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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.

Twelve mature (5 sexually intact males, 4 castrated males, and 3 females) mixed-breed dogs were surgically thyroidectomized and used in a Latin-square design pharmacokinetic study of orally administered L-thyroxine. The dogs were treated with 44, 22, and 11 micrograms of L-thyroxine/kg as a single morning dose or in divided doses, morning and evening. Serum concentration of thyroxine (T4) was evaluated to determine a number of pharmacokinetic variables for comparison. Mean steady-state concentrations (Css) were determined from the area under the curve. Variables were analyzed for comparisons between dosages by use of ANOVA. Concentration at steady state was highest for dogs of the 44-micrograms/kg of body weight once-daily group and was lowest for dogs of the group given 11 micrograms/kg in 2 daily doses. Single daily administration resulted in higher Css, except at the 22-micrograms/kg/d dosage. Clearance was faster for the 22- and 44-micrograms/kg/d dosages than for the 11-micrograms/kg/d dosage. The half-life (t1/2) and mean residence time (MRT) also were shorter for the 44-micrograms/kg/d dosage, possibly indicating more rapid elimination of the drug at higher doses and dose-dependent kinetics. Perhaps, as the dogs' metabolism increased with higher iodothyronine concentrations, hormone degradation was accelerated. Interval (divided vs single dose) caused some expected changes: maximal concentration was higher and minimal concentration was lower when single administration was used. These undulations resulted in iodothyronine concentrations above the physiologic range for a number of hours, whereas concentration closer to physiologic ranges was achieved by use of divided doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Six healthy mature horses were orally administered a single dose of phenobarbital (26 mg/kg of body weight), then multiple doses (13 mg/kg) orally for 42 consecutive days. Seventeen venous blood samples were collected from each horse after the single dose study and again after the last dose on day 42. Plasma phenobarbital concentration was determined by use of a fluorescence assay validated for horses. Additional blood samples (n = 11) were collected on days 8 and 25 to determine peak and trough concentrations, as well as total body clearance. Phenobarbital disposition followed a one-compartment model. Mean kinetic variables after single and repeated orally administered doses (42 days) were: elimination half-life = 24.2 +/- 4.7 and 11.2 +/- 2.3 hours, volume of distribution = 0.960 +/- 0.060 and 0.914 +/- 0.119 L/kg, and clearance = 28.2 +/- 5.1 and 57.3 +/- 9.6 ml/h/kg, respectively. Results indicated that significant (P less than 0.05) difference in half-life and oral clearance existed between single and repeated dosing. The significant decrease in half-life after repeated dosing with phenobarbital may be indicative of enzyme induction. Significant difference was not observed between baseline serum enzyme concentration and concentration measured on day 42, except for gamma-glutamyltransferase activity, which was significantly increased on day 42 in 3 of the 6 horses. On the basis of increases in oral clearance observed over 42 days, dose adjustments may be required.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemorrhagic shock was induced in nonsplenectomized dogs by removing 41% of their blood volume over a 15-minute period. Hemodynamic and metabolic variables were determined prior to and for 3 hours after completion of hemorrhage. One group of 5 dogs was not treated. After the 30-minute sample was collected, a second group of 5 dogs was given lactated Ringer solution (LRS) at 88 ml/kg of body weight, IV. A third group of 5 dogs was given LRS (88 ml/kg, IV) and prednisolone sodium succinate (11 mg/kg, IV) 30 minutes after hemorrhage. The IV administration of LRS was completed within 15 minutes. The glucocorticoid was administered as an IV bolus after 500 ml of LRS had been given. The large volume and administration of LRS significantly (P = 0.05) improved many of the hemodynamic and metabolic effects of acute hemorrhage and hemorrhagic shock. At one time or another during the 2.5-hour observation period after the initiation of treatment, mean arterial pressure, cardiac index, systemic vascular resistance, heart rate, respiratory rate, lactate, glucose, and arterial and venous blood gas values were significantly (P = 0.05) improved, compared with baseline values. The addition of prednisolone sodium succinate to the treatment regimen improved the effectiveness of LRS alone only in some dogs at random sampling times. Significant trends were not observed except, possibly, the improvement of venous pH and A-V pH and PCO2 differences.

Ticlopidine hydrochloride was evaluated for its effectiveness in inhibiting platelet aggregation and serotonin release in 5 laboratory Beagles before and after heartworm implantation with 7 adult Dirofilaria immitis, and after embolization with 7 dead heartworms to mimic what happens after heartworm adulticide treatment. Five other laboratory Beagles, similarly implanted and embolized with heartworms, were used as nonmedicated controls. During the heartworm-negative stage, the dosage of ticlopidine that inhibited adenosine diphosphate (ADP)-induced platelet aggregation in 5 dogs by at least 50% after 5 days of treatment was 62 mg/kg of body weight once a day. In the same dogs implanted with 7 adult heartworms 21 days previously, mean (+/- SD) ticlopidine dosage required to obtain similar results was 71 (+/- 13) mg/kg given once daily. During the 21 days after dead heartworms were implanted in heartworm-infected dogs, mean ticlopidine dosage was 108 (+/- 35) mg/kg (range, 62 to 150 mg/kg). Ticlopidine treatment was associated with increased platelet numbers in all 5 dogs during the heartworm-negative stage and in 4 of 5 dogs during the heartworm implantation and heartworm embolization stages. Mean platelet volume tended to decrease as platelet numbers increased. At necropsy, gross and histologic pulmonary lesions were less severe in ticlopidine-treated dogs than in nonmedicated control dogs.

To determine the drug dose required to inhibit platelet reactivity by at least 50%, 2 drug regimens were evaluated in heartworm-negative, heartworm-infected, and heartworm-infected dogs embolized with dead heartworms. Aspirin, or a combination of aspirin and dipyridamole, were administered to 2 groups of Beagles (n = 5 each) for 5 to 9 days; a third group of 5 Beagles served as nontreated controls. For heartworm-negative dogs, mean (+/- SD) aspirin dosage that inhibited collagen-induced platelet reactivity by at least 50% was 6 (+/- 2) mg/kg of body weight given once daily. The aspirin/diphridamole combination dosage was 1 mg of each drug/kg given every 12 hours. All dogs (n = 15) were implanted with 7 adult heartworms each and remedicated (or not treated) beginning at 21 days after heartworm implantation. In heartworm-infected dogs, mean aspirin dosage required to inhibit collagen-induced platelet reactivity greater than or equal to 50% was 10 (+/- 6) mg/kg. Mean dosage of aspirin/dipyridamole combination was 1.6 +/- (0.5) mg of each drug/kg given every 12 hours. When platelet reactivity in response to collagen was determined to be inhibited by at least 50% in all medicated dogs, each dog (n = 15) was embolized with 7 dead adult heartworms to mimic heartworm adulticidal treatment. Platelet reactivity was monitored for 21 days after treatment, and drug dose was adjusted to maintain platelet inhibition by at least 50%. In embolized dogs, mean aspirin dosage was 17 (+/- 14) mg/kg given once daily. Mean dosage of the aspirin/dipyridamole combination was 2.8 (+/- 1.3) mg of each drug/kg given every 12 hours. All dogs (n = 15) were euthanatized 21 days after heartworm embolization. Each lung lobe was evaluated for severity of lesions and presence of organized or fibrinous thrombi. Lesion severity in the aspirin- and aspirin/dipyridamole-treated dogs was not significantly different from that in control dogs.

Ototoxicosis was evaluated in 6 healthy ponies given 5 mg of gentamicin/kg of body weight, q 8 h, IM. Ponies 1, 2, and 3 were dosed for 7 days and ponies 4, 5, and 6 were dosed for 14 days. Serum peak and trough concentrations of gentamicin were measured by radioimmunoassay at regular intervals. Brain stem auditory-evoked responses were recorded every 5 days up to 60 days after the first dose to monitor auditory function. Although serum gentamicin concentrations were within or above the accepted clinical therapeutic range, loss of auditory function was not observed at the frequency range (1 to 4 kHz) tested. Serum chemical values remained within the accepted clinical range and no evidence of nephrotoxicosis was observed. Seemingly, gentamicin given IM to healthy ponies was safe and had minimal risk of side effects.

A single dose of digoxin was injected, IV, into 5 mature male turkeys (0.066 mg/kg of body weight), 8 male ducks (0.066 mg/kg), and 6 roosters (0.33 mg/kg). Twenty-three serial venous blood samples were collected before (baseline) and after the administration of digoxin to turkeys, ducks, and roosters. Plasma concentrations of digoxin were determined in duplicate by a radioimmunoassay that was validated for avian species. The plasma concentrations were best fitted by a 3 (turkeys, ducks)- and 2 (roosters)-compartment open model, with first-order elimination from the central compartment. Significant (P less than 0.05) kinetic differences were determined among species. Mean half-life (t1/2) for ducks, roosters, and turkeys were 8.30 +/- 2.70 (mean +/- SD), 6.67 +/- 3.50, and 23.7 +/- 4.8 hours, respectively. The volume of distribution at steady state (Vss) was 14.7 +/- 2.9, 3.13 +/- 0.49, and 2.27 +/- 0.36 L/kg, and total body clearance (CL) of drug was 1.54 +/- 0.43, 0.461 +/- 0.187, and 0.136 +/- 0.022 L/h/kg for ducks, roosters, and turkeys, respectively. The mean residence time was 10.3 +/- 3.9, 8.37 +/- 4.97, and 16.8 +/- 2.2 hours, respectively. Volume of distribution at steady state and CL in ducks were several fold higher than that in turkeys. The terminal half-life of digoxin determined for ducks and roosters in this study was considerably shorter than those previously reported for several mammalian species.

Healthy mature roosters (n = 10) were given gentamicin (5 mg/kg of body weight, IV) and, 30 days later, another dose IM. Serum concentrations of gentamicin were determined over 60 hours after each drug dosing, using a radioimmunoassay. Using nonlinear least-square regression methods, the combined data of IV and IM treatments were best fitted by a 2-compartment open model. The mean distribution phase half-life was 0.203 +/- 0.075 hours (mean +/- SD) and the terminal half-life was 3.38 +/- 0.62 hours. The volume of the central compartment was 0.0993 +/- 0.0097 L/kg, volume of distribution at steady state was 0.209 +/- 0.013 L/kg, and the total body clearance was 46.5 +/- 7.9 ml/h/kg. Intramuscular absorption was rapid, with a half-life for absorption of 0.281 +/- 0.081 hours. The extent of IM absorption was 95 +/- 18%. Maximal serum concentration of 20.68 +/- 2.10 micrograms/ml was detected at 0.62 +/- 0.18 hours after the dose. Kinetic calculations predicted that IM injection of gentamicin at a dosage of 4 mg/kg, q 12 h, and 1.5 mg/kg, q 8 h, would provide average steady-state serum concentrations of 6.82 and 3.83 micrograms/ml, with minimal steady-state serum concentrations of 1.54 and 1.50 micrograms/ml and maximal steady-state serum concentrations of 18.34 and 7.70 micrograms/ml, respectively.

Digoxin (elixir, 0.022 mg/kg) was administered via stomach tube to healthy horses of mixed breeding and sexes. Serum digoxin concentrations reached a peak (2.21 +/- 0.6 ng/ml) at approximately 1 hour after dosing and had a half-life of 28.8 +/- 10.7 hours. Digoxin kinetics followed a triexponential curve, indicating that at least a 2 compartmental model is required to characterize the serum concentration-time curve after this route of administration. It was calculated that to achieve average serum concentrations of 1.1 ng/ml, an oral dose of 17.4 microgram of digoxin elixir/kg/day and an IV dose of 6.1 microgram of parenteral preparation/kg/day would be required. There was no significant (P greater than 0.05) alteration in base-line serum calcium, potassium, and sodium concentrations and heart rate, P-R interval, and mean arterial blood pressure.

In one experiment, 5 dogs were administered digoxin (0.022 mg/kg of body weight, IV), were rested for 2 weeks, were then given phenobarbital (13.2 mg/kg orally) for 14 days, and then were given digoxin again (0.022 mg/kg, IV). Comparing prephenobarbital (control) digoxin half-lives of 42.4 +/- 8.8 hours and postphenobarbital digoxin half-lives of 18.0 +/- 2.2 hours, the half-life was significantly (P less than 0.05) decreased after phenobarbital administration. Clearance was increased by 84%, and the volume of distribution given was decreased by 34%. In a second experiment, 5 dogs were given digoxin (0.022 mg/kg, orally) daily for 11 days, and the digoxin kinetics were evaluated after the last dosing. The dogs were then rested and given phenobarbital (13.2 mg/kg, orally) once daily for 14 days and digoxin (0.022 mg/kg) once daily for 11 days, and the pharmacokinetics of digoxin was determined on the last day of dosing. Significant differences in steady-state serum concentrations and the pharmacokinetics of digoxin were not found between the control and phenobarbital phases of the experiment. Mean (+/- SD) half-lives of digoxin were 29.0 +/- 7.2 hours before phenobarbital treatment (control) and were 34.8 +/- 7.2 hours after phenobarbital treatment. In comparing results of the single-dose experiment vs the oral multiple-dose experiment, dogs had shorter half-lives for digoxin after multiple dosing. Therefore, if phenobarbital and digoxin are to be chronically coadministered orally, an adjustment in the digoxin dose is not necessary.

Gentamicin (GT) was administered IM to 6 healthy mature mare ponies at a dosage of 5 mg/kg of body weight every 8 hours for 7 consecutive days (total, 21 doses). Two venous blood samples were collected before (trough) and at 1 hour (peak) after the 5th, 10th, 14th, and 19th doses. An endometrial biopsy was done of each mare on days 4 and 7. On the 7th day, just before the 21st administration of GT, base-line blood samples were collected, and 22 blood samples were collected over a period of 48 hours after GT was given. The mares were catheterized on the 7th day, and urine was collected for 24 hours. Serum, urine, and endometrial GT concentrations were determined by a radioimmunoassay technique (sensitivity of 0.3 micrograms/ml of serum). Serum GT concentration data obtained from the terminal phase were best fitted by a 1-compartment open model with a biological half-life of 2.13 +/- 0.43 hours. Total body clearance and renal clearance were 1.69 +/- 0.41 and 1.40 +/- 0.26 ml/min/kg, respectively. Mean endometrial concentrations on day 4 and day 7 were 5.02 +/- 3.3 and 12.75 +/- 1.6 micrograms/g. To achieve mean serum GT concentrations (micrograms/ml) at steady state of 6.47 +/- 1.51, a maximum steady-state concentration of 12.74 +/- 1.60, and a minimum steady-state concentration of 1.43 +/- 0.57, a dosage of 5 mg/kg every 8 hours is recommended. Serum urea nitrogen, serum creatinine, and the fractional clearance of sodium sulfanilate were determined before and after GT treatment. Renal function remained within the base-line range during 7 days of GT administration.

Six ponies and 1 horse were bilaterally adrenalectomized (BADX). The survival time of 2 of the 7 animals after BADX was 24 and 72 hours without supplemental corticosteroids. The cause of death was not related to the surgical technique. The biological half-life of cortisol (hydrocortisone) was estimated to be 2.1 +/- 0.6 hours. The disappearance of cortisol in the horse was found to be biphasic, composed of redistribution and elimination phases. Pathophysiologic changes (ie, increased serum sodium and chloride, increased PCV, and decreased serum potassium) similar to those seen in other species after BADX were found. Clearance of electrolytes was calculated, using the creatinine clearance method. These values were inversely correlated with the changes seen in serum electrolytes.

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.

Gentamicin was administered IM to 6 healthy, mature, lactating cows at a dosage of 3.5 or 5 mg/kg of body weight every 8 hours for 10 consecutive days (total, 30 doses). Endometrial biopsies were done at 72, 136 or 144, and 216 hours after the first dose was administered. On the 10th day, just before the last dose of gentamicin was administered, blood samples (designated 10th-day base-line samples) were obtained, and serial blood samples were obtained for 144 hours after the last injection was given. The cows were catheterized on the 10th day, and urine was obtained for 10 to 18 consecutive hours. Milk samples were also obtained. The cows were slaughtered at different times after the last dose was given, and samples were taken from 22 tissues and organs. Serum, milk, urine, and tissue gentamicin concentrations were determined by radioimmunoassay. Serum gentamicin concentrations were best fitted to a 2-compartment open model. The mean half-lives for absorption, distribution, and elimination were 0.16 +/- 0.14, 2.59 +/- 0.53, and 44.91 +/- 9.38 hours, respectively. Total body clearance and renal clearance were 1.65 +/- 0.69 and 1.32 +/- 0.25 ml/min/kg, respectively. The percentage of the dose excreted unchanged in the urine at 8 hours after the last dose was given was 98 +/- 15. As expected, of the tissues examined, the gentamicin concentrations in the kidney cortex and medulla were 1,500 times greater than those in serum. Renal function remained within the baseline range during the 10 days of gentamicin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of phenobarbital was studied in 10 healthy dogs after single IV or oral administration. Phenobarbital sodium was administered IV to 5 dogs in group A (5.5 mg/kg of body weight) and 5 dogs in group B (15 mg/kg). Serial venous blood samples (n = 21) were collected from each dog before (base line) and after the administration of phenobarbital sodium for pharmacokinetic evaluation. After a 30-day resting period, 3 dogs in group A and 3 in group B were randomly selected and used for an IV crossover treatment. The IV treatment mean half-life of phenobarbital sodium was 92.6 +/- 23.7 and 72.3 +/- 15.5 hours, whereas mean total clearance was 5.60 +/- 2.31 and 6.66 +/- 0.78 ml/hr/kg for doses of 5 and 15 mg/kg, respectively. The mean residence time was 124 +/- 34 hours and 106 +/- 23 hours for the 5.5 and 15 mg/kg, IV doses, respectively. Significant differences (P greater than 0.05) were not observed in pharmacokinetic parameters between the 2-dose study. After a 35-day resting period, dogs in groups A and B were treated as described for the single IV treatment, except that they were given a phenobarbital tablet orally. Serial venous blood samples (n = 24) were collected before (base line) and after the administration of phenobarbital. Mean bioavailability was 88.1 +/- 12.4% and 96.8 +/- 9.0%, half life of absorption was 0.263 +/- 0.185 and 0.353 +/- 0.443 hour, and lag time was 0.611 +/- 0.683 and 0.741 +/- 0.554 hour for groups A and B, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Endometrial tissue and blood serum gentamicin (GT) concentrations were determined in 6 ovariectomized pony mares given intrauterine infusions (50 ml of a 5% commercial aqueous solution of GT) each day for 5 consecutive days. The mares were subjected to the following 3 treatments: (1) GT infusion only (trial A, control); (2) progesterone plus GT (trial B, P + G); and (3) estradiol plus GT (trial C, E + G). Endometrial tissue concentrations of GT (micrograms/g) at 24 and 120 hours were significantly higher (P less than 0.05) in trials B (65.54 +/- 15.57 and 100.33 +/- 19.27) and C (73.33 +/- 22.53 and 74.09 +/- 8.60) than in trial A (4.23 +/- 0.70). Endometrial concentration for trial A at 120 hours was also significantly higher than trial A at 24 hours. There was no significant difference (P greater than 0.05) in endometrial concentrations among trials A, B, and C at 120 hours. Serum GT concentrations were significantly lower than endometrial tissue concentrations. The highest serum concentrations of GT found in every trial occurred at 6 hours after each intrauterine infusion of GT. The highest overall serum concentration of GT (micrograms/ml) determined occurred in trial B (8.30 +/- 1.28) at 78 hours. There was no significant difference in serum concentrations of GT between days of treatment, except for trial A at 78 and 102 hours, respectively. Serum concentrations of GT were significantly higher (P less than 0.05) than trial A at 30, 54, 78, and 102 hours in trial B, and at 78 and 102 hours in trial C. There was no significant difference in serum concentrations of GT between trials B and C.

Studies were conducted to examine the temporal changes in phenobarbital pharmacokinetics during chronic dosing in dogs. Ten dogs were allotted into 2 groups, administered a single oral dose, rested for 35 days, and then given the drug for 90 consecutive days. After single administration of 5.5 mg/kg of body weight or 15 mg/kg, the total body clearance (Clt/F) was 5.58 +/- 1.89 ml/h/kg and 7.28 +/- 1.07 ml/h/kg, respectively. The half-lives (t1/2) for the 2 groups were 88.7 +/- 19.6 hours for the 5.5-mg/kg dose and 99.6 +/- 22.6 hours for the 15-mg/kg dose. Significant differences in Clt/F or t1/2 were not observed between the 2 groups. Multiple-dosing regimens (5.5 mg/kg/day or 11 mg/kg/day) were initiated in the same dogs for 90 days. The Clt/F was significantly (P less than 0.05) greater on days 30, 60, and 90 than the single dose for both groups. After the last dose on day 90, several blood samples were obtained to determine phenobarbital t1/2. On day 90, the t1/2 was significantly (P less than 0.05) shorter and the Clt/F was significantly greater than single-dose values. The Clt/F and t1/2 were 10.2 +/- 1.7 ml/h/kg and 47.3 +/- 10.7 hours for the group given the low dose and 15.6 +/- 2.5 ml/h/kg and 31.1 +/- 4.4 hours for the group given the high dose, respectively. Both Clt/F and t1/2 were significantly (P less than 0.05) different between the 2 groups on day 90.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of gentamicin were studied in six healthy mature horses of mixed breeding and of both sexes. A parenteral preparation of gentamicin sulfate (5% aqueous solution) was administered rapidly (IV) at the dosage level of 5 mg/kg of body weight. Venous blood samples were taken at 0 (base line), 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, and 120 hours after gentamicin administration. Serum gentamicin was measured by a radioimmunoassay technique. The gentamicin concentration data was fitted to a one- and two-compartment open model with first-order elimination from the central compartment with the aid of nonlinear least squares program. The data were found to be best described by the two-compartment model with r2 = 0.997. Half-life, as determined from the terminal phase was 2.54 +/- 0.33 hours. Calculation of the total body clearance provided a mean of 1.16 +/- 0.11 ml/minute/kg of body weight (1.04 to 1.31 ml/minute/kg, range); the volume of distribution calculated from the area under the curve was determined separately for each animal and had a mean value of 0.254 +/- 0.036 L/kg. The initial exponential decline (alpha) in gentamicin serum concentration had an average value of 3.75 +/- 1.86 hours-1, whereas the terminal values were described by beta = 0.275 +/- 0.036 hours-1. Other pharmacokinetic values determined also are presented.

Pharmacokinetics of oxytetracycline HCl (OTC) was studied in rabbits. After 10 mg of OTC/kg of body weight was administered IV, the distribution half-life was 0.06 hour, terminal half-life was 1.32 hours, volume of distribution area was 0.861 L/kg, and total body clearance was 0.434 L/kg/h. After 10 mg of OTC/kg was given IM, the absorption half-life was 2.09 hours, extent of absorption was 71.4%, and total body clearance of the absorbed fraction was 0.576 L/kg/h. Based on these kinetic data, a dosage of 15 mg of OTC/kg, every 8 hours was developed. This dose given IM for 7 consecutive days resulted in observed steady-state maximum and minimum concentrations (mean +/- SD) of 4.7 +/- 0.3 micrograms/ml and 3.2 +/- 0.6 micrograms/ml, respectively. Twice this dose (30 mg of OTC/kg, every 8 hours) given IM caused anorexia and diarrhea.

Healthy mature cows (n = 6) were injected intrauterinally (IU) with gentamicin (50 ml of a 5% injectable solution) daily for 3 consecutive days. Venous blood and milk samples were collected at postinjection (initial) hours (PIH) 1, 3, 6, 9, 12, 24, 28, 31, 34, 37, 48, 51, 54, 57, 60, and 71, and endometrial biopsies were performed at PIH 6, 25, 48, 73, 95, and 119. Skeletal muscle biopsy samples were taken at PIH 25 and 73, and urine was collected every 1 or 2 hours during 12 consecutive hours after the first IU injection. Serum, milk, urine, and tissue concentrations of gentamicin were measured by radioimmunoassay. The highest mean serum concentration of gentamicin occurred during the 3 hours after each injection (2.49 +/- 1.46, 6.60 +/- 5.47, and 4.98 +/- 2.70 micrograms/ml). The mean peak concentration of gentamicin in milk occurred 3 to 6 hours after each injection. Mean peak urine concentration of gentamicin (256.8 +/- 127.9 micrograms/ml) was measured at PIH 6. The mean percentage of the first dose of gentamicin excreted in the urine within 12 hours was 14.78 +/- 3.56. The highest concentration of gentamicin in endometrial tissue (639.16 +/- 307.22 micrograms/g) was measured at PIH 6, decreasing to 9.64 +/- 3.55 micrograms/g before the next IU dose. Gentamicin was still detectable in endometrial tissue (0.86 +/- 0.43 microgram/g) 71 hours after the 3rd (last) IU injection.

Tritium-labeled prednisolone sodium succinate was administered IV to 4 healthy, awake, nonsplenectomized dogs. The concentration of prednisolone and its metabolites in the plasma were measured for 10 hours. Forty-one percent of the blood volume of these dogs was removed, and plasma prednisolone was measured again. The data before and after hemorrhage were fitted to a 2-compartment open model. From plasma profiles, a rapid distributional phase, followed by a slower phase, was observed in control and shock groups. Volume of the central compartment of prednisolone before and after hemorrhage was 165 ml/kg of body weight and 110 ml/kg, respectively; and the difference was significant (P less than 0.05). The rate of total body clearance of prednisolone before and after hemorrhage was 3.96 ml/min/kg and 2.53 ml/min/kg, respectively; the difference was significant. The mean plasma half-lives for prednisolone sodium succinate and its metabolites, before and after hemorrhage, were 166 and 197 minutes, respectively; the difference was not significant. The mean half-life data indicated that prednisolone sodium succinate may be repeated in a patient 2.5 to 3 hours after onset of treatment if signs of hypovolemic shock reappear.

Sodium phenobarbital (PHB) was administered orally as tablets 3 times a day to 6 healthy mature dogs of mixed breeding for 5 days at a dose of 2 mg/kg of body weight. On the 6th day, PHB was administered at 9 AM and venous blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 23, 35, 47, 59, 71, 83, 95, 107, 119, and 131 hours. Additional PHB was not given on day 6. Drug serum concentrations were described by a 1-compartment model with first-order absorption and elimination with fitted correlation coefficients of 0.991 +/- 0.007 (mean +/- SD). The observed PHB half-lives were between 37.3 and 74.6 hours with a mean of 53.0 +/- 15 hours. The calculated volume of distribution (Vd/F) was 743.6 +/- 69.8 ml/kg, and the total body clearance (ClT/F) was 0.173 +/- 0.053 ml/min/ kg. The absorption half-life was 1.27 +/- 0.21 hours. Based on the observed biological half-life after 5 days of dosing, approximately 11 days (8 to 15.5 days) of multiple dosing would be required to achieve steady-state serum concentrations. From average values, predicted maintenance doses of 1.8 mg/kg of body weight 3 times a day or 5.5 mg/kg once daily would be required to achieve average serum concentrations of 20 microg/ml. Due to intersubject variations in ClT/F, these doses would result in subtherapeutic or toxic serum concentrations in 2 of the 6 dogs. Further disposition and dosing regimen studies need to be performed during chronic PHB administration in dogs to evaluate autoinduction and intersubject differences in disposition kinetics.

Healthy mature lactating cows (n = 6) were given gentamicin (5 mg/kg of body weight) by IV route and another dose 19 days later by IM route. Serum gentamicin concentrations were determined over a period of 48 hours after each drug dosing, using radioimmunoassay. With the aid of a nonlinear least-square regression analysis program, the combined data of the IV and IM treatments were best fitted by a 2-compartment open model, as indicated by residual trends and improvements in the sum of squares by F test and the SD of the estimated values. The distribution phase half-life was 0.25 +/- 0.12 hour, and postdistribution half-life was 1.83 +/- 0.18 hours. The volume of the central compartment was 0.10 +/- 0.02 L/kg, volume of distribution at steady state was 0.16 +/- 0.03 L/kg, and the total body clearance was 1.32 +/- 0.17 ml/min/kg. Intramuscular absorption was rapid, with a half-life for absorption of 0.63 +/- 0.28 hour. The extent of IM absorption was 92% +/- 15%. The percentage of the IM dose eliminated in the urine during the first 8 hours was 83 +/- 8. Gentamicin was detected in milk for 48 hours. Kinetic calculations predicted that IM injection of gentamicin at a dosage of 3.5 mg/kg of body weight every 8 hours would provide average steady-state serum drug concentrations of 5.08 micrograms/ml, with minimum and maximum steady-state concentrations of 1.03 and 12.05 micrograms/ml, respectively, whereas an IM injection of a 5 mg/kg dosage every 8 hours would provide average steady-state serum concentrations of 7.26 micrograms/ml, with minimum and maximum steady-state serum concentrations of 1.47 and 17.21 micrograms/ml, respectively.

Cefotaxime was administered as single IV or IM dose for the purpose of examining its pharmacokinetics in healthy cats. The mean predicted plasma concentration of cefotaxime in 6 cats at 0 time after a single IV dosage of 10 mg/kg of body weight was 88.9 micrograms/ml. The mean plasma concentrations decreased to 10.8 micrograms/ml at 2 hours, 3.7 micrograms/ml at 3 hours, and 0.5 microgram/ml at 6 hours. The half-life was 0.98 +/- 0.25 hour (mean +/- SD), and the total body clearance was determined to be 2.76 +/- 1.25 ml/min/kg. After a single IM injection of 10 mg/kg of body weight, the mean maximum observed plasma concentration was 36.2 micrograms/ml at 0.75 hour. The mean absorption half-life was 0.24 hour. In 2 animals, the bioavailability of an IM injection was 98.2% and 93.0%.

Healthy mature pony mares (n = 6) were given a single dose of gentamicin (5 mg/kg of body weight) IV or IM 8 days apart. Venous blood samples were collected at 0, 5, 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 40, and 48 hours after IV injection of gentamicin, and at 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, and 30 hours after IM injection of gentamicin. Gentamicin serum concentration was determined by a liquid-phase radioimmunoassay. The combined data of IV and IM treatments were analyzed by a nonlinear least-square regression analysis program. The kinetic data were best fitted by a 2-compartment open model, as indicated by residual trends and improvements in the correlation of determination. The distribution phase half-life was 0.12 +/- 0.02 hour and postdistribution phase half-life was 1.82 +/- 0.22 hour. The volume of the central compartment was 115.8 +/- 6.0 ml/kg, volume of distribution at steady state was 188 +/- 9.9 ml/kg, and the total body clearance was 1.27 +/- 0.18 ml/min/kg. Intramuscular absorption was rapid with a half-life for absorption of 0.64 +/- 0.14 hour. The extent of absorption was 0.87 +/- 0.14. Kinetic calculations predicted that IM injections of 5 mg of gentamicin/kg every 8 hours would provide average steady-state serum concentrations of 7.0 micrograms/ml, with maximum and minimum steady-state concentrations of 16.8 and 1.1 micrograms/ml, respectively.