Biomedical subjects
Publications and source records attributed to R F Bevill.
Surgical procedures have been developed that permit the sampling of portal blood, bile and hepatic blood in intact pigs. Animals so prepared have been used to study liver metabolism and biliary excretion of N-nitrosodimethylamine (NDMA) following oral and intravenous dosing.
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The metabolism of furaltadone was examined by an in vitro hepatic study in cows and goats and an in vivo study in goats using 14C-labeled and unlabeled drug. The half-life of furaltadone was 13 min in the homogenates of caprine and bovine liver and 35 min in the in vivo study of the goat. Less than 2% of the parent drug was present in the urine of animals dosed either intravenously or intramammarily. No furaltadone was detected in the milk after 24 h. Overall, the parent compound was rapidly absorbed, distributed, and widely degraded in the lactating goat. The compound, labeled at the 2-formyl carbon of the furan ring, had a radioactivity recovery of 81% in the feces and urine. Of the total radioactivity, 99.4% infused into the udder had been absorbed after 72 h. Tissue distributions of radioactivity in decreasing order of abundance were: kidney, udder, liver, duodenum, muscular tissue, adipose tissue, and bile.
The concentration of sulfamethazine in plasma and sulfamethazine and its metabolites in urine were compared in male, female and castrated male swine. A surgical technique for placement of catheters in the urinary bladder was used to facilitate the collection of urine in males and castrated males. The elimination rate of sulfamethazine from plasma and the excretion of parent drug and metabolites into urine did not differ significantly among females, males and castrated male swine.
Previously determined pharmacokinetic parameters of the disposition of oxytetracycline (OTC) in cows were used to predict an IV priming dose and a rate of constant IV infusion of OTC sufficient to approach steady-state equilibrium of the drug between plasma and genital tissue concentrations in healthy postpartum cows and postpartum cows with endometritis. After 8 hours' constant IV infusion at rates calculated to maintain a plasma concentration of approximately 5 micrograms/ml, the mean concentrations of OTC in plasma (microgram/ml) and tissues (microgram/g) of healthy and infected postpartum cows, respectively, were: plasma, 4.95 and 5.23; uterine tissue, 3.65 and 4.18; and ovarian tissue, 4.57 and 4.53. The mean plasma to genital tissue ratios for healthy and infected postpartum cows, respectively, were 1.38 and 1.31 for uterine tissue and 1.09 and 1.16 for ovarian tissue. There were no significant differences (P greater than 0.28) between healthy and infected postpartum cows in any of the parameters investigated. However, plasma-to-genital tissue ratios of concentrations of OTC in postpartum cows as a group were significantly higher (P less than or equal to 0.03) than those previously determined in cycling cows. Computer-simulated uterine tissue concentrations of OTC, after twice daily IV doses of 11 mg of OTC/kg of body weight, indicated that this dosage regimen would provide postpartum uterine tissue concentrations greater than 5 micrograms/g during most of the dosage interval.
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.
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.
Pharmacokinetic parameters of the disposition of oxytetracycline (OTC) were investigated in healthy cycling dairy cows after a single IV dose of 22 mg/kg of body weight. The biological half-life of OTC was 6.5 hours. These data were used to predict an IV priming dose and a rate of constant IV infusion of OTC sufficient to approach steady-state equilibrium of the drug between a plasma concentration of approximately 5 microgram/ml and a uterine tissue concentration. After 8 hours' constant IV infusion, the mean plasma concentration of OTC was 4.86 +/- 0.68 microgram/ml and the mean uterine tissue concentration of OTC was 4.50 +/- 0.45 microgram/ml. The mean ratio of plasma-to-uterine tissue OTC concentrations was 1.08. Computer-stimulated IV multiple doses of OTC at 11 mg/kg every 12 hours and 11 mg/kg every 24 hours suggested that the former dosage regimen could provide uterine tissue concentrations greater than 5 microgram/ml during the dosage interval, whereas the latter could provide such concentrations for only the first 12 hours of a 24-hour dosage interval.
A gas chromatographic assay employing electron-capture detection for the determination of selenium in biological samples is reported. A calibration curve of 4-nitro-o-phenylene-diamine derivative of selenium as a function of peak area was linear from 5-1000 pg. The limit of detection for the electron-capture detector was approximately 0.5 pg. Recoveries of selenium added to various biological materials ranged from 95-105%. This procedure reduces the number of transfers thereby reducing errors associated with losses or contamination. One advantage of the present method is that interfering compounds occurring in previously employed chromatographic methods are eliminated. This procedure can be used for routine microanalysis of selenium. Samples containing less than 2 ng selenium in 200 microliter of biological fluid can be routinely analyzed using this method.
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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.
The pharmacokinetics of theophylline in swine were investigated following the oral and intravascular administration of single doses of theophylline free base. The mean half-life of theophylline following intravascular administration was 11.0 h, and the apparent specific volume of distribution was 0.61 liter/kg. Following oral administration, theophylline in solution was absorbed quite rapidly with a bioavailability of 79%. The similarity of the pharmacokinetics of theophylline in swine and humans suggests that swine may provide a useful model for the study of the bioequivalency of theophylline dosage forms intended for human use. The pharmacokinetic characteristics of theophylline also favor its consideration for usage as a therapeutic agent in swine.
Two possible causes of violative sulfonamide residues in swine were studied. To determine if sulfamethazine accumulated in the tissues of swine when the drug was administered in feed, the rates of plasma drug disappearance following a single oral dose and continuous feeding of the drug were compared. The rate of plasma drug disappearance was not significantly different (alpha = 0.05) when the two methods of drug dosing were compared. When feed containing 2 micrograms sulfamethazine/gm was fed to swine during a 7-day period preceding slaughter, the animal's liver contained violative residues. Violative concentrations of sulfamethazine were detected in the livers, kidneys, and skeletal muscle of swine which consumed feed containing 8 micrograms sulfamethazine/gm.
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.
An improved extraction procedure for the determination of oxytetracycline, tetracycline and chlortetracycline in urine, plasma and tissues by high-performance liquid chromatography is described. The addition of phenylbutazone (3,5-dioxo-1,2-diphenyl-4-n-butylpyrazolidine) to water, urine or plasma enhances the extraction of these compounds by ethyl acetate. The recovery of oxytetracycline from plasma is increased six fold and the need for two separate extractions of urine and plasma is eliminated. The formation of phenylbutazone-tetracycline ion pairs and their role in the extraction process is discussed.
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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 high-performance liquid chromatographic separation and quantitative analysis of oxytetracycline, tetracycline, and chlortetracycline from urine and plasma were effected on an octadecylsilane reversed-phase packing. The calcium complexes of the tetracyclines were extracted from urine and plasma with ethylacetate and then reextracted into hydrochloric acid. Following the injection of the hydrochloric acid extracts onto the column, the individual tetracyclines were eluted isocratically and quantitated spectrophotometrically. Concentrations of less than 1 microng/ml in urine and 1.5 microng/ml in plasms were quantitatively determined with a relative standard deviation of less than 5%.