Thiacetarsamide in dogs with Dirofilaria immitis: influence of decreased liver function on drug efficacy

The influence that decreased functional hepatic mass had on blood arsenic concentrations in dogs after they were treated with thiacetarsamide, on the clearance of indocyanine green (ICG), on arsenic concentrations in the heartworm (Dirofilaria immitis), and on drug efficacy was studied. Dogs which were partially hepatectomized and treated with thiacetarsamide (1.76 mg/kg, 2 times a day for 2 days) had a significantly (P less than 0.01) reduced ICG clearance, significantly (P less than 0.01) higher arsenic levels in heartworms, and a significantly (P less than 0.01) higher proportion of heartworms killed than did dogs that were sham operated and treated with thiacetarsamide or sham operated and untreated. There were no significant differences in blood arsenic (thiacetarsamide) concentrations 2 minutes after injection between hepatectomized and nonhepatectomized groups. More male heartworms were killed than were female worms in the thiacetarsamide-treated groups. Indocyanine green half-life was longer (12.43 minutes) in the hepatectomized group than it was in the nonhepatectomized sham-operated groups (5.09 and 4.94 minutes). Indocyanine green clearance rate was lower in the hepatectomized group (0.54 ml/min/kg) than that in the nonhepatectomized groups (1.36 and 1.56 ml/min/kg). A parallel seemed to exist between ICG and thiacetarsamide removal from the blood by the liver. This parallel also was suggested in the higher worm arsenic (thiacetarsamide) concentrations for the hepatectomized group vs that for nonhepatectomized groups. Apparently, the slower the removal of thiacetarsamide from the blood by the liver, the higher the worm arsenic level and, consequently, the higher the worm kill.     

Clearance of indocyanine green in dogs with partial hepatectomy, hepatic duct ligation, and passive hepatic congestion

Clearance of 5 submaximal doses of indocyanine green (ICG) was measured in 5 dogs to determine the maximal removal rate (0.188 mg/kg of body weight/min) and Michaelis constant (Km, 1.25 mg/kg). From these results, 5 mg of ICG/kg of body weight was chosen on the basis of the recommendation that the dose should be at least 4 X Km to achieve sensitivity as a measure of hepatic function and independence from hepatic blood flow. Clearances of low (0.5 mg/kg) and high (5 mg/kg) doses of ICG were measured in 35 healthy dogs to determine reference values. Fractional disappearance was 15.1 +/- 10%/min for the low dose and 3.9 +/- 1%/min for the high dose; plasma half-life was 6.3 +/- 3.6 minutes and 19 +/- 4.8 minutes, respectively. The sensitivity of 2 doses of ICG was evaluated in dogs with 20% and 40% hepatectomy, nonhyperbilirubinemic obstructive cholestasis, or hepatic congestion; sham-operated dogs served as controls. Fractional disappearance and plasma half-life of ICG in the 40% hepatectomy and hepatic congestion groups were significantly different (P less than 0.05) from those in controls using both ICG doses, indicating that both doses were affected by hepatic perfusion, as well as hepatic mass. The fractional disappearance of the dye in the cholestasis group also differed significantly (P less than 0.05) from that of the controls at the high dose. Plasma clearance of both doses by dogs with 20% hepatectomy was not significantly different from that of controls.     

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 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.     

Single- and repeat-dose pharmacokinetic studies of chloramphenicol in horses: values and limitations of pharmacokinetic studies in predicting dosage regimens

A single-dose pharmacokinetic study of chloramphenicol in propylene glycol was done in 6 horses after 22 mg/kg was administered IV. Serum drug concentrations obtained at various predetermined intervals were determined by an electroncapture gas-chromatographic technique. The time-concentration data were described by a 2-compartment open model, and various pharmacokinetic variables were estimated. The median elimination rate constant was estimated to be -0.0185 minute-1 (-0.0225 to -0.0148 minute-1), and the median half-life was 37.36 minutes (30.74 to 46.90 minutes). The median apparent volume of distribution and total body clearance were 1.46 L/kg (1.13 to 1.60 L/kg) and 25.56 ml/kg/min (23.66 to 32.21 ml/kg/min), respectively. On the basis of these data, single- and repeat-dose kinetic studies were done in another group of 6 animals. The drug was administered at a dosage of 22 mg/kg every 4 hours for 3 days. Blood samples were obtained for pharmacokinetic studies after the first and the last doses were given. The half-life, volume of distribution, and total body clearance did not change significantly (Wilcoxon signed rank test) after 3 days of therapy with chloramphenicol. The IV dose schedule for treating bacterial infections with organisms of different sensitivities has been determined from the estimates of the pharmacokinetic variables. The limitations of calculating the dose schedules for chloramphenicol on the basis of pharmacokinetic variables in horses are discussed.     

Pharmacokinetics of ceftazidime given alone and combination with probenecid to unweaned calves

Ceftazidime pharmacokinetic values were studied in unweaned calves given the antibiotic alone or in combination with probenecid. Ceftazidime was administered IV to 9 calves at a dosage of 10 mg/kg of body weight and IM (10 mg/kg) to 8 calves, to 7 calves (10 mg/kg plus probenecid [40 mg/kg]), and to 9 calves (10 mg/kg plus probenecid [80 mg/kg]). Serum concentration-vs-time data were analyzed, using noncompartmental methods based on statistical moment theory. The data for IV ceftazidime administration also were fitted by use of a linear, open 2-compartment model. The mean (+/- SD) terminal half-life was 138.7 +/- 23.6 minutes and 126.3 +/- 10.5 minutes after IV and IM administrations, respectively. The mean residence time was 167.3 +/- 21.1 minutes and 201.4 +/- 16.8 minutes after IV and IM administrations, respectively. Coadministeration of probenecid did not affect the terminal half-life or mean residence time values. The total body clearance was 1.75 +/- 0.26 ml/min/kg, and the volume of distribution at steady state was 0.294 +/- 0.064 L/kg. The estimated mean absorption time was 34.1 minutes. There were no significant differences between the mean residence time calculated by statistical moment theory or by compartmental analysis, indicating central compartment output of ceftazidime. The 90% minimal inhibitory concentration values of ceftazidime determined for Escherichia coli, Salmonella spp, Pasteurella multocida, and P haemolytica isolates ranged from less than 0.01 to 0.1 micrograms/ml.     

Compartmental and noncompartmental pharmacokinetic analyses of minocycline hydrochloride in the dog

Six adult dogs were given 5 mg of minocycline hydrochloride/kg of body weight IV. Pharmacokinetic evaluation of the serum drug concentration versus time data was performed, using the 2-compartment open model, the 3-compartment open model, and a noncompartmental model involving use of the statistical moment theory. All pharmacokinetic values except clearance were model independent. Minocycline half-life ranged between 6.48 and 7.24 hours; volume of distribution at steady state, between 1.859 +/- 0.368 and 2.001 +/- 0.468 L/kg; and clearance, between 3.195 +/- 0.618 and 3.424 +/- 0.684 ml/min/kg. These data are similar to those reported for oxytetracycline and indicate that the frequency of administration of the 2 tetracyclines should be the same. Three of the 6 dogs developed an adverse response to the IV injection of minocycline. Dog 1 developed urticaria and had initial serum drug concentrations of approximately 2 times the mean concentrations for the other dogs; values were not included in the pharmacokinetic analysis. Two other dogs had transient signs indicating cardiovascular depression or hypotension; their data were included. Due to the frequency of the unexpected reactions found in this study, it was concluded that dogs should not be given minocycline rapidly IV.     

Pharmacokinetics of gentamicin in the calf: developmental changes

The purpose of this study was to determine the pharmacokinetic values for gentamicin in neonatal calves and to compare these values with those in adult cattle (cows). Gentamicin (4 mg/kg of body weight) was administered IV to 7 Holstein bull calves on days 1 (between 12 and 24 hours of age), 5, 10, and 15 after birth, and was administered once IV to 7 Holstein cows. Serum was collected from each animal before administration and at 22 different time intervals from 2 to 400 minutes after injection. Sera were analyzed for gentamicin concentrations. Decay of serum gentamicin concentrations was best described by a 2-compartment pharmacokinetic model. Elimination half-life (t1/2 (beta)) of gentamicin decreased from day 1 (149 minutes) to day 5 (119 minutes), but did not change between days 5 and 15 (111 minutes). Compared with the t1/2(beta) in 1- and 15-day-old calves, the t 1/2 (beta) in cows was shorter (76 minutes). In the calves, apparent volume of distribution (based on total area under the disposition curve) did not change between 1 (393 ml/kg) and 5 (413 ml/kg) days of age, decreased on day 10 (341 ml/kg) and cows day 15 (334 ml/kg), and was markedly smaller than that in cows (140 ml/kg). Total body clearance of gentamicin in cows (1.29 ml/min X kg) was lower than that seen in calves on day 1 (1.92 ml/min X kg) and on day 15 (2.10 ml/min X kg). The decrease in apparent volume of distribution of gentamicin was mirrored by a large decrease in the extracellular fluid volume, as measured by inulin space.(ABSTRACT TRUNCATED AT 250 WORDS)     

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%.     

Comparative study of the pharmacokinetics of alfentanil in rabbits, sheep, and dogs

The central arterial pharmacokinetics of alfentanil, a short-acting opioid agonist, were studied in rabbits, sheep, and dogs after short-duration infusion of the drug. Alfentanil was infused until a set end point (high-amplitude, slow-wave activity on the EEG) was reached. This required a larger alfentanil dose and a higher alfentanil arterial concentration in sheep, compared with rabbits and dogs. The plasma concentration-time data for each animal were fitted, using nonlinear regression, and in all animals, were best described by use of a triexponential function. In this study, differences in the disposition kinetics of alfentanil among the 3 species were found for only distribution clearance and initial distribution half-life. In dogs, compared with rabbits and sheep, the first distribution half-life was longer, probably because of pronounced drug-induced bradycardia (mean +/- SD, 48 +/- 21 beats/min). Distribution clearance was faster in sheep, compared with dogs, also probably because of better blood flow in sheep. Elimination half-life was similar in all species (rabbits, 62.4 +/- 11.3 minutes; sheep, 65.1 +/- 27.1 minutes; dogs, 58.3 +/- 10.3 minutes). This rapid half-life resulted from a small steady-state volume of distribution (rabbits, 908.3 +/- 269.0 ml/kg; sheep, 720.0 +/- 306.7 ml/kg; dogs, 597.7 +/- 290.2 ml/kg) and rapid systemic clearance (rabbits, 19.4 +/- 5.3 ml/min/kg; sheep, 13.3 +/- 3.0 ml/min/kg; dogs, 18.7 +/- 7.5 ml/min/kg). On the basis of these pharmacokinetic variables, alfentanil should have short duration of action in rabbits, sheep, and dogs. This may be beneficial in veterinary practice where rapid recovery would be expected after bolus administration for short procedures or after infusion for longer procedures.     

Pharmacokinetics and bioavailability of ceftriaxone administered intravenously and intramuscularly to calves

Ceftriaxone was administered to Israeli-Friesian male calves by IV and IM routes. The antibiotic was administered IV (10 mg/kg) to 10 calves and IM to 23 calves; 8 were given the antibiotic at the rate of 10 mg/kg of body weight, 5 were given 20 mg/kg, and 10 were given 10 mg/kg, together with probenecid at 40 mg/kg. Serum concentration vs time profiles measured after IV and IM administration were analyzed by use of statistical moment theory. The following mean values +/- SD were found: elimination half-life (t1/2) was 83.8 +/- 8.6 minutes after IV administration and significantly longer 116.8 +/- 20.5 minutes (P less than 0.001) after IM administration at 10 mg/kg. The t1/2 was increased to 141.3 +/- 24.4 minutes by the coadministration of probenecid and to 145.0 +/- 48.2 minutes by doubling the IM dosage to 20 mg/kg. The total body clearance was 3.39 +/- 0.42 ml/min/kg and the renal clearance 2.37 +/- 0.74 ml/min/kg. The specific volume of distribution was 0.2990 +/- 0.0510 L/kg. The average mean residence time (MRT) was 94.0 +/- 12.3 minutes after IV administration and 137.6 +/- 19.9 minutes after IM administration of ceftriaxone at 10 mg/kg. The MRT was increased to 198 +/- 48.8 minutes by the coadministration of probenecid and to 191.0 +/- 59.4 minutes by doubling the IM dose. The former value was significantly different from the MRT after IM administration of the antibiotic at 10 mg/kg. Bioavailability of ceftriaxone after IM administration at 10 mg/kg and at 20 mg/kg was 78% and 83%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Pharmacokinetics of ticarcillin in the dog

Five healthy adult dogs were given a single IV dose (40 mg/kg of body weight) of ticarcillin disodium. Serum concentrations were measured serially over a period of 12 hours. Five days later, the drug was administered IM to the dogs at the same dose rate, and serum concentrations were measured serially for 12 hours. The mean peak serum concentration after IM administration was 120.5 micrograms/ml at 1.5 hours. Pharmacokinetic values following IV administration were (i) elimination rate constant = 0.8/hour-1, (ii) half-life = 0.8 hour, (iii) serum clearance = 292 ml/hr/kg, and (iv) apparent volume of distribution = 347 ml/kg. Estimated values after IM administration were (i) elimination rate constant = 0.6/hour, (ii) half-life = 1.1 hours, (iii) serum clearance = 218 ml/hr/kg, and (iv) apparent volume of distribution = 345 ml/kg; only the elimination rate constants were significantly different between the 2 routes of administration.     

Pharmacokinetics of prednisolone sodium succinate and its metabolites in normovolemic and hypovolemic dogs

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.     

Tissue concentrations and pharmacokinetics of florfenicol in male veal calves given repeated doses

The pharmacokinetic disposition of florfenicol was studied in male veal calves given 11 mg of florfenicol/kg of body weight, IV and 11 mg of florfenicol/kg PO every 12 hours for 7 doses. After florfenicol administration IV, the median elimination half-life was 222.8 minutes, whereas the median half-life of the distribution phase was 7.94 minutes. Median body clearance and apparent volume of distribution were 2.87 ml/kg/min and 0.907 L/kg, respectively. After florfenicol administration, PO, there was a wide variation in the calculated half-life, which was attributed to variation in the rate of florfenicol absorption. The half-life was 167.4 to 534.9 minutes after the first oral dose and 190 to 808.8 minutes after the seventh dose. The median bioavailability after the first oral dose was 0.8888. Peak and trough concentrations of florfenicol were increased after subsequent doses were administered, compared with those after the first oral dose. The percentage of protein binding in serum from one adult cow was 22% to 26%. Florfenicol concentrations in tissues and body fluids of male veal calves were studied after the seventh dose of 11 mg of florfenicol/kg. High concentrations of florfenicol were measured in the urine, kidney, and bile. Low concentrations were measured in the brain, CSF, and aqueous humor. Concentrations in all other tissues and fluids studied were similar to the concurrent serum concentration.     

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).     

Pharmacokinetic properties of theophylline given intravenously and orally to ruminating calves

The disposition of theophylline in healthy ruminating calves was best described by a first-order 2-compartment open pharmacokinetic model. The drug had a mean elimination half-life of 6.4 hours and a mean distribution half-life of 22 minutes. Total body clearance averaged 91 ml/kg/h. The mean values for the pharmacokinetic volume of the central compartment, pharmacokinetic volume of distribution during the terminal phase, and volume of distribution at steady state were 0.502, 0.870, and 0.815 L/kg, respectively. Theophylline was readily absorbed after oral administration to the ruminating calf, with a mean fraction of 0.93 absorbed. The plasma concentrations after oral dosing peaked in approximately 5 to 6 hours, with a mean absorption half-life of 3.7 hours. A flip-flop model (rate constant of input is much smaller than the rate constant of output) of drug absorption was not found because the elimination process roughly paralleled that of the study concerning IV administration. In a multiple-dose trial that used a dosage regimen based on single-dose pharmacokinetic values, clinically normal calves responded as predicted. However, diseased calves had higher than expected plasma concentrations after being given multiple oral doses of theophylline at 28 mg/kg once daily. Overt signs of toxicosis were not seen, but this aspect of the drug was not formally investigated. Theophylline can be used as an ancillary therapeutic agent to treat bovine respiratory disease, but not without risk. The suggested oral dose of theophylline at 28 mg/kg of body weight once daily should be tailored to each case.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Hepatobiliary transport of indocyanine green and sulfobromophthalein in fed and fasted horses

Fasting is associated with unconjugated hyperbilirubinemia in several species, including the horse. Studies in ponies showed that a 3-day fast decreased plasma clearance of bilirubin, cholic acid, and sulfobromophthalein (BSP). Since these organic anions are conjugated with different substrates, it is possible that observed differences in plasma clearance result from a general decrease in hepatic conjugating capacity during the animals' fasting. To test this hypothesis, the effects of a 3-day fast on plasma clearance of IV injected BSP (4.4 to 5.1 mg/kg), which is conjugated to glutathione, and indocyanine green (ICG; 0.8 to 1.1 mg/kg), which is not conjugated, were studied in 10 healthy horses and 2 ponies with diverted enterohepatic circulations (indwelling T tubes). Blood samples were obtained for 30 minutes after injection, and bile samples from ponies were obtained for 3 hours. Fasting increased plasma bilirubin concentration in all animals studied (from 1.03 +/- 0.337 mg/dl in control animals to 3.49 +/- 1.01 mg/dl in fasted animals). Kinetic values of ICG disappearance were determined from single exponential functions, and those for BSP were determined from both single and curvilinear (2-exponential) functions. Plasma clearance of BSP in fed horses (8.65 +/- 1.02 ml X min-1 X kg-1) was greater than clearance of ICG (3.54 +/- 0.67 ml X min-1 X kg-1), results similar to those reported in dogs, cats, rats, and persons. Fasting significantly decreased fractional plasma disappearance rate of both BSP (-36%) and ICG (-58%) and similarly reduced plasma clearance (BSP,-48%; ICG,-55%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of procainamide hydrochloride in dogs

Pharmacokinetics of procainamide hydrochloride were studied in 2 groups of dogs. In a group of 6 dogs, procainamide was administered IV at a small dose of 8 mg/kg (group 1), and blood samples were obtained for 3.5 hours. In another group of 6 dogs, procainamide was administered IV and orally at an average dose of 25.5 mg/kg (group 2) in a crossover manner. Blood samples were obtained for 48 hours. In 2 dogs (previously used in part II), N-acetylprocainamide (NAPA) was administered IV at a dose of 10 mg/kg. Plasma samples were assayed for procainamide by fluorescence polarization immunoassay, and NAPA samples were assayed by high-performance liquid chromatography. In group 1, the elimination of procainamide was described by a 1-compartment, open pharmacokinetic model. The elimination half-life was 2.43 hours, the apparent volume of distribution was 1.44 L/kg, and the systemic clearance was 0.412 L/kg/hr. In group 2, 2 of the 6 dogs were described by a 1-compartment model, and 4 of the 6 dogs were described with a 2-compartment pharmacokinetic model. The elimination half-life for the IV dosage was 2.85 hours, the apparent volume of distribution was 2.13 L/kg, and the systemic clearance was 0.519 L/kg/hr. For the orally administered dose, the bioavailability was 85%, and the absorption half-life was 0.5 hours. There was no evidence of acetylation of procainamide to NAPA or deacetylation of NAPA to procainamide. The estimated elimination half-life of NAPA was 4.7 hours.