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Didemnin B has undergone trials in cancer patients, and has antiviral and immunosuppressive properties. [(3)H]didemnin B was administered intraperitoneally (i.p.) to mice at 320 or 1280 microg/kg. Urine and feces were collected until 168 h, at which time the mice were killed and tissues collected. Additionally, [(3)H]didemnin B was given i.p. at 320 microg/kg, and mice were killed at 1-120 h post-dosing. Radiolabel increased rapidly in blood then rapidly declined. Most radiolabel in urine, feces and tissues represented parent compound. Concentrations of [(3)H]didemnin B were greatest in the liver > gallbladder > lower digestive tract congruent with pancreas > spleen > kidney congruent with adipose tissue congruent with urinary bladder with urine. The pancreas had the longest terminal half-life of the tissues and the highest radioactivity at 7 days. Intermediate concentrations were in the duodenum congruent with jejunum > lung > iliopsoas > stomach congruent with testes congruent with skin > heart. Low concentrations were in the humerus congruent with femur congruent with quadriceps congruent with triceps >> brain. Fecal excretion accounted for 45.9%-58.3% of the dose and declined after 24 h, followed by an increase, suggesting possible enterohepatic recycling or an impact of circadian rhythms. Urinary excretion accounted for 18.4%-25.2% of the dose, but was minimal after 24 h. The concentrations were highest in organs previously found to be sensitive in animals and humans. Didemnin B should be evaluated in animal models for treatment of pancreatic cancer., (Copyright (c) 2005 John Wiley & Sons, Ltd.)

Two crossover bioequivalence trials of an enantioselectively enterohepatic recycled drug, carprofen, were conducted in dogs with the same racemic oral formulation to determine: (i) the influence of feeding patterns, and (ii) the effect of the analytical method (enantioselective vs non-enantioselective) on the statistical power of the trials. The first trial was conducted with a standard feeding protocol and the second with a special feeding protocol selected to ensure constant biliary flow into the duodenum. Using a non-enantioselective technique, 90% confidence intervals provided conclusions of bioequivalence in 100% of the cases for both area under the plasma concentration versus time curve (AUC) and maximum plasma drug concentration (Cmax) with the special feeding protocol, but only 50% for AUC and 13% for Cmax with the standard feeding protocol, suggesting that a feeding pattern that diminishes plasma drug concentration rebound for an enterohepatically recycled drug increases the power of a bioequivalence trial. Whatever the feeding protocol, an enantioselective method decreased the power of the trials for AUC but increased the power of the trials for Cmax. For an enterohepatically recycled drug, feeding pattern can influence the power of a bioequivalence trial, and the analytical technique that provides the greatest power depends on the assessed bioequivalence parameter and the feeding pattern., (Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association)

Polyacrylonitrile is used in the manufacture of dialysis membranes. These membranes are fundamental to the functioning of implantable probes for microdialysis and ultrafiltration sampling of tissue fluids. Although in vivo experimentation using polyacrylonitrile has been reported to cause little inflammatory response when implanted subcutaneously, such information is not available for intramuscular implantation in sheep. The procaine and benzathine salts of penicillin are formulated for intramuscular injection. These salts of penicillin or the formulation excipients may cause inflammatory reactions. Use of polyacrylonitrile probes to draw samples from sites at which these formulations have been injected may be compromised by inflammation or direct interaction between formulation excipients and the dialysis membrane. The aim of this project was to describe tissue responses to intramuscular implantation of polyacrylonitrile in the presence and absence of either procaine or procaine plus benzathine salts of penicillin G. Each of 20 normal sheep was implanted with two ultrafiltration probes, one at the site of an injection of procaine or benzathine plus procaine penicillin G. Similar injections were also made at remote intramuscular sites. After 8, 9, and 11 days of the experiment, sheep were killed and the injection and implantation site muscle were excised and prepared for histopathological examination. The implantation of the probe alone caused greater inflammatory response than the injection of procaine or procaine plus benzathine penicillin G at remote intramuscular sites. The histopathological lesions were greatest where the implantation site was coupled with the injection of either formulation of penicillin G. Polyacrylonitrile may not be a suitable dialysis membrane material for intramuscular implantation in sheep.

The excretion and tissue retention of three 14C-labeled lower chlorinated biphenyls were examined in prepubertal male and female Sprague-Dawley rats following IV administration. Urine and feces were collected individually at different time intervals up to 72 h for pharmacokinetic analyses. After 72 h, different organs were removed and extracted in acetone:hexane (1:1, v/v) to determine radioactivity. Within the first 10 h after dosing, 2,2', 5-trichlorobiphenyl (PCB 18) was rapidly excreted in urine (8-18% of the administered dose), whereas only 0.6-0.8% of 2,2',4, 4'-tetrachlorobiphenyl (PCB 47) and 0.3-0.8% 3,3',4, 4'-tetrachlorobiphenyl (PCB 77) were found in urine during this time period. The half-life of elimination was shortest for PCB 18 (37.5 to 49.2 h). The half-lives for PCB 47 and PCB 77 were 351 to 672 h and 152 to 186 h, respectively. The cumulative total excretion (urinary + fecal) of PCB 18 within 72 h was 51-62%, of PCB 77 was 22-25%, and of PCB 47 was 7-10%. No parent PCBs were detected in urine. PCB 47 accumulated preferentially in adipose tissues (subcutaneous fat > mesenteric fat); relatively high levels of PCB 47 were also found in adrenals, ovaries, lungs, liver, and skin. The highest concentration of PCB 77 was found in serum, followed by adipose tissues. Very low concentrations of PCB 18 were found in most tissues; the highest being found in serum, followed by ovaries and adrenal glands. This study suggests that prepubertal rats retain higher short-term serum levels and have lower excretion rates than adult rats.

A bioequivalence trial is a statistically based comparison of two formulations to demonstrate with a controlled consumer (patient) risk that two formulated drug products are interchangeable. The basic assumption underlying a bioequivalence trial is that essentially the same plasma time-course leads to essentially the same effect allowing two formulations to be interchanged. Bioequivalence is generally assessed using kinetic end points and in practice, two formulations in which bioavailability parameters (rate and extent) differ by 20% or less, with a 90% degree of confidence, are considered to be bioequivalent. In this review, the design and evaluation of bioequivalence studies are presented with special attention given to scientific issues.

The toxicokinetics of tritiated dihydromicrocystin-LR ([3H]2H-MCLR) were studied in anesthetized, specific-pathogen-free pigs. Pigs were dosed with radiolabeled plus non-labeled 2H-MCLR at 25 or 75 micrograms/kg i.v., or via an isolated ileal loop at 75 micrograms/kg. The i.v. doses were rapidly removed from the blood. At either i.v. dose, more than half the radiolabel from [3H]2H-MCLR present in the blood at 1 min postdosing was cleared by 6 min. The blood clearance at the 75 micrograms/kg dose was slower than at the 25 micrograms/kg dose. Accordingly, at the high dose, the concentrations of the toxin in blood were disproportionately higher from 10 min after dosing until the study ended 4 hr later. The decreased clearance is presumably due to decreased elimination from the blood as a consequence of the hepatic injury that was observed histologically. Following administration of [3H]2H-MCLR at 75 micrograms/kg via the ileum, the maximal toxin concentration in blood was achieved at 90 min after dosing. At that time the [3H]2H-MCLR concentration in portal venous blood was 3.6 times higher than in peripheral venous blood. Although bile production varied, following i.v. dosing radioactivity was detected in bile as early as 12 min postdosing in one animal. This study demonstrated that [3H]2H-MCLR is rapidly removed from the blood of anesthetized swine and that excretion of the radiolabel into bile may begin within 30 min of dosing.

A new method of collection of interstitial fluid (ISF) (the site of most bacterial infections) was developed for the determination of free (unbound) penicillin G concentrations in sheep. Dialysis fiber bundles for the collection of ISF were first characterized in vitro and subsequently implanted in the subcutaneous fascia of the dorsal thorax parallel to the vertebral column in sheep. The sheep were then dosed intravenously with 26.4 and 52.9 mg/kg of sodium penicillin G using a crossover experimental design. Plasma and ISF dialysate were collected after dosing for determination of penicillin G concentrations using high pressure liquid chromatography (HPLC). The concentration of penicillin G in the ISF dialysate was calculated with the recovery ratio determined for each fiber bundle. The decline of penicillin G concentrations in ISF dialysate paralleled the disappearance of the drug from plasma providing evidence for the rapid diffusion of penicillin G into the fiber bundles. Pharmacokinetic analysis determined that the disposition of penicillin G was best described by a two-compartment open model with penicillin concentrations in plasma (Cp) defined by two biexponential equations, Cp = 170.64e-7.16t + 31.04e-1.56t for the low dose and Cp = 418.19e-1.56t for the high dose.

Effective renal plasma flow (ERPF) was evaluated, using continuous-infusion p-aminohippurate clearance (CLPAH) and single-injection plasma clearance of technetium-99m mercaptoacetyltriglycine (99mTc-MAG3; CLMAG3) methods. Simultaneous clearance determinations were made in 6 dogs: 2 determinations for each dog before, and 1 determination after renal failure was induced by administration of amphotericin B. Linear regression analysis was used to derive an equation to estimate ERPF from CLMAG3 after the single IV injection. A Student's t-test was used to compare pharmacokinetics between the dogs when they were healthy and when they were in renal failure. An F-test was used to determine the appropriate Student's t-test. Results indicated that CLMAG3 correlated reasonably well (r = 0.83, P < 0.0001) with ERPF obtained from the CLPAH value. The volume of distribution and elimination of 99mTc-MAG3 decreased during renal failure. Although there was minimal binding of 99mTc-MAG3 to erythrocytes, it was significantly (P = 0.0008) lower during renal failure. Protein binding was not significantly different during renal failure. All dogs had signs of nausea and emesis at variable times after injection of 99mTc-MAG3. Determination of CLMAG3 after a single injection provides an adequate means to rapidly assess ERPF in dogs. The technique could easily be performed in dogs with renal disease, thus providing valuable information regarding progression of naturally acquired renal failure.

The disposition of the estrogenic mycotoxin, zearalenone (ZEN) in female, 10- to 14-week-old Yorkshire pigs was investigated. Pigs were administered [3H]ZEN intravenously (IV; n = 4; 5 mg/kg; 15 microCi/kg), orally (n = 4; 10 mg/kg; 30 microCi/kg), or intravenously with bile removal (IVB; n = 2; 5 mg/kg; 15 microCi/kg). Plasma, urine, feces, and bile (IVB pigs only) were serially collected and analyzed for radioactivity. Metabolite profiles were determined in plasma and bile by HPLC. The biological half-life of total plasma radioactivity in IV and orally dosed pigs (86.6 hr) was much larger than that of IVB animals (3.34 hr). Metabolite profiles of plasma concentration vs time demonstrated secondary peaks in concentration during the terminal elimination phase in IV and orally dosed pigs. In IVB pigs these peaks were absent, relative metabolite profiles were altered, and ZEN and metabolites were no longer detectable after 16 hr post-dosing. Biliary recovery of radioactivity, principally as glucuronide conjugates, was extensive (45.61 +/- 4.7%) in IVB pigs and significantly greater (p < 0.05) than that of fecal recovery of radioactivity in IV (6.56 +/- 0.78) or orally dosed (21.74 +/- 1.56%) pigs. Intraduodenal administration of bile containing [3H]ZEN and metabolites resulted in recovery of 64.56 +/- 4.89% of the dose in bile, 20.78 +/- 3.94% in urine, and the presence of glucuronide conjugates of ZEN and alpha-zearalenol (ZEL) in portal and jugular plasma. Differences in metabolite profiles between administered bile and sampled plasma suggest that the intestinal mucosa was active in reducing ZEN to ZEL and conjugating these metabolites with glucuronic acid. These studies provide evidence for extensive biliary secretion and enterohepatic cycling of ZEN and metabolites in pigs.

The pharmacokinetics of a parenteral formulation of metoclopramide (monochloride monohydrate) were determined following single intravenous (i.v.) and intramuscular (i.m.) 0.5-mg/kg doses to two groups of 4 goats in a crossover design. Mean serum concentrations of metoclopramide following i.v. administration of 0.5 mg/kg declined rapidly from a peak of 277.5 ng/ml at 3 min post-dosing to 25 ng/ml at 90 min. Serum concentrations were not detectable by 120 min after drug administration. The curve of serum concentrations vs. time was characteristic of a two-compartment open model. Mean parameters from analysis of the individual i.v. data gave a biological half-life of 0.62 h and a volume of distribution of the central compartment of 1.34 l/kg. Serum concentrations of metoclopramide following i.m. administration of 0.5 mg/kg rose rapidly to a peak of 160.9 ng/ml at 15 min post-dosing and then declined in parallel with the elimination phase of the i.v. study. These data were best described by a two-compartment open model with first-order absorption. The mean biological half-life was 1.04 h. There were no adverse reactions associated with metoclopramide at the 0.5-mg/kg dose administered by either route.

Sodium salicylate was administered to rabbits in order to compare its disposition with that in other major and minor agricultural species. A dose of 44 mg/kg was given orally (p.o.) or intravenously (i.v.), and plasma and urine samples were collected for 36 h and 96 h, respectively. The majority of the drug was excreted as salicylic acid (SA) within 12 h. The major metabolites following an oral dose were salicyluric acid (SUA) and the glucuronide conjugates of SA and SUA. Following i.v. dosing, sulfate conjugates of both SA and SUA were also evident. Both SA and SUA were detected in plasma. Following i.v. administration, SA was distributed with a Vss of 0.249 +/- 0.082 l/kg and cleared at a rate of 0.0432 +/- 0.006 l/h/kg. The biological half-life, calculated from the terminal disposition-rate constant, was 4.3 h (i.v.) or 9.7 h (p.o.). The urinary elimination pattern of SA and metabolites in the rabbit was similar to that previously reported by our laboratories for cattle and goats, although total recovery of the administered dose was not as high as for the latter two species. However, the volume of distribution was larger than for cattle and goats, and rabbits cleared the drug more slowly than those species. As a consequence, the biological half-life was eight to ten times longer than in the ruminants studied previously.

Studies of theophylline pharmacokinetics in humans have shown that a higher peak concentration and area under the curve (AUC), with a shorter time to peak (tp) occur after a morning dose than after an evening dose. The purpose of this study was to determine whether theophylline pharmacokinetics in the cat were also influenced by the administration time of day. Theophylline was administered to six cats in a three-way cross-over study as a single dose of intravenous aminophylline and oral sustained-release theophylline (Slo-bid Gyrocaps and Theo-Dur Tablets), between 08.00-09.00 h (Phase I) and 20.00-21.00 h (Phase II). Subjects were maintained on a 12-h light (08.00-20.00 h): 12-h dark cycle. Similar to the human studies, the tp was shorter following the morning dose. Conversely, however, the peak plasma theophylline concentrations achieved in these cats following intravenous aminophylline and oral Slo-bid were significantly higher following the evening dose. The AUC obtained for Theo-Dur was also significantly greater following the evening dose. No single pharmacokinetic parameter could account for the higher plasma concentrations achieved following the evening dose.

Six ponies with recurrent obstructive lung disease were studied during two separate 60 min periods while receiving constant equal volume infusions of either aminophylline or sterile water. Dynamic lung compliance, pulmonary resistance, respiratory rate, tidal volume, blood gas tensions and heart rate were measured. Plasma samples were obtained for determination of theophylline concentrations before, and at 10 min intervals during, the infusion period. Excitability was assessed subjectively at these same time periods. The plasma theophylline concentrations in ponies were well predicted by a previously published model of theophylline pharmacokinetics in the horse. Sterile water had no effect on lung function. Aminophylline produced significant changes in lung function compared to baseline values, including a decrease in resistance at 30 min when the mean plasma theophylline concentration was 59 +/- 14 mumol/litre and an increase in compliance at 60 mins at a mean plasma theophylline concentration of 102 +/- 23 mumol/litre. Excitement was noted between 40 and 50 mins in all ponies (mean plasma theophylline concentration 74 +/- 20 and 84 +/- 24 mumol/litre, respectively). Heart rate increased at 50 mins. The therapeutic range for intravenous (iv) theophylline concentration in 'heavey' ponies therefore appears to be between 59 and 84 mumol/litre when aminophylline is administered iv. Below 59 mumol/litre there was no consistent bronchodilator activity and above 84 mumol/litre excitement and tachycardia limited the usefulness of the drug.

Chlortetracycline hydrochloride was administered intra-arterially (11 mg/kg) and as an oral drench (33 mg/kg) to ten 21.0-31.5-kg pigs. Five of the pigs were fasted 18 h prior to dosing and five of the pigs were fed ad libitum prior to dosing. The mean volume of distribution determined by area-under-the-curve calculations for the fasted pigs (0.967 +/- 0.210 l/kg) was significantly less (P less than 0.05) than the mean volume of distribution for the fed pigs (1.39 +/- 0.31 l/kg). Mean total body clearance of the drug was also significantly less (P less than 0.05) in the fasted pigs (0.165 +/- 0.055 l/kg/h) as compared to the fed pigs (0.307 +/- 0.053 l/kg/h). The elimination constants (beta) were not found to be statistically different (P less than 0.05): 0.1811 +/- 0.0057 for the fasted pigs; 0.2260 +/- 0.0461 for the fed pigs. The bioavailability for both groups was similar; 19.12 +/- 8.3% for the fasted pigs and 17.88 +/- 5.3% for the fed pigs. In a second experiment three groups of six pigs which weighed 34.5-44.1 kg were fed a corn-soy diet ad libitum. The rations were fortified with chlortetracycline at 100, 400 or 1000 mg chlortetracycline hydrochloride/kg feed. Chlortetracycline concentrations were determined in plasma samples collected over a 6-day period. Plasma chlortetracycline concentrations reach a plateau within 24 h after initial access to the trial diets and were highly correlated with the dose of the drug consumed (r2 = 0.97).

A renal failure model was developed in the dog to evaluate the effect of varying degrees of renal failure on drug pharmacokinetics. A controlled impairment of renal function was induced by electrocoagulating portions of one kidney and excising the contralateral kidney. The magnitude of renal dysfunction, defined by the percentage of normal glomerular filtration rate (% NGFR), was estimated by 125I-iothalamate total body clearance. The model was evaluated by comparing the pharmacokinetics of oxytetracycline (OTC) before and after the induction of renal failure in two experiments: single intravenous dose (11 dogs); single intravenous and oral doses (8 dogs). Renal failure (RF) was studied in three classes according to % NGFR: less than 25%, severe RF; 25-39%, moderate RF; and greater than or equal to 40%, mild RF. Significant reductions were observed over RF class in OTC pharmacokinetic parameters for elimination and distribution but not for oral absorption.

Pharmacokinetic variables of etomidate were determined after IV administration of etomidate (3.0 mg/kg of body weight). Blood samples were collected for 6 hours. Disposition of this carboxylated imidazole best conformed to a 2- (n = 2) and a 3- compartment (n = 4) open pharmacokinetic model. The pharmacokinetic values were calculated for the overall best-fitted model, characterized as a mixed 2- and 3-compartmental model. The first and most rapid distribution half-life was 0.05 hour and a second distribution half-life was 0.35 hour. Elimination half-life was 2.89 hours, apparent volume of distribution was 11.87 +/- 4.64 L/kg, apparent volume of distribution at steady state was 4.88 +/- 2.25 L/kg, apparent volume of the central compartment was 1.17 +/- 0.70 L/kg, and total clearance was 2.47 +/- 0.78 L/kg/h.

Fenbendazole (FBZ) was administered intravenously (1 mg/kg) and orally (5 mg/kg) to catheterized, confined channel catfish. Blood samples were collected for 72 h, and resulting FBZ plasma concentrations were pharmacokinetically modelled. Following intravenous administration t 1/2 alpha was 0.51 h, t 1/2 beta was 16.8 h, body clearance (C1B) was 0.0598 L/kg/h, and Vd (area) was 1.45 L/kg. After oral administration the t 1/2 (abs) was 1.47 h, the t 1/2 beta was 20.1 h, and the tlag was 0.1 h. Following oral administration of 5 mg FBZ/kg body weight, the following tissues and body fluids were sampled for concentrations of FBZ, oxfendazole (FBZ-SO), sulphone metabolite (FBZ-SO2) and hydroxy metabolite (FBZ-OH): liver, posterior kidney, fat, muscle, bowel contents and urine. Fenbendazole was detected in the highest concentrations in abdominal fat, whereas oxfendazole was found primarily in the kidney, liver and abdominal fat. The sulphone metabolite was detected only in urine and bowel contents, while the hydroxy metabolite was found most often in the liver and abdominal fat samples.

Study was made of the pharmacokinetics and toxicopathy of deoxynivalenol (DON, vomitoxin) given IV to swine. In the 24 hours after swine were given DON, clinical signs of vomiting, diarrhea, muscular weakness, tremors, and twilight coma were similar to those observed with other 12,13-epoxytrichothecenes. Hypoglycemia and pancreatic islet cell lesions were observed which indicated that DON-induced changes in intermediary metabolism may be an insidious aspect of DON intoxication. Histopathologic examination of all organ systems revealed pancreatic acinar and islet cell necrosis and mild lympholysis of the mesenteric lymph nodes. The renal excretion of DON was altered by IV infusion of saline solution. Pharmacokinetic findings may indicate that DON was both secreted and reabsorbed by the renal tubules. The half-life of DON ranged from 2.08 to 3.65 hours. Residues of DON were not found in skeletal muscle of swine at 24 hours after dosing.

Oxytetracycline (OTC) was administered by constant IV infusion to 3 healthy postpartum cows at rates predicted to approach a steady-state plasma concentration of 5 micrograms/ml. After 8 hours of constant IV infusion, genital tissues were surgically removed. The mean plasma-to-tissue ratios of concentrations of OTC were 0.95, 1.33, 1.88, and 1.04 (2 cows only) for caruncles, endometrium, uterine wall, and ovaries, respectively. Differences between the ratios of any 2 of the uterine tissues were statistically significant (P less than 0.05). Intrauterine (IU) infusions of 5.5 mg of OTC/kg were administered to 3 healthy postpartum cows and 3 postpartum cows with metritis. The mean values of the fraction of the drug absorbed from the uteri of cows given IU infusions of OTC were 0.50 and 0.23 for healthy postpartum cows and postpartum cows with metritis, respectively. Concentrations of OTC were high in the caruncles and endometrium of all cows at 24 hours after IU infusions of the drug. Concentrations in the plasma, uterine wall, and ovaries were low, with mean concentrations of OTC in these tissues in postpartum cows with metritis being lower than those in the same tissues of healthy postpartum cows. Computer-simulated genital tissue concentrations of OTC after twice daily IV doses of 11 mg/kg indicated that this dosage regimen would provide postpartum uterine tissue concentrations greater than 5 micrograms/g throughout the dosage interval in all tissues, except the uterine wall.

Disposition of sulfathiazole in plasma and urine of swine was determined following single intravenous and oral doses. Pharmacokinetics of the drug were described by a 1-compartment open model. The drug was rapidly eliminated, mainly by renal excretion of unchanged sulfathiazole and metabolism to acetylsulfathiazole, with a biological half-life of 1.4 hours. Sulfathiazole (in solution) was absorbed rapidly (half-life 0.8 hour) and relatively completely (73%) following oral administration.

The pharmacokinetics of lidocaine in dogs were investigated following the intravenous and intramuscular administration of single doses of lidocaine hydrochloride. The mean elimination rate constant and the mean specific clearance determined for the intravenous portion of the study were 0.786 h-1 and 2.40 1/kg/h, respectively. Following intramuscular administration the mean absorption rate constant was 7.74 h-1. Absorption was nearly complete as the percentage of an intramuscular dose absorbed averaged 91.9%. Concentrations of two N-deethylated metabolites, determined following the administration of lidocaine suggest that monoethylglycinexylidide is eliminated rapidly while glycinexylidide is more slowly eliminated. The relative contribution of these metabolites to the therapeutic and toxic effects of lidocaine and the potential for glycinexylidide accumulation during lidocaine administration remain to be investigated.

Sulfadimethoxine was administered intravenously and orally to five swine. More than 75% of the dose was excreted into urine as the acetyl metabolite with 4-6% excreted unchanged. Plasma and urine data were not consistent when a linear pharmacokinetic model was used to describe the data. Sulfadimethoxine has a high affinity for plasma protein, and the data were subsequently fitted to a nonlinear model, which included saturable protein binding. The choice of a nonlinear model was further supported by a minimum value for the Akaike information criteria. The protein binding constant obtained was 2.8 X 10(4) M-1 and the total protein binding site concentration in plasma was 4.6 X 10(-4) M. Both values are comparable with in vitro data. This result suggests that the nonlinear model involving protein binding can be successfully applied to pharmacokinetic data. The apparent biological half-life of sulfadimethoxine (free and bound) in plasma was 14 hr; however, the half-life of elimination of free drug was 1.25 hr. Following oral administration, all of the dose was absorbed with an apparent absorption half-life of 2.9 hr.

The absolute bioavailability and pharmacokinetic parameters of two methylprednisolone formulations (methylprednisolone sodium succinate and methylprednisolone acetate) were determined in five dogs. Plasma concentrations of methylprednisolone, methylprednisolone sodium succinate, and methylprednisolone acetate were measured by sensitive and specific high-performance liquid chromatographic methods. After intravenous methylprednisolone sodium succinate administration, methylprednisolone was released rapidly but the extent of availability was rather low (43.6%). This has been tentatively explained in terms of its subsequent single-pass metabolism in the liver, i.e., hepatic hydrolysis of methylprednisolone sodium succinate followed by immediate hepatic elimination of the released methylprednisolone. After intramuscular administration of methylprednisolone acetate, its absorption was slow (half-time of absorption, 69.04 h) and the availability of the released methylprednisolone was low (42.7%). Therapeutic implications of these results are discussed, especially those which are relevant to shock therapy.

Plasma and urine data on sheep following administration of sulfathiazole as single intravenous and oral doses were examined. A one-compartment open model was developed to describe the pharmacokinetics of sulfathiazole in sheep. The drug was rapidly eliminated, primarily by renal excretion of unchanged sulfathiazole and metabolism to acetyl sulfathiazole, with a biological half-life of 1.3 hours. Sulfathiazole was absorbed slowly (half-life, 18 hours) and relatively completely (73%) after oral administration in solution.

The pharmacokinetics of lithium were determined in eight adult dogs. The data were fitted to a two-compartment model. Single intravenous doses of lithium chloride, and single oral doses of lithium carbonate were used. The mean plasma lithium half-life (t1/2) following the single intravenous dose was 21.6 h, and the mean apparent specific volume of distribution of the central compartment (V'c) was 0.189 l/kg. Mean bioavailability was 78.8% following oral administration.

Dichlorvos (dimethyl 2,2-dichlorovinyl phosphate) was administered orally to German Shorthair Pointer dogs at approximately 60 mg/kg (twice the usual clinical dose). Plasma and erythrocyte cholinesterase (ChE) was monitored prior to, 90 min, and 180 min post-ingestion. 2-PAM (20 mg/kg IV) and atropine sulfate (0.022 mg/kg IM) were administered 90 min after the dichlorvos to paired treated and control dogs. The telemetered electrocardiographic (ECG) signal was analyzed by a Vagal Tone Monitor (VTM) to yield mean heart period (msec) and an estimate of the amplitude of respiratory sinus arrhythmia (V in natural log values of msec2) for five min intervals. Dichlorvos did not cause cholinomimetic symptoms even though blood cholinesterase was significantly inhibited (plasma -51.3% and erythrocyte -43.7%). The atropine sulfate treatment resulted in the expected vagolytic effects in both the control and the dichlorvos treated dogs, but the atropine effects were attenuated in the latter dogs. Three weeks later, ChE activity was not significantly depressed in the dichlorvos treated dogs, and their V responses to atropine were more similar to the responses in control dogs.

The distribution of hexachlorobenzene (HCB) was studied in male beagles after a single 1-mg/kg iv dose of either 14C-HCB or unlabeled HCB. Distribution was also determined in animals after seven daily oral administrations of either 10 mg/kg or 100 mg/kg HCB. Excretion of HCB and metabolites through urinary and fecal routes was studied in all four animals receiving 14C-HCB. In addition, total bile was collected from one of the animals receiving 14C-HCB to determine the importance of biliary excretion. Immediately after iv administration, a large proportion of the dose was distributed to the lungs. From the lungs, HCB was rapidly distributed to highly perfused tissues including the visceral organs and brain. Further redistribution of HCB from highly perfused tissues to adipose tissue occurred at a much slower rate. In animals receiving daily oral doses of 10 or 100 mg of HCB per kg, adipose tissue was again found to accumulate the highest concentrations of HCB. Excretion of HCB and metabolites occurred primarily through fecal elimination, with urinary excretion being of less importance. Fecal excretion was found to be composed of two separate processes, biliary excretion and intestinal excretion. Of these two processes, biliary excretion was shown to be the major contributor to fecal excretion. After single 1-mg/kg IV doses of 14C-HCB in three beagles, blood, urine, and feces were monitored over a 12-week period for 14C content. Computer-assisted pharmacokinetic models were constructed to characterize these data. A three-compartment mammillary model provided the optimum fit to the observed data. Biological half-life values were projected to range from 6 weeks to 3 years.

Digoxin was administered as a single intravenous injection of 22 micrograms/kg to six cattle. The resulting serum concentrations were fitted by both a bi- and tri-exponential equation with the latter providing the best fit to the data of a majority of the animals. The biological half-life of digoxin in cattle was found to be 7.8 h. This relatively short half-life in comparison to other animal species dictates that digoxin should be administered more frequently to cattle to provide therapeutic concentrations in serum without broad fluctuations in serum concentrations. Computer simulations of various intravenous dosage regimens suggested that a loading dose of 22 micrograms/kg followed by an infusion of 0.86 micrograms/kg/h would offer the greatest safety and efficacy in bovine patients.

The pharmacokinetics of theophylline were investigated in dogs following intravenous, single oral, and multiple oral doses of aminophylline. Mean half-life (t1/2) of theophylline following single intravenous administration was 5.7 h and the apparent specific volume of distribution (V'd area) was 0.82 litre/kg. The bioavailability of theophylline was high (91%) following oral administration of aminophylline tablets and the absorption half-life (t1/2ab) was 0.4 h. Theophylline plasma concentrations observed following repeated oral administration of aminophylline tablets were somewhat greater than predicted. This suggests that theophylline plasma concentrations should be monitored and the dosage regimen individually adjusted in critically ill animals.

The pharmacokinetics and bioavailability of a formulation of chloramphenicol base in propylene glycol were determined following administration of single intravenous (i.v.) and subcutaneous (s.c.) 50 mg/kg doses of chloramphenicol to six non-lactating Holstein cows. Mean serum concentrations of chloramphenicol following i.v. administration of 50 mg/kg declined rapidly from a peak of greater than 100 micrograms/ml to 6.9 micrograms/ml at 12 h after administration. Serum concentrations were not detectable at 24 h after administration. The curve of serum concentrations vs time was characteristic of a two-compartment open model. Mean i.v. data gave a biological half-life of 4.3 h and a volume of distribution of the central compartment of 0.44 l/kg. Serum concentrations of chloramphenicol following s.c. administration of 50 mg/kg rose slowly to a broad peak near 20 micrograms/ml from 3 to 8 h after administration and then declined. These data were also analysed according to a two-compartment open model. The biological half-life was 4.2 h and the volume of distribution of the central compartment was 0.50 l/kg. Significant adverse reactions, including acute collapse, intravascular haemolysis and haemoglobinuria, were observed in cows when dosed i.v. Cows dosed s.c. exhibited local reactions at injection sites. The disadvantages of administration of 50 mg/kg doses of chloramphenicol base in propylene glycol appear to be significant and may outweight the potential advantages of parenteral use of the drug as presently formulated.

The quantitation of oxytetracycline, tetracycline, and chlortetracycline was accomplished by high-pressure liquid chromatography using an anion-exchange column. The tetracyclines were extracted from urine as their calcium complexes. Concentrations as low as 12 microgram of oxytetracycline/ml and 4 microgram of tetracycline and chlortetracycline/ml were quantitated accurately. The relative standard deviation of the method varied from 0 to 5%.

Serial blood samples were collected and plasma concentrations of florfenicol (FLO) were measured following the administration of an intravenous bolus of 50 mg/kg FLO to five healthy non-lactating dairy cows. A triexponential equation provided the best fit of the data for four of the five cows. The mean value for beta corresponded to a half-life of 3.2 h. The mean apparent volume of distribution was 0.67 l/kg, and the mean body clearance was 0.15 l/kg/h. The extent of binding of FLO to bovine plasma proteins was determined in vitro at concentrations of 5 micrograms/ml and 50 micrograms/ml by equilibrium dialysis and ultrafiltration. The drug was 18% and 19% bound by equilibrium dialysis, and 23% and 19% bound by ultrafiltration, at 5 micrograms/ml and 50 micrograms/ml, respectively. Phagocytosis of 32phosphorus-labelled Staphylococcus aureus by bovine blood neutrophils was compared in vitro between neutrophils incubated in phosphate-buffered saline alone or in combination with 5, 125, or 1000 micrograms/ml chloramphenicol or FLO. There was no significant effect of chloramphenicol at any concentration. Florfenicol significantly inhibited phagocytosis at all concentrations, but the percentage inhibition was small. The clinical significance, if any, of this effect of FLO remains to be demonstrated.

Date from plasma and urine samples from four ewe lambs were analyzed after administration of sulfamerazine as single IV and oral doses. A two-compartment pharmacokinetic model was developed to describe the disposition of sulfamerazine. The drug was eliminated, primarily by renal excretion of (i) unchanged sulfamerazine and metabolism to an acetyl metabolite, (ii) polar conjugates, and (iii) a third metabolite. The biological half-life of the drug was 6.6 hours. The average value of the absorption rate constant was 0.433 hour-1 (half-life 1.60 hours). Sulfarmerazine was relatively completely absorbed (approx 81% of dose) after oral administration in solution.

Sulfadimethoxine was administered intravenously and orally to four cattle, and plasma and urine samples were collected at various times postdose. Modeling these data with a linear pharmacokinetic model gave unsatisfactory fits, and the data were subsequently fitted to a one-compartment model with saturable protein binding. The saturable protein binding model included the usual linear excretion and elimination processes as well as protein binding parameters. The values obtained in vivo for the binding constant, 5.01 x 10(4) M-1, and the total protein concentration, 7.89 x 10(-4) M, compared favorably with previously reported in vitro values. These results indicate that protein binding can be successfully included in a pharmacokinetic model.

Pharmacokinetics of thiamylal were determined after 13.2 mg of thiamylal/kg of body weight was administered IV to 6 healthy cats. Blood samples were obtained for 12 hours. Disposition of thiamylal best conformed to 2 multicompartmental models, a 2-compartment (n = 1) and a 3-compartment (n = 5) open pharmacokinetic model. The pharmacokinetic values were calculated for the overall best-fitted model, a mixed 2- and 3-compartmental model. The first or rapid distribution half-life was 1.91 minutes and a second, or slower, distribution half-life was 26.51 minutes. The elimination half-life was 14.34 hours. The apparent volume of distribution was 3.61 +/- 1.8463 L/kg, whereas the apparent volume of the central compartment was 0.46 +/- 0.2034 L/kg, and the total clearance was 0.135 +/- 0.0616 L/kg/h.

The pharmacokinetics of theophylline were determined in adult cats and the data were fitted to a two-compartment model. Single intravenous and multiple oral doses of aminophylline were used. The mean plasma theophylline half-life (t1/2) following the single intravenous dose was 7.8 h and the mean apparent specific volume of distribution (V'd(area] was 0.46 1/kg. The absorption half-life (t1/2ab) was 0.5 h and the bioavailability was 96% following oral administration. There was excellent agreement between the predicted and observed plasma theophylline concentrations following multiple oral doses.

Six derivatives of ethylenediamine-N,N'-bis (alpha-2-hydroxy phenyl) acetic acid labeled with technetium 99m were prepared and their imaging qualities evaluated in ponies. The 6 agents produced good scintigraphic images of certain structures of the liver in the pony. For each agent, 13 different scans were taken. Dorsal views of the left lateral, right lateral, and quadrate lobe were obtained with dorsal scans. Left lateral and left lateral oblique (45 degrees) scans provided a left lateral view of the left lobe and a medial view of the right lateral lobe. Right lateral scans revealed the right lateral and quadrate lobes. Administration of 99mTc-labeled colloids which are commonly used in other species for liver scintigraphy resulted in extensive lung uptake in the pony.

Theophylline was administered in a three-way crossover design study to six cats intravenously (Aminophylline USP, Invenex Laboratories, Chagrin Falls, OH) and orally as two sustained-release formulations (Slo-bid Gyrocaps (SB), William H. Rorer, Inc., Fort Washington, PA; Theo-Dur Tablets (TD), Key Pharmaceuticals, Miami, FL). Values were determined for mean residence time (SB = 19.4 +/- 3.2 h; TD = 15.8 +/- 4.8 h), mean absorption time (SB = 8.0 +/- 2.3 h; TD = 4.8 +/- 2.3 h), absolute bioavailability (SB = 82 +/- 27%; TD = 76 +/- 38%), and time to peak plasma concentrations (SB = 8 h; TD = 8 h). After normalization to a dose of 25 mg/kg, the average peak plasma concentrations were also predicted (SB = 10.5 +/- 3.4 micrograms/ml; TD = 14.3 +/- 6.7 micrograms/ml). Slo-bid was predicted to provide the least peak:trough fluctuation in theophylline concentrations. Slo-bid and Theo-Dur appear to have pharmacokinetic characteristics which, if given once-daily, would maintain plasma theophylline concentrations of 5-20 micrograms/ml in the cat.

The purpose of this study was to define the minimum toxic concentrations and clinical signs of theophylline toxicity in healthy, conscious dogs. Five dogs were dosed orally in a five-way crossover design with sustained release theophylline (Theo-Dur tablets, Key Pharmaceuticals) at 0, 20, 40, 80, and 160 mg/kg. They were observed for a 9-h period for clinical signs of toxicity which had been previously determined in a pilot study. These signs included sinus tachycardia and central nervous stimulation (manifested as restlessness, excitement, or vomition). The Physiotel radiotransmitter telemetry system was used for the acquisition of the heart rate and ECG. Blood samples were obtained every hour for theophylline determination by high pressure liquid chromatography. The results showed that toxicity occurs at higher theophylline plasma concentrations in the dog (37-60 micrograms/ml) as compared to man (greater than 20 micrograms/ml) when dosed orally. Since current dosage regimens in dogs are designed to maintain trough-peak theophylline plasma concentrations between 10 and 20 micrograms/ml, the results indicate that the upper limit of this range appears to be safe in the dog.

The pharmacokinetics of the trichothecene mycotoxin, T-2 toxin, were determined in growing gilts and heifers. Following intra-aortal administration in swine and intravenous administration in calves, the disappearance of the parent T-2 toxin followed a 2-compartment open model. Mean elimination phase half-lives were 13.8 and 17.4 min and mean apparent specific volumes of distribution were 0.366 and 0.376 l/kg in swine and calves, respectively. The fraction of T-2 toxin eliminated as parent compound in the urine was negligible. In spite of administration of a lethal oral dose in swine (2.4 mg/kg) and toxic oral doses (up to 3.6 mg/kg) in calves, no parent T-2 toxin was detected in plasma or urine. After intra-aortal administration in swine, tissue concentrations of T-2 toxin were consistently highest in lymphoid organs. Tissue residues of T-2 toxin were rapidly depleted such that, in spite of administration of a potentially lethal intra-aortal dose, no quantifiable T-2 toxin was present in any of the tissues collected at 4 hr after dosing. No T-2 toxin could be detected in liver, even at 1 hr after dosing.

A field trial was conducted to determine the efficacy of theophylline in relieving respiratory distress associated with bovine respiratory disease complex (shipping fever). Theophylline (as aminophylline capsules) was administered PO at a dosage of 28 mg/kg of body weight daily for 3 days to 20 calves with naturally acquired disease. Twenty similarly affected calves from the same group were given a placebo, and all calves were administered antibiotics concurrently. Respiratory rate and rectal temperature decreased and physical appearance improved in both groups of calves and was attributed to antibiotic administration or to natural remission of the disease. Five of the calves administered theophylline died; however, no calves administered the placebo died. Plasma theophylline concentration was greatly increased, compared with that determined in clinically normal calves in a pilot study. Bovine respiratory tract disease and/or concurrent antibiotic administration appear to cause such a rapid accumulation of lethal concentration of theophylline that its use should be restricted to hospitals capable of monitoring plasma theophylline concentration.