Plasma and urine pharmacokinetics of intravenously administered flunixin in greyhound dogs

Medication control in greyhound racing requires information from administration studies that measure drug levels in the urine as well as plasma, with time points that extend into the terminal phase of excretion. To characterize the plasma and the urinary pharmacokinetics of flunixin and enable regulatory advice for greyhound racing in respect of both medication and residue control limits, flunixin meglumine was administered intravenously on one occasion to six different greyhounds at the label dose of 1 mg/kg and the levels of flunixin were measured in plasma for up to 96 hr and in urine for up to 120 hr. Using the standard methodology for medication control, the irrelevant plasma concentration was determined as 1 ng/ml and the irrelevant urine concentration was determined as 30 ng/ml. This information can be used by regulators to determine a screening limit, detection time and a residue limit. The greyhounds with the highest average urine pH had far greater flunixin exposure compared with the greyhounds that had the lowest. This is entirely consistent with the extent of ionization predicted by the Henderson–Hasselbalch equation. This variability in the urine pharmacokinetics reduces with time, and at 72 hr postadministration, in the terminal phase, the variability in urine and plasma flunixin concentrations are similar and should not affect medication control.     

Comparative pharmacokinetics of amoxicillin administered intravenously to sheep and goats

The pharmacokinetic behavior of sodium amoxicillin was studied after intravenous administration to six sheep and five goats to determine if there are species differences in disposition. The plasma drug concentrations vs. time following intravenous administration of 10 mg/kg were best described by the biexponential equations Cp = 42.9e-0.077.t + 3.68e-0.0134.t for goats, and Cp = 53.5e-0.06.t + 1.69e-0.015.t for sheep. The terminal disposition half-lives for sheep and goats were 46.3 and 66.9 min respectively and were not significantly different. Amoxicillin clearance for sheep and goats were 10.1 and 11.4 ml/min.kg respectively. There were no significant differences between any of the pharmacokinetic parameters measured in sheep and goats.     

Urinary excretion by dogs of intravenously administered simple sugars

Seven simple sugars, commonly used in intestinal function tests, were simultaneously administered intravenously to dogs and their urinary excretion was measured to assess their potential for metabolic degradation. Lactose, lactulose and 3-O-methyl-D-glucose were excreted unchanged, but small proportions of palatinose and sucrose were not, and were assumed to have been metabolised. More than half of the administered D-xylose and a quarter of L-rhamnose was not excreted and was assumed to have been metabolised. These findings may be significant for the interpretation of differential sugar absorption tests and the D-xylose tolerance test.     

Pharmacokinetics and bioavailability of 2-mercaptopropionylglycine administered intravenously and orally in dogs

The pharmacokinetic disposition of 2-mercaptopropionylglycine (2-MPG) given as a single intravenous injection and/or as a single oral dose was studied in 9 normal and 13 cystinuric dogs. After intravenous injection of approximately 10 or 20 mg/kg body weight the pharmacokinetics were best described by a three-exponential function. The first phase involved a distribution process apparently including establishment of drug-plasma protein and drug-tissue binding. The second phase involved rapid renal elimination and 60% of the drug was excreted within 3 h of administration. There was also a slow terminal third phase with a long half-life after both intravenous (t1/2 = 23 h) and oral (t1/2 = 22 h) administration. No dose dependency was observed. A deep pool of reversibly tissue-bound 2-MPG was indicated by a Vss of 3.3 +/- 0.9 l/kg body weight and the long terminal elimination phase. Total clearance was estimated as 4.1 +/- 0.9 ml/min/kg body weight. 2-MPG was eliminated mainly by renal excretion, but there was a difference in recovery of dose between normal and cystinuric dogs. During the first 24 h after intravenous and oral administration, 69% and 54%, respectively, of the drug was recovered in the urine of normal dogs. The corresponding figures in cystinuric dogs were 44% and 29%, respectively. The absolute bioavailability (FAUC) was 88 +/- 20% in normal dogs.     

Evaluation of the pharmacokinetics and bioavailability of intravenously and orally administered amiodarone in horses

OBJECTIVE: To determine the clinical effects and pharmacokinetics of amiodarone after single doses of 5 mg/kg administered orally or intravenously. ANIMALS: 6 healthy adult horses. PROCEDURE: In a cross over study, clinical signs and electrocardiographic variables were monitored and plasma and urine samples were collected. A liquid chromatography-mass spectrometry method was used to determine the percentage of protein binding and to measure plasma and urine concentrations of amiodarone and the active metabolite desethylamiodarone. RESULTS: No adverse clinical signs were observed. After IV administration, median terminal elimination half-lives of amiodarone and desethylamiodarone were 51.1 and 75.3 hours, respectively. Clearance was 0.35 L/kg x h, and the apparent volume of distribution for amiodarone was 31.1 L/kg. The peak plasma desethylamiodarone concentration of 0.08 microg/mL was attained 2.7 hours after IV administration. Neither parent drug nor metabolite was detected in urine, and protein binding of amiodarone was 96%. After oral administration of amiodarone, absorption of amiodarone was slow and variable; bioavailability ranged from 6.0% to 33.7%. The peak plasma amiodarone concentration of 0.14 microg/mL was attained 7.0 hours after oral administration and the peak plasma desethylamiodarone concentration of 0.03 microg/mL was attained 8.0 hours after administration. Median elimination half-lives of amiodarone and desethylamiodarone were 24.1 and 58.6 hours, respectively. CONCLUSION AND CLINICAL RELEVANCE: Results indicate that the pharmacokinetic distribution of amiodarone is multicompartmental. This information is useful for determining treatment regimens for horses with arrythmias. Amiodarone has low bioavailability after oral administration, does not undergo renal excretion, and is highly protein-bound in horses.     

Pharmacokinetics of clindamycin HCl administered intravenously, intramuscularly and subcutaneously to dogs

A buffered aqueous solution of clindamycin Hcl (200 mg/mL) was injected intravenously (i.v.) intramuscularly (i.m.) and subcutaneously (s.c.) in a non-randomized, partial cross-over trial involving six male and six female dogs. Blood samples were collected at conventional, predetermined time periods and serum drug concentrations were determined by microbiological assay. Dogs were observed clinically for signs of pain, and activity of serum creatine phosphokinase (CPK) was monitored after i.m. dosing. The i.v. data from five of the dogs best fitted a two-compartment open-system pharmacokinetic model whereas a non-compartment model was most suitable for analysis of the data from the remaining seven dogs. The mean i.v. elimination half-life (t1/2 beta) and the mean residence time (MRT) were 124 and 143 min, respectively. The mean volume of distribution at steady state (Vss) was 0.86 L/kg. Little pain was recorded upon i.m. injection; mean peak serum drug concentration (Cmax) was 4.4 micrograms/mL, the elimination half-life (t1/2el) was 247 min and the calculated bioavailability (F) was 115% of the i.v. dose. Serum CPK activity was elevated to 25-fold the pretreatment level in samples collected 4, 8 and 12 h after i.m. injection. Pain was not recorded after s.c. drug administration; the mean Cmax of 20.8 micrograms/mL was significantly greater than the corresponding value for the i.m. route, and F was 310%. The s.c. route appears to be superior to the i.m. route in terms of local tolerance and serum drug level; a 10 mg/kg SID treatment regimen is suggested for treatment of canine infections due to clindamycin sensitive bacteria.     

Intraocular pharmacokinetics of intravenously administered marbofloxacin in rabbits with experimentally induced acute endophthalmitis

OBJECTIVE: To compare penetration of IV administered marbofloxacin in intraocular fluids of healthy and inflamed eyes in rabbits with endotoxin-induced endophthalmitis. ANIMALS: 35 pigmented rabbits. PROCEDURES: Endophthalmitis was induced in the right eye via intravitreal administration of Escherichia coli endotoxin. The left eye was a control eye. After 24 hours, a single dose of marbofloxacin (4 mg/kg, IV) was administered. Groups of rabbits (n = 5/group) were euthanized 0.5, 1, 2, 4, 6, 10, and 18 hours later, and blood and ocular fluids were collected. Marbofloxacin concentrations were determined via reverse-phase high-performance liquid chromatography, and pharmacokinetic analysis of the data was performed with a mono-compartmental model. RESULTS: Mean area under the aqueous concentration-time curve was significantly lower in control eyes (1.64 +/- 0.07 microg*h/mL) than in inflamed eyes (3.31 +/- 0.11 microg*h/mL). Similarly, drug penetration into aqueous humor was 33% and 65% for control eyes and inflamed eyes, respectively. Mean area under the vitreous humor concentration-time curve for control eyes(1.75 +/- 0.05 microg*h/mL) was significantly less than for inflamed eyes (2.39 +/- 0.16 microg*h/mL). In the vitreous humor, corresponding penetrations were 34% and 47%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Penetration of marbofloxacin into the aqueous and vitreous humor after IV administration was significantly enhanced by intraocular inflammation, suggesting a role for this antimicrobial in the prophylaxis or treatment of bacterial endophthalmitis caused by susceptible pathogens.     

Pharmacokinetics of pethidine administered intramuscularly and intravenously to dogs over 10 years old

The pharmacokinetics of pethidine administered postoperatively both intravenously and intramuscularly was investigated in dogs aged over 10 years. When the drug was given intravenously (2 mg kg-1), plasma levels declined in a biexponential manner, with an elimination half-life of 62.7 minutes. Following its intramuscular administration at the same dose rate, absorption was very slow and two distinct rates of absorption were observed. Maximum plasma concentrations were not achieved until 33 minutes after drug administration. The elimination of the intramuscularly administered drug was also slow with a t 1/2 beta' of 145.9 minutes. Thus, it seems that in elderly animals pethidine has a long elimination half-life and a slowed rate of absorption. However, the total body clearance of the drug does not seem to be affected by age.     

Effect of organic vehicles on the pharmacokinetics of aminophylline administered intravenously to goats

Aminophylline dissolved in water, propylene glycol, or dimethyl sulfoxide was administered intravenously to goats in a randomized cross-over experiment. Model-dependent and model-independent pharmacokinetic parameters for theophylline were compared on the basis of the solvent used in the dosage form administered. No difference was found in any pharmacokinetic parameter. Thus, we found no evidence for the possibility that the organic solvents studied would confound pharmacokinetic investigations of theophylline and similar lipophilic drugs.     

Sedative effects and pharmacokinetics of detomidine when administered intravenously and intravaginally as a gel in alpacas

ObjectivesTo evaluate the sedative effects and pharmacokinetics of detomidine gel administered intravaginally to alpacas in comparison with intravenously (IV) administered detomidine.Study designRandomized, crossover, blinded experiment.AnimalsA group of six healthy adult female Huacaya alpacas (70.3 ± 7.9 kg).MethodsAlpacas were studied on two occasions separated by ≥5 days. Treatments were IV detomidine hydrochloride (70 μg kg⁻¹; treatment DET–IV) or detomidine gel (200 μg kg⁻¹; treatment DET–VAG) administered intravaginally. Sedation and heart rate (HR) were evaluated at intervals for 240 minutes. Venous blood was collected at intervals for 360 minutes after treatment for analysis of detomidine, carboxydetomidine and hydroxydetomidine using liquid chromatography–tandem mass spectrometry. Measured variables were compared between treatments and over time using mixed model analysis. Data are presented as the mean ± standard error of the mean, and a p value of <0.05 was considered significant.ResultsOnset of sedation was faster in treatment DET–IV (1.6 ± 0.2 minutes) than in treatment DET–VAG (13.0 ± 2.5 minutes). Time to maximum sedation was shorter in treatment DET–IV (8.3 ± 1.3 minutes) than in treatment DET–VAG (25 ± 4 minutes). Duration of sedation was not different between treatments. There was a significant linear relationship between sedation score and plasma detomidine concentration. HR was less than baseline for 60 and 125 minutes for treatments DET–IV and DET–VAG, respectively. The maximal decrease in HR occurred at 15 minutes for both treatments. The mean maximum plasma concentration of detomidine, time to maximum concentration and bioavailability for treatment DET–VAG were 39.6 ng mL⁻¹, 19.9 minutes and 20%, respectively.Conclusions and clinical relevanceDetomidine administration at the doses studied resulted in moderate sedation when administered IV or intravaginally to alpacas.     

Wintertime pharmacokinetics of intravenously and orally administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus)

ObjectiveTo investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).Study designA crossover design with an 11 day washout period.AnimalsA total of eight young male reindeer, aged 1.5–2.5 years and weighing 74.3 ± 6.3 kg, mean ± standard deviation.MethodsThe reindeer were administered meloxicam (0.5 mg kg^–1 IV or orally). Blood samples were repeatedly collected from the jugular vein for up to 72 hours post administration. Plasma samples were analysed for meloxicam concentrations with ultraperformance liquid chromatography combined with triple quadrupole mass spectrometry. Noncompartmental analysis for determination of pharmacokinetic variables was performed.ResultsThe pharmacokinetic values, median (range), were determined. Elimination half-life (t_½) with the IV route (n = 4) was 15.2 (13.2–16.8) hours, the volume of distribution at steady state was 133 (113–151) mL kg^?1 and clearance was 3.98 (2.63–5.29) mL hour^–1 kg^–1. After oral administration (n = 7), the peak plasma concentration (C_max) was detected at 6 hours, t_½ was 19.3 (16.7–20.5) hours, C_max 1.82 (1.17–2.78) μg mL^–1 and bioavailability (n = 3) 49 (46–73)%. No evident adverse effects were detected after either administration route.Conclusions and clinical relevanceA single dose of meloxicam (0.5 mg kg^–1 IV or orally) has the potential to maintain the therapeutic concentration determined in other species for up to 3 days in reindeer plasma.     

The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs

Eighteen male Beagle dogs were randomized to oral (p.o.) or subcutaneous (s.c.) carprofen administration in a two-sequence, two-period crossover design with a 10-day washout between periods. Twenty-five milligrams of carprofen was administered p.o. or s.c. every 12 h for 7 days. Plasma concentrations of carprofen collected after the first and last treatments were determined by high-performance liquid chromatography. Carprofen concentration data were natural log transformed and geometric means were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0--12) following the first dose and Cmax and AUC0--12 following administration of the last dose. Formulations were considered bioequivalent if the 90% confidence interval (CI) of the mean difference for each variable between formulations were within -20% and 25% of the oral formulation. The mean Cmax and AUC0--12 were 16.9 microg/mL and 73.1 microg. h/mL, respectively, following a single oral dose and 8.0 microg/mL and 64.3 microg x h/mL, respectively, following a single s.c. injection. The 90% CI for Cmax (-56.8 to -48.7%) was outside of the bioequivalence criteria whereas the 90% CI for AUC0--12 (-16.3 to -7.5%) was within the bioequivalence criteria. At steady-state, the mean Cmax and AUC0--12 were 18.7 microg/mL and 101.9 microg x h/mL, respectively, following p.o. administration and 14.7 microg/mL and 111.0 microg x h/mL, respectively, following s.c. injection. The 90% CI was outside the bioequivalence criteria for Cmax (-30.8 to -10.8) but within the bioequivalence criteria for AUC0--12 (2.3-15.9%). The results of this study indicate that peak plasma concentrations of carprofen differ when administered p.o. and s.c., but that total drug exposure following a single dose and at steady-state are bioequivalent.     

The pharmacokinetics of ketamine administered intravenously in calves and the modifying effect of premedication with xylazine hydrochloride

Ketamine hydrochloride was administered intravenously to unpremedicated and xylazine-treated calves. The plasma concentrations of ketamine and norketamine were measured at several time intervals after drug administration and the data were fitted to a two-compartment open model. In unpremedicated female calves the distribution and elimination half-lives averaged 6.9 and 60.5 min, respectively. The volume of the central compartment was 1.21 1/kg and the peripheral compartment was 4.04 1/kg. Total body clearance of ketamine averaged 40.4 ml/ min/kg. Premedication with xylazine, whilst not affecting the half-lives signifi-candy, reduced volumes of distribution and the clearance rate of the drug by approximately 50%. The results for the male calves which were premedicated were intermediate between the two groups of female calves.     

Comparison of quality of induction of anaesthesia between intramuscularly administered ketamine, intravenously administered ketamine and intravenously administered propofol in xylazine premedicated cats

The quality of induction of general anesthesia produced by ketamine and propofol, 2 of the most commonly used anaesthetic agents in cats, was assessed. Eighteen cats admitted for elective procedures were randomly assigned to 3 groups and then premedicated with xylazine 0.75 mg/kg intramuscularly before anaesthesia was induced with ketamine 15 mg/kg intramuscularly (KetIM group), ketamine 10 mg/kg intravenously (KetIV group) or propofol 4 mg/kg intravenously (PropIV group). Quality of induction of general anaesthesia was determined by scoring ease of intubation, degree of struggling, and vocalisation during the induction period. The quality of induction of anaesthesia of intramuscularly administered ketamine was inferior to that of intravenously administered ketamine, while intravenously administered propofol showed little difference in quality of induction from ketamine administered by both the intramuscular and intravenous routes. There were no significant differences between groups in the ease of intubation scores, while vocalisation and struggling were more common in cats that received ketamine intramuscularly than in those that received intravenously administered ketamine or propofol for induction of anaesthesia. Laryngospasms occurred in 2 cats that received propofol. The heart rates and respiratory rates decreased after xylazine premedication and either remained the same or decreased further after induction for all 3 groups, but remained within normal acceptable limits. This study indicates that the 3 regimens are associated with acceptable induction characteristics, but administration of ketamine intravenously is superior to its administration intramuscularly and laryngeal desensitisation is recommended to avoid laryngospasms.     

Kinetics of intravenously administered lactose in cows

Four adult Norwegian Red cows were employed in an experiment designed to study the kinetics of lactose. The cows were given 50 g or 60 g of lactose by rapid intravenous injection of a 10 % lactose solution. Blood samples were taken at different intervals after injection, and lactose concentrations in the samples determined by an enzymatic/spectrophotometric method.The mean half-time for lactose elimination was 85.7 min, and for distribution 8.4 min. The mean apparent volume of distribution was calculated to be 0.189 1/kg, and total body clearance 1.55 ml min⁻¹ kg⁻¹.There was evidence to suggest that lactose mainly is eliminated renally from its distribution volume by glomerular filtration in the cow.     

Effect of cimetidine on pharmacokinetics of orally administered cyclosporine in healthy dogs.

OBJECTIVE: To describe the pharmacokinetics of cyclosporine (CyA) in healthy dogs after oral administration alone or in combination with orally administered cimetidine. ANIMALS: 10 healthy adult Beagles. PROCEDURE: Dogs were randomly assigned to receive CyA alone or CyA in combination with cimetidine. After a washout period of 2 weeks, dogs then received the alternate treatment. The CyA plus cimetidine treatment required administration of cimetidine (15 mg/kg of body weight, PO, q 8 h) for 8 days and administration of CyA (5 mg/kg, PO, q 24 h) on days 6 through 8. The CyA treatment alone required administration of CyA (5 mg/kg, PO, q 24 h) for 3 days. On the third day of CyA administration during each treatment, blood samples were collected immediately before (time 0) and 0.5, 1, 1.5, 2, 2.5, 3, 5, 7, 9, 11, 13, 15, 21, and 24 hours after initiating CyA administration. RESULTS: Time until maximum CyA concentration was significantly longer for CyA in combination with cimetidine. Assessment of estimated pharmacokinetic variables revealed a significantly faster rate of change in the distribution phase for CyA in combination with cimetidine. Maximum CyA concentration differed significantly among dogs but did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of our data suggests that cimetidine may affect absorption of orally administered CyA, but overall, it does not affect the pharmacokinetics of CyA. There is considerable variability in the maximum concentration of CyA among dogs, and monitoring of blood concentrations of CyA during treatment is advised.     

犬微量注射泵持续静脉输注舒眠宁的麻醉效果研究

舒眠宁是本实验室研制的一种新型犬、猫用复方麻醉剂,在犬肌肉及静脉推注麻醉的基础上,用微量注射泵持续静脉输注舒眠宁,研究其对犬心血管、呼吸系统及麻醉效果的影响。选用成年杂种犬8只,无麻醉前用药,先静注舒眠宁0.05 mL/kg,然后接微量注射泵持续输注,其输注速率为0.1 mL/(kg.h),持续输注1 h。每隔5 min测定心率、呼吸频率、体温、血压、血氧饱和度、呼气末二氧化碳分压、血气指标,评分镇静、镇痛、肌松效果。结果表明:舒眠宁单次给药后起效迅速,微量注射泵持续输注麻醉平稳,各时相呼吸数、体温、血氧饱和度、呼气末二氧化碳分压、血气指标与麻醉前比较差异不显著(P>0.05),心率、血压个别时相差异显著(P<0.05),但均在正常生理范围内;在整个输注过程中,试验犬镇静、镇痛、肌松效果好。说明舒眠宁单次麻醉起效快,持续微量静脉输注麻醉平稳,外科麻醉期长,苏醒快,对心血管、呼吸系统影响小,未见明显不良反应。