i.v. was 5.50±2.66 L/kg. Total body clearance (Cl) i.v. was 4.62±1.09 h; Cl/F for oral administration was 39.5±23 L/h/kg. The i.v. mean residence time (MRT) was 0.720±0.264. Oral adsorption (F) was low (5.9-19.1%) at almost three times the i.v. dosage with a large inter-subject variation. This may be due to binding with the rumen contents or enzymatic destruction. Assuming linear nonsaturable pharmacokinetics and absorption processes, a dosage of 6.7 times orally would be needed to achieve the same i.v. serum concentration of tramadol. The t(1/2) of all three metabolites was longer than the parent drug; however, O-DMT, N-DMT, and Di-DMT metabolites were not detectable in all of the alpacas. Because of the poor bioavailability and adverse effects noted in this study, the oral administration of tramadol in alpacas cannot be recommended without further research.

Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows.

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(½ß) 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.

Distribution of voriconazole in seven body fluids of adult horses after repeated oral dosing.

The purpose of this study was to assess safety and alterations in body fluid concentrations of voriconazole in normal horses on days 7 and 14 following once daily dose of 4 mg/kg of voriconazole orally for 14 days. Body fluid drug concentrations were determined by the use of high performance liquid chromatography (HPLC). On day 7, mean voriconazole concentrations of plasma, peritoneal, synovial and cerebrospinal fluids, aqueous humor, epithelial lining fluid (ELF), and urine were 1.47 +/- 0.63, 0.61 +/- 0.22, 0.70 +/- 0.20, 0.62 +/- 0.26, 0.55 +/- 0.32, 79.45 +/- 69.4, and 1.83 +/- 0.44 microg/mL respectively. Mean voriconazole concentrations in the plasma, peritoneal, synovial and cerebrospinal fluids, aqueous humor, ELF and urine on day 14 were 1.60 +/- 0.37, 1.02 +/- 0.27, 0.86 +/- 0.25, 0.64 +/- 0.21, 0.68 +/- 0.13, 47.76 +/- 45.4 and 3.34 +/- 2.17 respectively. Voriconazole concentrations in the bronchoalveolar cell pellet were below the limit of detection. There was no statistically significant difference between voriconazole concentrations of body fluids when comparing days 7 and 14. Results indicated that voriconazole distributes widely into body fluids.

Pharmacokinetics of lidocaine in serum and milk of mature Holstein cows.

The purpose of this study was to evaluate the pharmacokinetics of lidocaine in mature Holstein cows following an inverted L and caudal epidural nerve block. Plasma and milk concentrations were determined using high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following administration via inverted L nerve block, serum T(max) was 0.521 +/- 0.226 h and serum C(max) was 572 +/- 207 ng/mL. Serum AUC was 1348 +/- 335 ng.h/mL. Apparent serum t((1/2)beta) was 4.19 +/- 1.69 h and MRT was 5.13 +/- 2.33 h with clearance uncorrected for the extent of absorption of 2.75 +/- 0.68 L/kg/h. The last measurable time of lidocaine detection in serum was 8.5 +/- 1.4 h with a mean concentration of 51 +/- 30 ng/mL. Milk T(max) was detected at 1.75 +/- 0.46 h with C(max) of 300 +/- 139 ng/mL. Milk AUC till the last time was 1869 +/- 450 ng.h/mL with the mean AUC milk to AUC serum ratio of 1.439 +/- 0.374. The last measurable time of lidocaine detection in milk was 32.5 +/- 16.2 h with a mean concentration of 46 +/- 30 ng/mL. There was no detectable lidocaine concentration in any samples following caudal epidural administration.

Pharmacokinetics of voriconazole after single dose intravenous and oral administration to alpacas.

Voriconazole is a new antifungal drug that has shown effectiveness in treating serious fungal infections and has the potential for being used in large animal veterinary medicine. The objective of this study was to determine the plasma concentrations and pharmacokinetic parameters of voriconazole after single-dose intravenous (i.v.) and oral administration to alpacas. Four alpacas were treated with single 4 mg/kg i.v. and oral administrations of voriconazole. Plasma voriconazole concentrations were measured by a high-performance liquid chromatography method. The terminal half-lives following i.v. and oral administration were 8.01 +/- 2.88 and 8.75 +/- 4.31 h, respectively; observed maximum plasma concentrations were 5.93 +/- 1.13 and 1.70 +/- 2.71 microg/mL, respectively; and areas under the plasma concentration vs. time curve were 38.5 +/- 11.1 and 9.48 +/- 6.98 mg.h/L, respectively. The apparent systemic oral availability was low with a value of 22.7 +/- 9.5%. The drug plasma concentrations remained above 0.1 microg/mL for at least 24 h after single i.v. dosing. The i.v. administration of 4 mg/kg/day voriconazole may be a safe and appropriate option for antifungal treatment of alpacas. Due to the low extent of absorption in alpacas, oral voriconazole doses of 20.4 to 33.9 mg/kg/day may be needed.

Enhancement of transdermal delivery of phenylbutazone from liposomal gel formulations through deer skin.

Phenylbutazone (PBZ) is a nonsteroidal anti-inflammatory drug used in the treatment of chronic pain and arthritis. Topical and transdermal administration of PBZ would be beneficial in large animals in terms of minimizing gastro-intestinal ulcerations and other side effects, easy administration to legs and joints and minimizing the dose to reduce systemic toxicity of the drug. A topical liposomal preparation with different concentrations of a mono-substituted alkyl amide (MSA) and PBZ was formulated. The formulations were evaluated by in vitro skin-permeation kinetics through deer skin using Franz diffusion cells. By increasing drug loading from 1% to 5% w/w, the steady-state flux (microg/cm(2)/h) of PBZ was increased twofold (P < 0.001). Similarly, by increasing the MSA concentration from 0% to 4%, the steady-state flux (microg/cm(2)/h) of PBZ was increased twofold (P < 0.001). Overall, by increasing the drug load and the use of an appropriate amount of the penetration enhancer, the steady-state flux of PBZ through skin was increased fourfold (P < 0.001). MSA at both 2% and 4% w/w concentrations significantly increased the skin levels of PBZ as compared with control (P < 0.05). In conclusion, MSA served as an effective skin-penetration enhancer in the liposomal gel of PBZ for deer.

Enantiomeric disposition of ketorolac in goats following administration of a single intravenous and oral dose.

The purpose of this study was to investigate the stereospecific pharmacokinetics of ketorolac (KT) in goats following a single 2 mg/kg intravenous (i.v.) dose and a single 6 mg/kg oral dose. A stereoselective high pressure liquid chromatography assay was used to quantify ketorolac plasma concentrations. Pharmacokinetic parameters for both stereoisomers were estimated by model independent methods. Following an i.v. dose, the plasma concentration profiles for the stereoisomers were similar with half-lives of 1.05 +/- 0.62 h for R-KT and 1.05 +/- 0.61 h for S-KT. Clearance values for R- and S-KT after an i.v. dose were 0.53 +/- 0.23 and 0.54 +/- 0.23 L.h/kg, respectively. Following an oral dose, the terminal half-lives were longer with values of 34.08 +/- 11.81 and 33.97 +/- 12.19 h for R-KT and S-KT, respectively. The average bioavailability was 133 +/- 23% for R-KT and S-KT, respectively. The longer half-lives and high apparent bioavailability after oral dosing are suggestive of a slow absorption process in the gastrointestinal tract and recycling. The results indicate that interconversion of the stereoisomers of ketorolac is absent in goats. However, studies with individual isomers are needed before any conclusion can be drawn about the lack of bioinversion.

Stereoselective pharmacokinetics of ketorolac in calves after a single intravenous and oral dose.

The purpose of this study was to establish the stereospecific pharmacokinetics of ketorolac (KT) in calves following a single 2 mg/kg intravenous (i.v.) and a single 8 mg/kg oral dose. Plasma concentrations were determined using a stereoselective HPLC assay. Pharmacokinetic parameters for both the stereoisomers were estimated by model-independent methods. Following an i.v. dose, the plasma concentration profiles of the stereoisomers were similar with half-lives of 5.9 +/- 5.1 h for R-KT and 6.0 +/- 4.9 h for S-KT. Clearance values for R- and S-KT after an i.v. dose were 0.0470 +/- 0.0370 and 0.0480 +/- 0.0370 L/h/kg respectively. After an oral dose, the terminal half-lives were longer than following i.v. administration with values of 14.77 +/- 3.08 and 14.55 +/- 2.95 h for R-KT and S-KT respectively. The average oral bioavailability was 86.5 +/- 20.6% for R-KT and 86.7 +/- 20.3% for S-KT. The results indicate that the stereoisomers of KT have similar pharmacokinetic profiles in calves. Although, unlike humans, bioinversion between KT stereoisomers appears minimal in calves, studies with individual isomers are needed before any firm conclusions can be drawn about this lack of KT bioinversion.

Ceftiofur distribution in plasma and joint fluid following regional limb injection in cattle.

The objective of this study was to evaluate the efficacy of regional intravenous (i.v.) injection of ceftiofur in delivery of this drug to joint fluid and plasma in a limb distal to a tourniquet in five, healthy, adult, mixed breed beef cattle. A tourniquet was positioned in the mid-metacarpal region, and 500 mg of ceftiofur was administered through a catheter in the dorsal common digital vein (DCDV). Plasma samples were collected from the catheter at 15, 30 and 45 min postinjection, and from the abaxial proper palmar vein (APPV) at 15 min postinjection. Synovial fluid was collected from the metacarpal phalangeal joint at 45 min postinjection. Ceftiofur concentrations were estimated in plasma and synovial fluid using high-pressure liquid chromatography (HPLC) and a microbiological assay utilizing Pasteurella haemolytica as the test organism. Both assays indicated highest plasma concentrations of ceftiofur at 15 min, with the concentrations declining with time. Concentrations of ceftiofur in plasma obtained from the DCDV were not significantly different from APPV levels, indicating rapid distribution of ceftiofur within the limb. Microbiological assay always demonstrated higher concentrations of ceftiofur compared with HPLC assay, because the former probably also detected the active metabolites of ceftiofur as well as the parent compound. At 45 min, ceftiofur concentrations determined by HPLC were 251+/-97 and 15+/-5 microg/mL in plasma and synovial fluid, respectively. Regional intravenous injection appears to be a feasible technique to produce rapid distribution of ceftiofur within the limb well above therapeutic concentrations.

Stereospecific pharmacokinetics of free and protein-bound ketoprofen in serum and synovial fluid of horses after intravenous and intramuscular administration.

OBJECTIVE: To determine intravascular and intrasynovial pharmacokinetics of the R and S enantiomers of ketoprofen after i.v. and i.m. administration to horses. ANIMALS: 6 healthy adult mares. PROCEDURE: Horses were weighed and ketoprofen (2.2 mg/kg of body weight) was administered i.v. Blood and synovial fluid samples were obtained and analyzed for concentrations of the R and S enantiomers by means of a modified reverse-phase stereospecific high-pressure liquid chromatographic method. Three weeks later, the procedure was repeated, except that ketoprofen was given IM. Protein binding of ketoprofen enantiomers was determined by means of ultrafiltration. Nonlinear least squares methods were used to calculate pharmacokinetic parameters. RESULTS: Data obtained after i.v. administration best fit an open, two-compartment model. Mean +/- SD S-to-R serum concentration ratios after i.v. and i.m. administration were 1.36 +/- 0.214 and 1.34 +/- 0.245, respectively. Intrasynovial concentrations of the R and S enantiomers of ketoprofen could be measured for only the first 3 hours after i.v. administration; concentrations were less than the limit of quantification by 4 hours after i.v. administration and at all times after i.m. administration. Extent of protein binding of the R enantiomer was not significantly different from extent of protein binding of the S enantiomer; extent of protein binding did not appear to be concentration dependent. Mean free S-to-free R serum concentration ratios, adjusted for protein binding, after i.v. and i.m. administration were 1.58 and 1.56, respectively. CONCLUSIONS: The R and S enantiomers of ketoprofen are rapidly absorbed and eliminated, have low volumes of distribution, and are highly protein bound.

Pharmacokinetics of caffeine in lactating dairy cows.

Because caffeine is metabolized by the hepatic P-450 cytochrome oxidase system, clearance of caffeine is an excellent quantitative test of hepatic function in human beings. It is currently used in much the same way that creatinine clearance is used to assess renal function. Caffeine clearance was measured in lactating dairy cows initially to determine the suitability of caffeine clearance as an indicator of hepatic function in cattle. Pharmacokinetic variables of caffeine were studied in 6 adult lactating dairy cows after i.v. administration of a single dose of caffeine sodium benzoate (2 mg of caffeine/kg of body weight). Caffeine concentration was analyzed by use of an automated enzyme immunoassay. The lower limit of detection of the assay for caffeine in serum was 0.079 micrograms/ml. Serum caffeine concentration-time curves best fit an open two-compartment pharmacokinetic model. Harmonic mean elimination half-life was 3.8 (range, 2.6 to 6.9) hours, and total clearance was 0.118 (range, 0.090 to 0.197) L/kg/h. Milk caffeine concentration was similar to serum concentration 1.5 to 24 hours after caffeine administration. Adverse effects were not observed in cows given caffeine.

Pharmacokinetics of ciprofloxacin in ponies.

The pharmacokinetics of ciprofloxacin was investigated in healthy, mature ponies. Ciprofloxacin was administered intravenously to six ponies at a dose of 5 mg per kg body weight. Seven days later, ciprofloxacin was administered orally to each pony at the same dose. Intravenous ciprofloxacin concentration vs. time data best fit a two-compartment open model with first-order elimination from the central compartment. Mean plasma half-life, based on the terminal phase, was 157.89 min (harmonic mean). Total body clearance of ciprofloxacin was 18.12 +/- 3.99 mL/min/kg. Volume of distribution at steady-state was 3.45 +/- 0.72 L/kg. From the pharmacokinetic data and reported minimum inhibitory concentrations for equine gram-negative pathogens, the appropriate dosage of ciprofloxacin was determined to be 5.32 mg per kg body weight at 12 h intervals. Bioavailability of oral ciprofloxacin in ponies was 6.8 +/- 5.33%. Owing to the poor bioavailability, a dosage regimen could not be proposed for oral ciprofloxacin administration in horses. Ciprofloxacin concentrations were determined in tissues and body fluids at 1, 2 and 4 h after intravenous administration. At all times, tissue concentrations exceeded plasma concentrations of ciprofloxacin. Highest concentrations were achieved in kidneys and urine. Potentially therapeutic concentrations were obtained in cerebrospinal and joint fluid, but low concentrations were achieved in aqueous humour.

The pharmacokinetics and pharmacodynamics of procainamide in horses after intravenous administration.

Six horses were administered either 15 or 20 mg/kg body weight (b.w.) procainamide (PA) as an intravenous (i.v.) dose over 10 min. The plasma concentrations of PA and N-acetylprocainamide (NAPA) as well as the pharmacodynamic effect (prolongation of the QT interval) were monitored. The PA plasma concentrations could be described by a one-compartment model with a t1/2 of 3.49 +/- 0.61 h. The total body clearance of PA was 0.395 +/- 0.090 l/hr/kg and the volume of distribution was 1.93 +/- 0.27 l/kg. As observed after PA administration, NAPA (an active metabolite) had a t1/2 longer than PA of 6.31 +/- 1.49 h. Peak NAPA concentrations (1.91 +/- 0.51 micrograms/ml) occurred at 5.2 h after the PA i.v. dose. The ratio of area under the curves for NAPA to PA was 0.46 +/- 0.15 which is similar to that expected in humans classified as slow acetylators. Percentage change in the QT interval was examined with respect to PA and PA + NAPA plasma concentrations. For PA, % delta QT = 41.2 log (PA) - 13.26 and correlations (r) ranged from 0.77 to 0.91 among the horses. In the case of PA+ NAPA, % delta QT = 57.3 log (PA + NAPA) - 31.83 and ranged from 0.77 to 0.90. No evidence of toxicity was noted with respect to changes in the PR interval.

Caffeine clearance in the horse.

The pharmacokinetic properties of intravenously administered caffeine were studied in 10 horses using a commercially available automated enzyme immunoassay. The harmonic mean for the distribution half-life was 5.2 min (range 1.4-18.7). The harmonic mean for the elimination half-life was 10.18 h (range 6.82-20.92). The harmonic mean of the volume of distribution was 0.32 L/kg (range 0.22-0.53). There was no correlation between the dose of caffeine/kg body weight and the elimination half-life (Spearman's coefficient of rank correlation = 0.19).

Maturation of insulin and glucose responses to normal feeding in foals.

Postprandial insulin and glucose concentrations were measured in 3 Arabian and 3 Thoroughbred foals at 1 day, 1 week, 1 month and 3 months of age. Prefeeding serum insulin concentrations were similar in foals at 1 day (25.9 +/- 5.1 pmol/L), 1 week (32.4 +/- 5.8 pmol/L), and 1 month (38.2 +/- 7.9 pmol/L), but had increased significantly to 131.0 +/- 20.2 pmol/L at 3 months of age (P < 0.05). There was significantly increased serum insulin secretion after a feed in foals at 3 months of age (P < 0.05) when compared with that at younger ages. Prefeeding serum glucose concentrations ranged from 6.0 +/- 0.7 mmol/L at 1 day, to 5.9 +/- 0.9 mmol/L at 1 week, 4.9 +/- 1.7 mmol/L at 1 month, and 4.4 +/- 1.5 mmol/L at 3 months of age. There were lower postprandial glucose concentrations with advancing age. It appeared that there was a period of maturation in pancreatic beta-cell function after birth in foals, which reached adult levels by 3 months of age.

Effect of diet on gentamicin-induced nephrotoxicosis in horses.

Gentamicin sulfate-induced nephrotoxicosis was compared in 2 groups of horses fed different rations. Four horses were fed only alfalfa hay, and 4 other horses were fed only whole oats. Seven days after initiation of the diet, all horses were given gentamicin IV (5 mg/kg of body weight) every 12 hours for 22 days. Urinary gamma-glutamyl-transferase to urinary creatinine (UGGT:UCr) ratio was calculated daily, and serum concentration of gentamicin was measured at 1 and 12 hours after drug administration. Results indicated that horses fed oats had greater renal tubular damage than did horses fed alfalfa. Mean UGGT:UCr for horses fed alfalfa was 47.1 +/- 18.8 and was 100.0 +/- 19.0 for horses fed oats (P = 0.007). The UGGT:UCr in horses fed oats was greater than 100 for a total of 54 days; horses fed alfalfa had UGGT:UCr greater than 100 for only 7 days. Two horses not given gentamicin were fed only oats and 2 were fed only alfalfa. These horses had mean UGGT:UCr of 17.6 +/- 2.2 and 30.5 +/- 3.0, respectively. Mean peak and trough concentrations of gentamicin were statistically different for horses fed oats and those fed alfalfa (peak 23.16 +/- 1.87 and 14.07 +/- 1.79 micrograms/ml, respectively [P = 0.0001], and trough, 1.81 +/- 0.69 and 0.71 +/- 0.70 micrograms/ml, respectively [P = 0.0270]). Mean half-lives of gentamicin (estimated from peak and trough concentrations) for horses fed alfalfa (2.58 +/- 0.26 hours) and horses fed oats (2.88 +/- 0.27 hours) were not significantly different. Horses fed only oats had greater degree of gentamicin-induced nephrotoxicosis than did those fed only alfalfa.