A comparative study of the pharmacokinetics of thiopental in the rabbit, sheep and dog

The central arterial pharmacokinetics of thiopental were studied in six rabbits, six sheep and six dogs after a short infusion at approximately 10 mg/kg min. Thiopental was infused to a defined electro-encephalographic endpoint (EEG burst suppression). The time to reach early burst suppression was longer in the dog (3.9 +/- 0.5 min) compared with the sheep (3.0 +/- 0.6 min) and the rabbit (2.5 +/- 0.5 min). The total dose required to produce the same level of EEG activity was higher in the dog (35.9 +/- 6.8 mg/kg) compared with the sheep (24.3 +/- 5.3 mg/kg) and the rabbit (21.6 +/- 6.8 mg/kg). The plasma concentration-time data for each animal was fitted using non-linear regression to a bi- or tri-exponential function. In all animals, the plasma-time profile was best described as a tri-exponential decay. The initial volume of distribution was similar in all three species (rabbit, 38.6 +/- 10.0 mg/kg; sheep, 44.5 +/- 9.1 ml/kg; dog, 38.1 +/- 18.4 ml/kg). The maximum arterial plasma thiopental concentration achieved at EEG burst suppression was higher in the sheep (221.8 +/- 27.9 micrograms/ml) than the dog (164.7 +/- 29.9 micrograms/ml) or the rabbit (112.3 +/- 15.1 micrograms/ml). Thiopental distribution clearance was slower in the sheep (43.6 +/- 15.1 ml/min/kg) compared with the rabbit (110.5 +/- 18.7 ml/min kg) and the dog (97.2 +/- 47.2 ml/min kg). Elimination half-life was extended in the sheep (251.9 +/- 107.8 min) and dog (182.4 +/- 57.9 min) relative to the rabbit (43.1 +/- 3.4 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative pharmacokinetics of enrofloxacin in mice, rats, rabbits, sheep, and cows.

OBJECTIVE: To compare pharmacokinetic variables of enrofloxacin (ENR) after IV administration in mice, rats, rabbits, sheep, and cows and to perform allometric analysis of ENR. ANIMALS: 47 mice, 5 rats, 5 rabbits, 5 sheep, and 5 cows. PROCEDURE: Serially obtained plasma samples were assayed for ENR concentration, using high-performance liquid chromatography. In vitro plasma protein binding was determined by ultrafiltration. Plasma ENR concentration versus time curves were fitted by use of nonlinear least-squared regression analysis. Pharmacokinetic variables were correlated further with body weight. RESULTS: In all species studied, the best fit was obtained for a two-compartment open model; ENR half-life ranged from 89 minutes in mice to 169 minutes in cows. Volume of distribution was large in all species studied, with values ranging from 10.5 L/kg in mice to 1.5 L/kg in sheep. Body clearance ranged from 68.1 ml/min/kg for mice to 4.6 ml/min/kg for sheep. Unbound ENR was found to be (mean +/- SD) 58+/-2, 50+/-6, 50+/-2, 31+/-2, and 40+/-3% in plasma of mice, rats, rabbits, sheep, and cows, respectively. The only pharmacokinetic variables that could be correlated with body weight were elimination half-life, clearance, and volume of distribution. Allometric exponents denoting proportionality of half-life, body clearance, and volume of distribution with body weight were 0.06, 0.82, and 0.90, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: An allometric approach could provide a suitable method for determining a scale for ENR pharmacokinetics among various mammalian species. This would faciliatate the administration of appropriate doses of ENR to all animals.     

Pharmacokinetics of enrofloxacin after intravenous and intramuscular injection in rabbits.

The pharmacokinetics and bioavailability of enrofloxacin were determined after IV and IM administration of 5 mg/kg of body weight to 6 healthy adult rabbits. Using nonlinear least-squares regression methods, data obtained were best described by a 2-compartment open model. After IV administration, a rapid distribution phase was followed by a slower elimination phase, with a half-life of 131.5 +/- 17.6 minutes. The mean body clearance rate was 22.8 +/- 6.8 ml/min/kg, and the mean volume of distribution was 3.4 +/- 0.9 L/kg. This large volume of distribution and the K12/K21 ratio close to 1, indicated that enrofloxacin was widely distributed in the body, but not retained in tissues. After a brief lag period (6.2 +/- 2.86 min), IM absorption was rapid (4.1 +/- 1.3 min) and almost complete. The mean extent of IM absorption was 92 +/- 11%, and maximal plasma concentration of 3.04 +/- 0.34 micrograms/ml was detected approximately 10 minutes after administration.     

Pharmacokinetics and bioavailability of cephalothin in horse mares

The pharmacokinetics and bioavailability of cephalothin given to 6 horse mares at a dosage level of 11 mg/kg of body weight IV or IM were investigated. The disposition of cephalothin given IV was characterized by a rapid disposition phase with a mean half-life of 2.89 minutes and a subsequent slower elimination phase with a mean half-life of only 14.7 minutes. The mean residence time of cephalothin was 10.6 +/- 2.11 minutes. The total plasma clearance of cephalothin averaged 13.6 ml/min/kg and was caused by metabolism and renal elimination. Renal clearance of cephalothin averaged 1.32 ml/min/kg and accounted for elimination of about 10.1% of the administered dose. The volume of distribution at steady state averaged 151 mg/kg. Plasma protein binding of cephalothin at a concentration of 10 micrograms/ml averaged 17.9 +/- 2.5%. Cephalothin was rapidly metabolized to desacetylcephalothin. Maximum plasma desacetylcephalothin concentrations were observed in the blood samples collected 5 minutes after IV doses and averaged 22.9 micrograms/ml. The apparent half-life of desacetylcephalothin in plasma was 41.6 minutes and its renal clearance averaged 4.49 +/- 2.43 ml/min/kg. An average of 33.9% of the dose was recovered in the urine as desacetylcephalothin. The maximum plasma cephalothin concentration after IM administration was 11.3 +/- 3.71 micrograms/ml. The terminal half-life was 47.0 minutes and was longer than the half-life after IV administration. The bioavailability of cephalothin given IM ranged from 38.3% to 93.1% and averaged 65.0 +/- 20.5%.     

Pharmacokinetics and bioavailability of cefazolin in horses

The pharmacokinetics and bioavailability of cefazolin given (IV, IM) to horses at the dosage of 11 mg/kg were investigated. The disposition of cefazolin given by IV route was characterized by a rapid disposition phase with a half-life of 5 to 10 minutes and a subsequent slower elimination phase with a half-life of 35 to 46 minutes. The total plasma clearance of cefazolin averaged 5.51 ml/min/kg and was due mainly to renal clearance (5.39 ml/min/kg) of unchanged drug. The volume of distribution at steady-state averaged 188 ml/kg. Plasma protein binding of cefazolin at a concentration of 10 micrograms/ml averaged 8.1 +/- 1.9%. Given by the IM route, cefazolin was rapidly absorbed; the extent of bioavailability was 78.4 +/- 18.8%, and the terminal half-life ranged from 49 to 99 minutes. Thus, cefazolin was extensively absorbed, but was eliminated more slowly than after IV administration.     

Pharmacokinetic variables of mivacurium chloride after intravenous administration in dogs.

OBJECTIVE: To determine pharmacokinetic variables of mivacurium chloride after IV administration in dogs. ANIMALS: 5 healthy Labrador Retrievers. PROCEDURE: Anesthesia was induced with thiopental and maintained with halothane in oxygen. Dogs were ventilated mechanically to an end-tidal P(CO)2 value between 35 and 40 mm Hg. Heart rate, direct blood pressure, and arterial pH were recorded throughout the experiment. Core temperature, end-tidal P(CO)2, and halothane concentration were kept constant throughout the experiment. Paired blood samples for determination of plasma cholinesterase activity were collected prior to administration of a bolus of mivacurium (0.05 mg/kg of body weight), which was administered IV during a 2-second period. Arterial blood samples were obtained for determination of plasma mivacurium concentration 0, 1, 3, 5, 10, 30, 60, 120, 150, and 180 minutes after administration of mivacurium. Blood was collected into tubes containing EDTA and 0.25% echothiophate. Mivacurium concentration was determined, using reversed-phase high-performance liquid chromatography. RESULTS: For the trans-trans isomer, mean +/- SEM volume of distribution was 0.18+/-0.024 L/kg, median half-life was 34.9 minutes (range, 26.7 to 53.5 minutes), and clearance was 12+/-2 ml/min/kg. For the cis-trans isomer, values were 0.31+/-0.05 L/kg, 43.4 minutes (range, 31.5 to 69.3 minutes), and 15+/-2 ml/min/kg, respectively. Values for the cis-cis isomer were not calculated, because it was not detectable in plasma 60 minutes after mivacurium administration in all 5 dogs. CONCLUSIONS AND CLINICAL RELEVANCE: The transtrans and cis-trans isomers of mivacurium have a long half-life and slow clearance in healthy dogs anesthetized with halothane.     

Pharmacokinetics and cardiopulmonary effects of fentanyl in isoflurane-anesthetized rhesus monkeys (Macaca mulatta)

OBJECTIVE: To determine pharmacokinetics and selected cardiopulmonary effects of fentanyl in isoflurane-anesthetized rhesus monkeys. ANIMALS: 6 adult male rhesus monkeys. PROCEDURE: Fentanyl (8 mg/kg of body weight, IV) was administered to 6 monkeys anesthetized with isoflurane. End-tidal isoflurane concentration and esophageal temperature were kept constant, and ventilation was mechanically assisted. Heart rate, rhythm, aortic blood pressure, and blood pH, gas, and fentanyl concentrations were determined before and for 8 hours after administration of fentanyl. Pharmacokinetics of fentanyl were derived by use of noncompartmental methods based on statistical moment theory. RESULTS: Heart rate and mean arterial pressure decreased transiently following fentanyl administration. Maximal decreases were observed 5 to 15 minutes after administration. Arterial pH, Paco2, and Pao2 ranged from 7.46 +/- 0.04 to 751 +/- 0.05 units, 29.2 +/- 3 to 34.6 +/- 4.4 mm Hg, and 412.6 +/- 105.3 to 482.9 +/- 71.2 mm Hg, respectively. The clearance, volume of distribution area, volume of distribution steady state, mean residence time, area under the curve, elimination rate constant, and half-life were 32.5 +/- 2.48 ml/kg/min, 9.04 +/- 1.91 L/kg, 70 +/- 1.2 L/kg, 218.5 +/- 35.5 min, 0.247 +/- 0.019 mg/ml/min, 0.004 + 0.001/min, and 192.0 +/- 33.5 min, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Transient but potentially clinically important decreases in heart rate and mean arterial pressure were observed following fentanyl administration. Distribution and clearance data were similar to those reported for dogs and humans.     

Pharmacokinetics of probenecid and the effect of oral probenecid administration on the pharmacokinetics of cefazolin in mares

The pharmacokinetics and bioavailability of probenecid given IV and orally at the dosage level of 10 mg/kg of body weight to mares were investigated. Probenecid given IV was characterized by a rapid disposition phase with a mean half-life of 14.0 minutes and a subsequent slower elimination phase with a mean half-life of 87.8 minutes in 5 of 6 mares. In the remaining mare, a rapid disposition phase was not observed, and the half-life of the elimination phase was slower (172 minutes). The mean residence time of probenecid averaged 116 minutes for all 6 mares and 89.2 minutes for the 5 mares with biphasic disposition. The total plasma clearance of probenecid averaged 1.18 +/- 0.49 ml/min/kg, whereas renal clearance accounted for 42.6 +/- 9.3% of the total clearance. The steady-state volume of distribution of probenecid averaged 116 +/- 28.2 ml/kg. Plasma protein binding of probenecid was extensive, with 99.9% of the drug bound at plasma probenecid concentrations of 10 micrograms/ml. The maximum plasma probenecid concentration after 10 mg/kg orally averaged nearly 30 micrograms/ml. The half-life of probenecid after oral administration was approximately 120 minutes. Oral bioavailability was good with greater than 90% of the dose absorbed. The effect of probenecid on tubular secretion of organic anions was evaluated by determining the pharmacokinetics of IV cefazolin (11 mg/kg) administered alone and 15 minutes after probenecid (10 mg/kg orally). Treatment with probenecid did not affect pharmacokinetic values of cefazolin. This failure of probenecid to alter the pharmacokinetics of cefazolin may be caused by insufficient plasma probenecid concentrations after the oral dose.     

Pharmacokinetics of phenobarbital in the horse

Pharmacokinetics of phenobarbital was examined in 6 mature horses after 12 mg of phenobarbital/kg of body weight was infused over 20 minutes. Biexponential decrease in serum phenobarbital concentrations was observed with a distribution-phase half-life of 0.101 +/- 0.086 hour (mean +/- SD) and a terminal-phase elimination half-life of 18.3 +/- 3.65 hours. The volume of distribution at steady state was 0.803 +/- 0.070 L/kg. Total body clearance of phenobarbital was 30.8 +/- 6.2 ml/h/kg. The high clearance in the horse seems to explain the markedly shorter half-life of phenobarbital in this species. Seemingly, 6.65 mg of phenobarbital/kg as a 20-minute infusion given every 12 hours would provide approximate peaks of 29 micrograms/ml and troughs of 15 micrograms/ml. A loading dose of 12 mg of phenobarbital/kg would be appropriate for this regimen.     

Bioavailability of gentamicin in dogs after intramuscular or subcutaneous injections

Healthy adult mixed-breed dogs, assigned to 2 groups of 6 dogs each, were given 3 mg of gentamicin sulfate/kg of body weight on 3 injection days 7 days apart. Group 1 was given gentamicin by rapid IV injection, by injection into the belly of the longissimus muscle at the first lumbar vertebrae (IM site 1), and by injection in the belly of the biceps femoris muscle (IM site 2). Group 2 was given gentamicin by rapid IV injection, by SC injection into the space over the cranial angle of the scapula on the midline (SC site 1), and by SC injection just caudal to the crest of the ilium (SC site 2). Pharmacokinetic values (mean +/- SD) from 12 dogs given gentamicin IV were 54.4 +/- 15.4 minutes for the effective half life, 2.29 +/- 0.48 ml/kg/min for clearance, and 172 +/- 25.4 ml/kg for volume of distribution at steady state. Bioavailability (93.92 to 96.65%) and peak plasma gentamicin concentration (9.43 to 10.89 micrograms/ml) were independent of injection site, but time to peak concentration when gentamicin was given at SC site 2 (43.33 minutes) was significantly (P less than 0.05) longer than that when gentamicin was given at IM site 1 (27.50 minutes). Absorption half-life was shorter after injections were given at both IM sites (8.9 and 9.8 minutes) than after injection was given at SC site 2 (18 minutes).     

Influence of gastrointestinal tract disease on pharmacokinetics of lidocaine after intravenous infusion in anesthetized horses

OBJECTIVE: To determine the disposition of lidocaine after IV infusion in anesthetized horses undergoing exploratory laparotomy because of gastrointestinal tract disease. ANIMALS: 11 horses (mean +/- SD, 10.3 +/- 7.4 years; 526 +/- 40 kg). PROCEDURE: Lidocaine hydrochloride (loading infusion, 1.3 mg/kg during a 15-minute period [87.5 microg/kg/min]; maintenance infusion, 50 microg/kg/min for 60 to 90 minutes) was administered IV to dorsally recumbent anesthetized horses. Blood samples were collected before and at fixed time points during and after lidocaine infusion for analysis of serum drug concentrations by use of liquid chromatography-mass spectrometry. Serum lidocaine concentrations were evaluated by use of standard noncompartmental analysis. Selected cardiopulmonary variables, including heart rate (HR), mean arterial pressure (MAP), arterial pH, PaCO2, and PaO2, were recorded. Recovery quality was assessed and recorded. RESULTS: Serum lidocaine concentrations paralleled administration, increasing rapidly with the initiation of the loading infusion and decreasing rapidly following discontinuation of the maintenance infusion. Mean +/- SD volume of distribution at steady state, total body clearance, and terminal half-life were 0.70 +/- 0.39 L/kg, 25 +/- 3 mL/kg/min, and 65 +/- 33 minutes, respectively. Cardiopulmonary variables were within reference ranges for horses anesthetized with inhalation anesthetics. Mean HR ranged from 36 +/- 1 beats/min to 43 +/- 9 beats/min, and mean MAP ranged from 74 +/- 18 mm Hg to 89 +/- 10 mm Hg. Recovery quality ranged from poor to excellent. CONCLUSIONS AND CLINICAL RELEVANCE: Availability of pharmacokinetic data for horses with gastrointestinal tract disease will facilitate appropriate clinical dosing of lidocaine.     

Pharmacokinetics and renal clearance of ampicillin in sheep

Pharmacokinetics and renal clearance of ampicillin were investigated in 13 sheep, following one single oral dose of 750 mg. A peak concentration in plasma 0.38 +/- 0.04 microgram/ml (mean +/- SEM) was achieved 95.3 +/- 5.95 min after drug administration. Absorption half-life was 44.4 +/- 4.4 min. The area under the plasma concentration curve was 94.6 +/- 4.5 micrograms.hour.ml-1, while in the case of urine it was 370.5 +/- 28.3 micrograms.hour.ml-1. Biological half-life of ampicillin was 110 +/- 3 min, with an elimination rate constant of 0.0064 +/- 0.0002 min-1. The values for volume of distribution and total body clearance were 8.2 +/- 0.71/kg or 52.0 +/- 4.2 ml/kg/min, respectively. The priming and maintenance doses, using MIC as 0.05 microgram/ml, were suggested to be 8.8 or 8.4 mg/kg, respectively, at an 8-h interval. For MIC of 0.5 microgram/ml, this dose should be 10 times higher. Renal clearance of ampicillin seemed to involve active tubular secretion. Renal excretion indicated either extensive metabolism or excretion through routes other than kidneys.     

The pharmacokinetics and locomotor activity of alfentanil in the horse

The pharmacokinetics of alfentanil were investigated in the horse. Four doses of alfentanil (4, 10, 20 and 40 micrograms/kg) were given to four horses at different times and their locomotor activity monitored. Doses of 20 and 40 micrograms/kg produced a significant increase in locomotor activity. The plasma concentrations of alfentanil were measured in six standing horses and the pharmacokinetics calculated. It was found that the decay curves were best described by a biexponential equation. The elimination half-life (t1/2 beta) was 21.65 +/- 3.99 min and the clearance (Cl) was 14.1 +/- 0.7 ml/kg/min. The same horses were anaesthetized with xylazine-ketamine and maintained with halothane in oxygen for the first experiment and isoflurane in oxygen for the second experiment. The pharmacokinetics were again calculated from measured plasma alfentanil concentrations. There were significant differences between the kinetics in the conscious and the anaesthetized animals but there were no significant differences in alfentanil kinetics between the two anaesthetic agents. The t1/2 beta for alfentanil under halothane and isoflurane anaesthesia were 55.95 +/- 20.77 and 68.03 +/- 23.22 min, respectively, and the Cl values were 14 +/- 1.7 and 13.6 +/- 1.32 ml/kg/min.     

Pharmacokinetics and pharmacologic effects of the S(-) isomer of bupivacaine after intravenous and epidural administration in dogs.

OBJECTIVE: To determine pharmacokinetic variables and pharmacologic effects of the S(-) isomer of bupivacaine (S[-]-BPV) in dogs. ANIMALS: 6 adult male Beagles. PROCEDURE: Dogs received S(-)-BPV (1 mg/kg of body weight) i.v., and 15 days later, the same dogs received 1.8 mg/kg epidurally. Pharmacokinetic variables and pharmacologic effects were determined for each route of administration. RESULTS: After i.v. administration, plasma concentration versus time curves were adjusted, using biexponential equations that indicated a rapid distribution phase followed by a slower elimination phase, with a mean +/- SD half-life of 33.5 +/- 17.0 minutes. Mean plasma clearance was 21.0 +/- 10.7 ml/min/kg, and mean volume of distribution at steady state was 0.8 +/- 0.2 L/kg. After i.v. administration, mean peak plasma concentration was 2.6 +/- 0.7 micrograms/ml; after epidural administration, it was 0.9 +/- 0.5 microgram/ml at approximately 3 minutes. Half-life after epidural administration was 5 times longer than that observed after i.v. administration. Motor block began immediately after the end of epidural administration and lasted for 3 to 4 hours. Changes in systolic blood pressure and heart rate after epidural administration were slight but occurred at the same time that plasma concentration peaked. After i.v. administration, motor block or variations in physiologic variables studied were not observed. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, the pharmacologic behavior of S(-)-BPV was similar to that of the bupivacaine racemate, but motor block attributable to S(-)-BPV lasted longer than that attributable to the racemate, with lower plasma concentrations observed at equivalent sample collection times.     

Total intravenous anesthesia in greyhounds: pharmacokinetics of propofol and fentanyl--a preliminary study

OBJECTIVE: To evaluate concomitant propofol and fentanyl infusions as an anesthetic regime, in Greyhounds. ANIMALS: Eight clinically normal Greyhounds (four male, four female) weighing 25.58 +/- 3.38 kg. DESIGN: Prospective experimental study. METHODS: Dogs were premedicated with acepromazine (0.05 mg/kg) by intramuscular (i.m.) injection. Forty five minutes later anesthesia was induced with a bolus of propofol (4 mg/kg) by intravenous (i.v.) injection and a propofol infusion was begun (time = 0). Five minutes after induction of anesthesia, fentanyl (2 microg/kg) and atropine (40 microg/kg) were administered i.v. and a fentanyl infusion begun. Propofol infusion (0.2 to 0.4 mg/kg/min) lasted for 90 minutes and fentanyl infusion (0.1 to 0.5 microg/kg/min) for 70 minutes. Heart rate, blood pressure, respiratory rate, end-tidal carbon dioxide, body temperature, and depth of anesthesia were recorded. The quality of anesthesia, times to return of spontaneous ventilation, extubation, head lift, and standing were also recorded. Blood samples were collected for propofol and fentanyl analysis at varying times before, during and after anesthesia. RESULTS: Mean heart rate of all dogs varied from 52 to 140 beats/min during the infusion. During the same time period, mean blood pressure ranged from 69 to 100 mm Hg. On clinical assessment, all dogs appeared to be in light surgical anesthesia. Mean times (+/- SEM), after termination of the propofol infusion, to return of spontaneous ventilation, extubation, head lift and standing for all dogs were 26 +/- 7, 30 +/- 7, 59 +/- 12, and 105 +/- 13 minutes, respectively. Five out of eight dogs either whined or paddled their forelimbs in recovery. Whole blood concentration of propofol for all eight dogs ranged from 1.21 to 6.77 microg/mL during the infusion period. Mean residence time (MRTinf) for propofol was 104.7 +/- 6.0 minutes, mean body clearance (Clb) was 53.35 +/- 0.005 mL/kg/min, and volume of distribution at steady state (Vdss) was 3.27 +/- 0.49 L/kg. Plasma concentration of fentanyl for seven dogs during the infusion varied from 1.22 to 4.54 ng/mL. Spontaneous ventilation returned when plasma fentanyl levels were >0.77 and <1.17 ng/mL. MRTinf for fentanyl was 111.3 +/- 5.7 minutes. Mean body clearance was 29.1 +/- 2.2 mL/kg/min and Vdss was 2.21 +/- 0.19 L/kg. CONCLUSION AND CLINICAL RELEVANCE: In Greyhounds which were not undergoing any surgical stimulation, total intravenous anesthesia maintained with propofol and fentanyl infusions induced satisfactory anesthesia, provided atropine was given to counteract bradycardia. Despite some unsatisfactory recoveries the technique is worth investigating further for clinical cases, in this breed and in mixed breed dogs.     

Single- and multiple-dose pharmacokinetics of intravenously administered vancomycin in dogs

Vancomycin was administered IV to healthy adult female dogs at a dosage of 15 mg/kg of body weight every 12 hours for 10 days. Pharmacokinetic values were determined after the first and last doses. The disposition of vancomycin was not altered by multiple dosing, and little accumulation attributable to multiple dosing was observed. Serum vancomycin concentration after the first and last dose were described, using a 2-compartment open model with first-order elimination. The distribution and elimination half-lives after the single dose were 15.4 +/- 2.7 minutes and 137 +/- 21.8 minutes (geometric mean +/- pseudo-SD), respectively; whereas the distribution and elimination half-lives after the last dose were 11.3 +/- 2.61 minutes and 104 +/- 11.2 minutes, respectively. The mean (+/- SD) area-derived volume of distribution was 396 +/- 156 ml/kg and 382 +/- 160 ml/kg after the first and last dose, respectively. Serum vancomycin clearance was 2.13 +/- 0.35 ml/min/kg and 2.49 +/- 0.79 ml/min/kg after the first and last dose, respectively, and 25 to 49% of the total dose of vancomycin was recovered in the urine in the first 24 hours after the single dose administered IV. Mean serum vancomycin concentration reached 101.8 +/- 30.6 micrograms/ml and 99.7 +/- 28.0 micrograms/ml at 5 minutes after a single dose and the last of the multiple doses, respectively, and decreased to 0.94 +/- 0.58 microgram/ml and 1.51 +/- 1.44 micrograms/ml, respectively, at 12 hours after administration. The side effects that accompany vancomycin treatment in human beings were not observed in the dogs; all remained healthy through the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of excretion of inulin, creatinine, sodium sulfanilate, and phenolsulfonphthalein to assess renal function in goats

Excretion of creatinine, sodium sulfanilate (SS), and phenolsulfonphthalein (PSP) was studied in healthy goats. In conscious goats, mean (+/- SEM) inulin clearance was 2.26 +/- 0.08 ml/min/kg of body weight. Endogenous creatinine clearance, 1.97 +/- 0.09 ml/min/kg, underestimated inulin clearance (P less than 0.01), probably because of the presence of noncreatinine chromogens in caprine plasma. The estimated renal clearance of PSP was 6.88 +/- 0.39 ml/min/kg, whereas the estimated renal clearance of SS was 3.71 +/- 0.39 ml/min/kg. Both exceeded inulin clearance (P less than 0.01), confirming renal tubular secretion of both compounds. In 6 anesthetized goats, exogenous creatinine clearance and SS clearance exceeded inulin clearance (P less than 0.05). Results of stop-flow experiments documented secretion of creatinine and SS by the proximal portion of the caprine nephron. Plasma half-life of PSP in uninephrectomized goats exceeded that in intact goats (20.2 +/- 1.5 min vs 11.9 +/- 0.7 min; P less than 0.01). Similarly, plasma half-life of SS was greater in goats after uninephrectomy (58.2 +/- 6.2 min vs 30.4 +/- 1.2 min; P less than 0.01).     

Pharmacokinetics of amikacin in cats

Six mixed-breed adult cats were given 5 mg of amikacin sulfate/kg of body weight by rapid IV, IM, and SC routes of administration. The serum concentration-vs-time data were analyzed, using a noncompartmental model. The harmonic mean +/- pseudo-SD of the effective half-life of amikacin was 78.8 +/- 19.3 minutes after IV administration, 118.7 +/- 14.4 minutes after IM administration, and 117.7 +/- 12.8 minutes after SC administration. The arithmetic mean +/- SD of mean residence time was 118.3 +/- 21.7 minutes, 173.4 +/- 19.9 minutes, and 171.7 +/- 19.1 minutes after IV, IM, and SC drug administration, respectively. The mean apparent volume of distribution at steady state was 0.17 +/- 0.02 L/kg, and the mean total body clearance was 1.46 +/- 0.26 ml/min/kg. Mean bioavailability was 95 +/- 20% after IM administration and 123 +/- 33% after SC drug administration. A recommended dosage of 10 mg/kg, q 8 h can be expected to provide a therapeutic serum concentration of amikacin with a mean steady-state concentration of 14 micrograms/ml. The SC route of administration is preferred, because of rapid absorption, good bioavailability, and ease of administration.     

Cardiopulmonary, anesthetic, and postanesthetic effects of intravenous infusions of propofol in greyhounds and non-greyhounds.

The cardiopulmonary, anesthetic, and postanesthetic effects of an IV infusion of the hypnotic agent propofol were assessed in 6 Greyhounds and 7 non-Greyhounds. After IM injection of acetylpromazine and atropine, a bolus injection of propofol sufficient to allow endotracheal intubation (mean +/- SEM = 4.0 +/- 0.3 mg/kg of body weight in Greyhounds; 3.2 +/- 0.1 mg/kg in non-Greyhounds) was administered, followed by continuous infusion at a rate of 0.4 mg/kg/min for 60 minutes, during which time dogs breathed 100% oxygen. In 23% of all dogs (3 of 13), apnea developed after initial bolus administration of propofol. Arterial blood pressure was well maintained in all dogs, but heart and respiratory rates were decreased significantly (P less than 0.05) during the infusion in Greyhounds. In Greyhounds, mild respiratory acidosis developed after 45 minutes, whereas arterial carbon dioxide tension was increased at all times after propofol administration in non-Greyhounds. In all dogs, PCV and total plasma proteins were unaffected by propofol. Rectal temperature decreased during treatment. Muscle tremors were observed in approximately 50% of dogs (in 3 of 6 Greyhounds and 3 of 7 non-Greyhounds) during and after infusion of propofol. Non-Greyhounds lifted their heads, assumed sternal recumbency, and stood 10 +/- 1, 15 +/- 3, and 28 +/- 5 minutes, respectively, after the end of the infusion; in Greyhounds, the corresponding times were 36 +/- 4, 43 +/- 6, and 63 +/- 7 minutes.     

The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.