Inflammatory response to intramuscular implantation of polyacrylonitrile ultrafiltration probes in sheep.

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.

Short-term distribution, metabolism, and excretion of 2,2',5-tri-, 2, 2',4,4'-tetra-, and 3,3',4,4'-tetrachlorobiphenyls in prepubertal rats.

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.

Veterinary drug bioequivalence determination.

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.

Toxicokinetics of tritiated dihydromicrocystin-LR in swine.

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.

Pharmacokinetics of penicillin G in plasma and interstitial fluid collected with dialysis fiber bundles in sheep.

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.

Evaluation of the single-injection plasma disappearance of technetium-99m mercaptoacetyltriglycine method for determination of effective renal plasma flow in dogs with normal or abnormal renal function.

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.

Biliary excretion and enterohepatic cycling of zearalenone in immature pigs.

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.

Pharmacokinetics of metoclopramide in goats.

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.

Pharmacokinetics and elimination of salicylic acid in rabbits.

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.

Chronopharmacokinetics of theophylline in the cat.

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.

Plasma theophylline concentration and lung function in ponies with recurrent obstructive lung disease.

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 in swine--bioavailability and pharmacokinetics in fasted and fed pigs.

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).

An experimental model for pharmacokinetic analysis in renal failure.

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.

Pharmacokinetics of etomidate in cats.

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.

Pharmacokinetics and metabolism of fenbendazole in channel catfish.

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.

Field trial of theophylline in cattle with respiratory tract disease.

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.