Population pharmacokinetics of methadone hydrochloride after a single intramuscular administration in adult Japanese sika deer (Cervus nippon nippon)

ObjectiveTo assess the population pharmacokinetics of methadone in deer.Study designProspective non-randomized experimental trial.AnimalsTwelve healthy adult sika deer (nine males and three females).MethodsDeer received intramuscular administration of racemic methadone hydrochloride at 0.5 mg kg⁻¹ or 1 mg kg⁻¹. Plasma methadone and its metabolite 2-Ethylidene-1,5-Dimethyl-3,3-Diphenyl-Pyrolidine (EDDP) concentrations were determined by validated liquid chromatography coupled to tandem mass spectrometry methods, at times 0, 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours. Population pharmacokinetics analysis was undertaken using a non-linear mixed effects modelling (NONMEM).ResultsA two-compartment linear disposition model best described observed time-concentration profiles of methadone and EDDP. Population parameter estimates of methadone were elimination clearance (17.3 L hour⁻¹), metabolic clearance (34.6 L hour⁻¹), volume of distribution of compartment 1 (216.0 L) and volume of distribution of compartment 2 (384.0 L). Population parameter estimates of EDDP were elimination clearance (121.0 L hour⁻¹), volume of distribution of compartment 3 (1.08 L) and volume of distribution of compartment 4 (499.5 L). The total clearance and total volume of distribution of methadone and EDDP were 51.9 L hour⁻¹, 121.0 L hour ⁻¹, 600.0 L and 500.6 L, respectively. The methadone terminal elimination half-life was 8.19 hours. No adverse effects were observed after methadone administration.Conclusions and Clinical relevanceFollowing intramuscular injection, methadone was characterized by a large total volume of distribution, high systemic clearance and intermediate terminal half-life in sika deer.     

Pharmacokinetics of buprenorphine and its metabolite norbuprenorphine in neutered male cats anesthetized with isoflurane

ObjectiveTo characterize the pharmacokinetics of buprenorphine and norbuprenorphine in isoflurane-anesthetized cats.Study designProspective experimental study.AnimalsA group of six healthy adult male neutered cats.MethodsCats were anesthetized with isoflurane in oxygen. Catheters were placed in a jugular vein for blood sampling and in a medial saphenous vein for buprenorphine and lactated Ringer’s solution administration. Buprenorphine hydrochloride (40 μg kg^–1 over 5 minutes) was administered intravenously. Blood samples were collected before buprenorphine administration and at various times up to 12 hours after administration. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using nonlinear mixed effect (population) modeling.ResultsA five-compartment model (three compartments for buprenorphine and two compartments for norbuprenorphine) best fitted the data. Typical value (% interindividual variability) for the three buprenorphine volumes of distribution, and the metabolic clearance to norbuprenorphine, the remaining metabolic clearance and the two distribution clearances were 157 (33), 759 (34) and 1432 (43) mL kg^–1, and 5.3 (33), 16.4 (11), 58.7 (27) and 6.0 (not estimated) mL minute^–1 kg^–1, respectively. Typical values (% interindividual variability) for the two norbuprenorphine volumes of distribution, and the norbuprenorphine metabolic and distribution clearances were 1437 (30) and 8428 (not estimated) mL kg^–1 and 48.4 (68) and 235.9 (not estimated) mL minute^–1 kg^–1, respectively.Conclusions and clinical relevanceThe pharmacokinetics of buprenorphine in isoflurane-anesthetized cats were characterized by a medium clearance.     

Nitrogen Retention and Plasma Amino Acid Responses in Mature Geldings Fed Three Dietary Concentrations of Lysine

Six mature Quarter Horse geldings (age, 11.5 ± 4.7 years; body weight [BW], 526 ± 9.2 kg) were used in a replicated 3 × 3 Latin square design to determine the effects of three dietary lysine (Lys) levels on nitrogen (N) retention and plasma amino acid (AA) concentrations. The geldings were fed a basal diet of concentrate and Bermuda grass hay supplemented with synthetic essential amino acids (EAA) to meet estimated requirements for EAA. Geldings were fed one of three dietary treatments: (1) a basal diet deficient in Lys (L−; 0.027 g of Lys•kg⁻¹ BW•d⁻¹); (2) a basal diet supplemented with synthetic Lys to meet National Research Council (NRC; 2007) requirements (L+; 0.036 g of Lys•kg⁻¹ BW•d⁻¹); or (3) a basal diet supplemented at twice the recommended Lys requirement (2 × L; 0.070 g Lys•kg⁻¹ BW•d⁻¹). Horses fed the 2 × L diet had higher N intakes (P = .0056) than horses fed either the L− or L+ diet. However N retention (P = .63) was not different between treatments. Plasma Lys was greater (P < .0001) in 2 × L than L− and L+ diets. Plasma threonine (Thr; P < .01), methionine (Met; P = .03), and total plasma non-EAA (P < .05) concentrations decreased as dietary Lys increased. These results suggest N retention is not a good response criterion for evaluating the AA requirements of mature horses. However, plasma AA data indicated more efficient use of Thr and Met when horses were fed dietary Lys in concentrations greater than the current requirement recommended by the Nutrient Requirements of Horses (National Research Council, 2007).     

Pharmacokinetics of midazolam in sevoflurane-anesthetized cats

ObjectiveTo estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats.Study designProspective pharmacokinetic study.AnimalsA group of six healthy adult, female domestic cats.MethodsAnesthesia was induced and maintained with sevoflurane. After 30 minutes of anesthetic equilibration, cats were administered midazolam (0.3 mg kg^–1) over 15 seconds. Venous blood was collected at 0, 1, 2, 4, 8, 15, 30, 45, 90, 180 and 360 minutes after administration. Plasma concentrations for midazolam and 1-hydroxymidazolam were measured using high-pressure liquid chromatography. The heart rate (HR), respiratory rate (f_R), rectal temperature, noninvasive mean arterial pressure (MAP) and end-tidal carbon dioxide (Pe′CO₂) were recorded at 5 minute intervals. Population compartment models were fitted to the time–plasma midazolam and 1-hydroxymidazolam concentrations using nonlinear mixed effect modeling.ResultsThe pharmacokinetic model was fitted to the data from five cats, as 1-hydroxymidazolam was not detected in one cat. A five-compartment model best fitted the data. Typical values (% interindividual variability where estimated) for the volumes of distribution for midazolam (three compartments) and hydroxymidazolam (two compartments) were 117 (14), 286 (10), 705 (14), 53 (36) and 334 mL kg^–1, respectively. Midazolam clearance to 1-hydroxymidazolam, midazolam fast and slow intercompartmental clearances, 1-hydroxymidazolam clearance and 1-hydroxymidazolam intercompartment clearance were 18.3, 63.5 (15), 22.1 (8), 1.7 (67) and 3.8 mL minute^–1 kg^–1, respectively. No significant changes in HR, MAP, f_R or Pe′CO₂ were observed following midazolam administration.Conclusion and clinical relevanceIn sevoflurane-anesthetized cats, a five-compartment model best fitted the midazolam pharamacokinetic profile. There was a high interindividual variability in the plasma 1-hydroxymidazolam concentrations, and this metabolite had a low clearance and persisted in the plasma for longer than the parent drug. Midazolam administration did not result in clinically significant changes in physiologic variables.     

Population pharmacokinetics of marbofloxacin in horses: preliminary analysis

Population pharmacokinetic of marbofloxacin was investigated on 21 healthy and 16 diseased horses to assess interindividual variability of drug exposure. Demographic, physiologic and disease covariables were tested using mixed effects models. As a preliminary analysis, this study has demonstrated that none of the tested covariables were significant in regression models for compartmental volumes or clearance of distribution, but the clinical status of the horse (healthy/diseased) was a significant covariable (P < 0.01) for systemic clearance. Clearance had a lower mean and a higher variance for diseased horses than healthy horses, with respectively a mean of 0.209 and 0.284 L/h/kg and a coefficient of variation of 52 and 15%. Consequently, variability of AUC was greater in diseased horses. Considering an AUC/MIC ratio below 60 h as a prediction of poor efficacy, a dosage regimen of 2 mg/kg intravenous was deemed to be inadequate for 19% of diseased horses if the MIC of the bacteria was 0.1 microg/mL. However 93% of diseased horses could achieve a ratio above 125 h, predicting a very good efficacy, for the MIC(90) of Enterobacteriacae (0.027 microg/mL).     

The pharmacokinetics of glycopyrrolate in Standardbred horses

The disposition of plasma glycopyrrolate (GLY) is characterized by a three‐compartment pharmacokinetic model after a 1‐mg bolus intravenous dose to Standardbred horses. The median (range) plasma clearance (Clp), volume of distribution of the central compartment (V₁), volume of distribution at steady‐state (Vss), and area under the plasma concentration–time curve (AUC_0‐inf) were 16.7 (13.6–21.7) mL/min/kg, 0.167 (0.103–0.215) L/kg, 3.69 (0.640–38.73) L/kg, and 2.58 (2.28–2.88) ng*h/mL, respectively. Renal clearance of GLY was characterized by a median (range) of 2.65 (1.92–3.59) mL/min/kg and represented approximately 11.3–24.7% of the total plasma clearance. As a result of these studies, we conclude that the majority of GLY is cleared through hepatic mechanisms because of the limited extent of renal clearance of GLY and absence of plasma esterase activity on GLY metabolism. Although the disposition of GLY after intravenous administration to Standardbred horses was similar to that in Thoroughbred horses, differences in some pharmacokinetic parameter estimates were evident. Such differences could be attributed to breed differences or study conditions. The research could provide valuable data to support regulatory guidelines for GLY in Standardbred horses.     

Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane

ObjectiveTo characterize the pharmacokinetics of vatinoxan in isoflurane-anesthetized cats.Study designProspective experimental study.AnimalsA group of six adult healthy male neutered cats.MethodsCats were anesthetized using isoflurane in oxygen. Venous catheters were placed to administer the drug and sample blood. Vatinoxan, 1 mg kg^–1, was administered intravenously over 5 minutes. Blood was sampled before and at various times during and up to 8 hours after vatinoxan administration. Plasma vatinoxan concentration was measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time–concentration data using population methods and nonlinear mixed effect modeling.ResultsA three-compartment model best fitted the data. Typical value (% interindividual variability) for the three volumes (mL kg^–1), the metabolic clearance and two distribution clearances (mL minute^–1 kg^–1) were 34 (55), 151 (35), 306 (18), 2.3 (34), 42.6 (25) and 5.6 (0), respectively. Hypotension increased the second distribution clearance to 10.6.Conclusion and clinical relevanceThe pharmacokinetics of vatinoxan in anesthetized cats were characterized by a small volume of distribution and a low clearance. An intravenous bolus of 100 μg kg^–1 of vatinoxan followed by constant rate infusions of 55 μg kg^–1 minute^–1 for 20 minutes, then 22 μg kg^–1 minute^–1 for 60 minutes and finally 10 μg kg^–1 minute^–1 for the remainder of the infusion time is expected to maintain the plasma concentration within 90%–110% of the plasma vatinoxan concentration previously shown to attenuate the cardiovascular effects of dexmedetomidine (25 μg kg^–1) in conscious cats.     

Pharmacokinetics and bioavailability of moxifloxacin in buffalo calves

The pharmacokinetics of moxifloxacin were investigated in buffalo calves following a single intravenous and intramuscular administration of moxifloxacin (5 mg kg⁻¹ body wt.). Moxifloxacin concentrations in plasma and urine were determined by microbiological assay. Pharmacokinetic analysis of disposition data indicated that intravenous administration data were best described by a two compartment open model, whereas intramuscular administration data were best described by a one compartment open model. Following intravenous administration, the elimination half life (t_1/2β), volume of distribution (Vd_(area)) and total body clearance were 2.69 ± 0.14 h, 1.43 ± 0.08 L kg⁻¹ and 371.2 ± 11.2 ml kg⁻¹ h⁻¹, respectively. Following intramuscular administration, the absorption half life (t_1/2ka) was 0.83 ± 0.20 h. The systemic bioavailability (F) of moxifloxacin in buffalo calves was 80.0 ± 4.08%. Urinary excretion of moxifloxacin was less than 14% after 24 h of administration of drug. In vitro binding of moxifloxacin to plasma proteins of buffalo calves was 28.4 ± 3.77%. From the data of surrogate markers (AUC/MIC, C_max/MIC), it was determined in the buffalo calves that when administered by intravenous or intramuscular route at 5 mg kg⁻¹, moxifloxacin is likely to be effective against bacterial isolates with MIC ? 0.1 μg ml⁻¹.     

Behavioral and Antinociceptive Effects of Alfentanil,Butorphanol, and Flunixin in Horses

To determine the behavioral and antinociceptive effects of narcotic and non-narcotic analgesics administered by intravenous injection in horses, 10 thoroughbred mares weighing between 450 and 550 kg and ranging in age from 8 to 13 years old were analyzed. The effects of alfentanil, butorphanol, flunixin, and saline solution on the general activity of the horses were investigated by measuring spontaneous locomotor activity (SLA) and head height (HH) in two behavior stalls. The antinociceptive effects of alfentanil (0.02 mg kg⁻¹), butorphanol (0.1 mg kg⁻¹), flunixin meglumine (0.5 mg kg⁻¹), and saline were determined by measuring skin twitch reflex latency (STRL) after thermal cutaneous nociceptive stimulation. A paired Student t-test was used to compare SLA and HH between the groups of horses receiving different doses of the same drug at various time points. The Tukey test was used to compare the antinociceptive effect of the treatments. Differences were considered significant when P value was <.05. Horses treated with opioid analgesics demonstrated excitation, as shown by a significant increase in SLA at all doses tested and by neighing and demonstrating attentive attitudes with movement of the ears, stereotypical walking, and ataxia in most of the animals. HH was elevated only in animals treated with alfentanil. Antinociception was observed at 5 and 30 minutes after administration of alfentanil and butorphanol, respectively. Increased SLA was observed at 30 and 90 minutes after administration of alfentanil and butorphanol, respectively. We observed no effect on antinociception in horses given flunixin. In conclusion, this study suggests that alfentanil has a faster onset and a shorter duration than butorphanol; however, both drugs are able to stimulate the central nervous system.     

Evaluation of iohexol clearance used to estimate glomerular filtration rate in clinically normal foals

OBJECTIVE: To determine whether pharmacokinetic analysis of data derived from a single i.v. dose of iohexol could be used to predict creatinine clearance and evaluate simplified methods for predicting serum clearance of iohexol with data derived from 2 or 3 blood samples in clinically normal foals. ANIMALS: 10 healthy foals. PROCEDURE: Serum disposition of iohexol and exogenous creatinine clearance was determined simultaneously in each foal (5 males and 5 females). A 3-compartment model of iohexol serum disposition was selected via standard methods. Iohexol clearance calculated from the model was compared with creatinine clearance. Separate limited-sample models were created with various combinations of sample times from the terminal slope of the plasma versus time profile for iohexol. Correction factors were determined for the limited-sample models, and iohexol clearance calculated via each method was compared with exogenous creatinine clearance by use of method comparison techniques. RESULTS: Mean exogenous creatinine clearance was 2.17 mL/min/kg. The disposition of iohexol was best described by a 3-compartment open model. Mean clearance value for iohexol was 2.15 mL/min/kg and was not significantly different from mean creatinine clearance. A method for predicting serum iohexol clearance based on a 2-sample protocol (3- and 4-hour samples) was developed. CONCLUSIONS AND CLINICAL RELEVANCE: Iohexol clearance can be used to predict exogenous creatinine clearance and can be determined from 2 blood samples taken after i.v. injection of iohexol. Appropriate correction factors for adult horses and horses with abnormal glomerular filtration rate need to be determined.     

Simultaneous infusions of propofol and ketamine in ponies premedicated with detomidine: a pharmacokinetic study

The pharmacokinetics of propofol and ketamine administered together by infusion were investigated in four ponies. Blood propofol and plasma ketamine and norketamine concentrations were measured by high performance liquid chromatography. After premedication with detomidine (20 μg kg⁻¹) anaesthesia was induced with ketamine (2·2 mg kg ⁻¹ intravenously). The trachea was intubated and the ponies were allowed to breathe 100 per cent oxygen. A bolus dose of propofol (0·5 mg kg⁻¹) was then administered intravenously and propofol and ketamine were infused for 60 and 45 minutes, respectively. The average mean infusion rate of propofol was 0·136 mg kg⁻¹ min⁻¹, and the ketamine infusion rate was maintained at 50 μg kg⁻¹ min⁻¹. The mean (SD) elimination half-lives of propofol and ketamine were 69·0 (8·0) and 89·8 (26·7) minutes, the mean volumes of distribution at steady state were 0·894 (0·161) litre kg⁻¹ and 1·432 (0·324) litre kg⁻¹ the mean body clearances were 33·1 (4·5) and 23·9 (3·8) ml kg⁻¹ min⁻¹ and the mean residence times for the infusion were 87·1 (4·1) and 110·7 (8·2) minutes, respectively. Norketamine, the main metabolite of ketamine, was detected throughout the sampling period. The mean residence time for norketamine was 144 (16) minutes. All the ponies recovered quickly from the anaesthesia; the mean times to sternal recumbency and standing were 11·1 (5·3) and 30·0 (20·8) minutes, respectively, from the end of the infusion.     

Intravenous and sublingual buprenorphine in horses: pharmacokinetics and influence of sampling site

ObjectiveTo describe the pharmacokinetics and adverse effects of intravenous (IV) and sublingual (SL) buprenorphine in horses, and to determine the effect of sampling site on plasma concentrations after SL administration.Study designRandomized crossover experiment; prospective study.AnimalsEleven healthy adult horses between 6 and 20 years of age and weighing 487–592 kg.MethodsIn the first phase; buprenorphine was administered as a single IV or SL dose (0.006 mg kg^?1) and pharmacokinetic parameters were determined for each route of administration using a noncompartmental model. In the second phase; the jugular and lateral thoracic veins were catheterized for simultaneous venous blood sampling, following a dose of 0.006 mg kg^?1 SL buprenorphine. For both phases, plasma buprenorphine concentrations were measured using ultra-performance liquid chromatography with mass spectrometry. At each sampling period, horses were assessed for behavioral excitement and gastrointestinal motility.ResultsFollowing IV administration, buprenorphine mean ± SD half-life was 5.79 ± 1.09 hours. Systemic clearance (Cl) following IV administration was 6.13 ± 0.86 mL kg^?1 minute^?1 and volume of distribution at steady-state was 3.16 ± 0.65 L kg^?1. Following IV administration, horses showed signs of excitement. Gastrointestinal sounds were decreased following both routes of administration; however, none of the horses exhibited signs of colic. There was a significant discrepancy between plasma buprenorphine concentrations measured in the jugular vein versus the lateral thoracic vein following phase 2, thus pharmacokinetic parameters following SL buprenorphine are not reported.Conclusions and clinical relevanceBuprenorphine has a long plasma half-life and results in plasma concentrations that are consistent with analgesia in other species for up to 4 hours following IV administration of this dose in horses. While buprenorphine is absorbed into the circulation following SL administration, jugular venous sampling gave a false measurement of the quantity absorbed and should not be used to study the uptake from SL administration.     

PK-PD integration and modeling of marbofloxacin in sheep

The fluoroquinolone antimicrobial drug, marbofloxacin, was administered intravenously (IV) and intramuscularly (IM) to sheep at a dose rate of 2 mg kg⁻¹ in a 2-period cross-over study. Using a tissue cage model of inflammation, the pharmacokinetic properties of marbofloxacin were established for serum, inflamed tissue cage fluid (exudate) and non-inflamed tissue cage fluid (transudate). For serum, after IV dosing, mean values for pharmacokinetic parameters were: clearance 0.48 L kg⁻¹ h⁻¹; elimination half-life 3.96 h and volumes of distribution 2.77 and 1.96 L kg⁻¹, respectively, for V_darea and V_ss. After IM dosing mean values for pharmacokinetic variables were: absorption half-time 0.112 h, time of maximum concentration 0.57 h, terminal half-life (T½el) 3.65 h and bioavailability 106%. For exudate, mean T½el values were 12.38 and 13.25 h, respectively, after IV and IM dosing and for transudate means were 13.39 h (IV) and 12.55 h (IM).The in vitro minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) and ex vivo time-kill curves for marbofloxacin in serum, exudate and transudate were established against a pathogenic strain of Mannheimia haemolytica. Integration of in vivo pharmacokinetic data with MIC determined in vitro provided mean values of area under curve (AUC)/MIC ratio for serum, exudate and transudate of 120.2, 156.0 and 156.6 h after IV dosing and 135.5, 165.3 and 146.2 h after IM dosing, respectively. After IM administration maximum concentration (C_max)/MIC ratios were 21.1, 6.76 and 5.91, respectively, for serum, exudate and transudate. The ex vivo growth inhibition data after IM administration were fitted to the sigmoid E_max (Hill) equation to provide values for serum of AUC_24 h/MIC producing, bactericidal activity (22.51 h) and virtual eradication of bacteria (35.31 h). It is proposed that these findings might be used with MIC₅₀ or MIC₉₀ data to provide a rational approach to the design of dosage schedules which optimise efficacy in respect of bacteriological as well as clinical cures.     

Heart Rate,Net Cost of Transport,and Metabolic Power in Horse Subjected to Different Physical Exercises

Considering that workload can also be expressed in terms of estimated net transport cost (COT), the metabolic energy needed to transport unit mass of animal unit distance, the aim of our study was to describe the heart rate (HR), COT, and the total metabolic power requirement per kilogram (P) during different exercises (aerobic, anaerobic, and aerobic–anaerobic exercises). On the basis of their attitude, 25 horses, divided into five equal groups, traveled a distance of 6,000 m, walking at 100 m/min in a horse walker (group A); performed 20-minute treadmill walk at 130 m/min, average speed up gradient of 5% (group B); performed a 700-m-long show jumping course with 13 fences (group C); traveled a distance of 2,100 m galloping at a speed of 700 m/min (group D); and traveled a distance of 2,000 m trotting at a speed of 660 m/min (group E). On each horse, HR was continuously recorded by means of an equine HR monitor. COT was calculated with the following formula: (HR − 35) kg⁻¹ m⁻¹ 10³; P was calculated applying the formula: (HR − 35) min⁻¹ kg⁻¹. COT and P values, estimated from the mean HR, measured continuously during each experimental condition showed no linear relationship with HR and speed. The use of combined weight of horse and tack (group C and D) and horse, tack, and sulky (group E) statistically changed the results of formula application. COT and P change in different exercises and provide additional information about performance in athletic horses.     

Alfaxalone for total intravenous anaesthesia in horses

Objective

To determine the suitability of alfaxalone total intravenous (IV) anaesthesia in horses and concurrently evaluate infusion rates, cardiovascular effects, pharmacokinetics and the quality of the anaesthetic recovery period.

Nonlinear mixed‐effects pharmacokinetic modeling of the novel COX‐2 selective inhibitor vitacoxib in dogs

The objective of this study was to develop a nonlinear mixed‐effects model of vitacoxib disposition kinetics in dogs after intravenous (I.V.), oral (P.O.), and subcutaneous (S.C.) dosing. Data were pooled from four consecutive pharmacokinetic studies in which vitacoxib was administered in various dosing regimens to 14 healthy beagle dogs. Plasma concentration versus time data were fitted simultaneously using the stochastic approximation expectation maximization (SAEM) algorithm for nonlinear mixed‐effects as implemented in Monolix version 2018R2. Correlations between random effects and significance of covariates on population parameter estimates were evaluated using multiple samples from the posterior distribution of the random effects. A two‐compartment mamillary model with first‐order elimination and first‐order absorption after P.O. and S.C. administration, best described the available pharmacokinetic data. Final parameter estimates indicate that vitacoxib has a low‐to‐moderate systemic clearance (0.35 L hr^?1 kg^?1) associated with a low global extraction ratio, but a large volume of distribution (6.43 L/kg). The absolute bioavailability after P.O. and S.C. administration was estimated at 10.5% (fasted) and 54.6%, respectively. Food intake was found to increase vitacoxib oral bioavailability by a fivefold, while bodyweight (BW) had a significant impact on systemic clearance, thereby confirming the need for BW adjustment with vitacoxib dosing in dogs.     

Disposition and dosage regimen of cephaloridine in calves

The disposition and dosage regimen of cephaloridine were investigated in healthy calves following a single intramuscular administration of 10 mg/kg. The absorption halflife, climination halflife, apparent volume of distribution and total body clearance were 0.107±0.025 h, 2.08±0.14 h, 0.70±0.07L kg^-1 and 235.8±21.9 ml kg^-1 h^-1, respectively. Therapeutic plasma levels (1 g/ml) were maintained for up to 7 h. A satisfactory intramuscular dosage regimen for cephaloridine in calves would be 10 mg/kg repeated at 8 h intervals.     

Disposition kinetics and urinary excretion of gentamicin in buffalo bulls (Bubalus bubalis)

The disposition kinetics and urinary excretion of gentamicin sulphate were studied in young buffalo bulls following a single intramuscular administration of the drug at 5 mg kg^-1 body weight. The time course of the serum gentamicin concentration was adequately described by the one-compartment open model. The values of the absorption and elimination halflives were 12.2±2.2 and 167.0±29.7 min respectively. The apparent volume of distribution was 0.29±0.01 L kg^-1. During the first 12 h, 63% of the total administered dose was excreted in urine. On the basis of the kinetic data, a satisfactory intramuscular dosage regimen for gentamicin sulphate would be at least 6 mg kg^-1 body weight repeated at 8 h intervals.     

Pharmacokinetics of low-dose methotrexate in horses

This study aimed to investigate both the pharmacokinetic behavior and tolerance of methotrexate (MTX) in horses to design a specific dosing regimen as a new immunomodulatory drug for long-term treatment. To determine the primary plasma pharmacokinetic variables after single intravenous, subcutaneous or oral administration, six horses were administered 0.3 mg/kg MTX in a crossover design study. After a 10-week washout, MTX was administered subcutaneously to three of the six previously treated horses at a dose of 0.3 mg/kg once per week for 3 months. In both studies, MTX and metabolite concentrations were measured using LC-MS/MS. The absolute bioavailability of MTX was 73% following subcutaneous administration but less than 1% following oral administration. The plasma clearance was 1.54 ml min⁻¹ kg⁻¹ (extraction ratio = 2%). After 24 hr, plasma concentrations were below the LOQ. No adverse effects were noted except for a moderate reversible elevation in liver enzymes (GLDH). With regards to the main metabolites of MTX, very low concentrations of 7-hydroxy-MTX were found, whereas polyglutamated forms (mainly short chains) were found in red blood cells. A subcutaneous dose of 0.2 mg kg⁻¹ week⁻¹ may be safe and relevant in horses, although this has yet to be clinically confirmed.