The Autosow raised miniature swine as a model for assessing the effects of dietary soy trypsin inhibitor.

Toxicological effects of dietary soy trypsin inhibitor (TI) were assessed in male miniature swine, a model chosen for its similarities to human digestive physiology and anatomy. The TI preparation was extracted from defatted raw soy flour. From 1 through 5 weeks of age, piglets were automatically fed either a TI liquid diet [Autosow TI group (ASTI)] or a control liquid diet [Autosow control group (ASC)]. From 6 to 39 weeks of age, these animals received either swine chow and TI or swine chow and control article. The TI diets were formulated to contain a TI activity of approximately 500 mg TI/100 g dry matter. A sow control (SC) group suckled from birth to 6 weeks of age and then fed as the ASC group with swine chow plus control article from 6 to 39 weeks of age. The SC piglets grew faster than ASC piglets during postnatal weeks 1 and 2; however, the ASC piglets were significantly heavier than the SC piglets (P=0.001) at 6 weeks of age. Compared with the ASC group, TI caused a moderate decrease in feed consumption and a moderate but reversible decrease in growth from 2 to 5 weeks of age, but not thereafter. Some control and TI-fed Autosow-reared piglets had loose stools until 6 weeks of age; the effect was significantly greater in the TI-fed group. Otherwise, all swine were active and had normal appearance and behavior.

Pathological evaluation, clinical chemistry and plasma cholecystokinin in neonatal and young miniature swine fed soy trypsin inhibitor from 1 to 39 weeks of age.

The potential toxicity of dietary soy trypsin inhibitor (TI) was evaluated in neonatal miniature swine. From 1 to 6 weeks of age, two groups of male piglets were artificially reared in an Autosow and automatically fed either TI or control liquid diet. From 6 to 39 weeks of age, these two groups were fed either TI or control chow diet. A third group, sow control (SC), suckled from birth to 6 weeks of age, were also weaned to control chow from 6 to 39 weeks of age. Clinical chemistry and plasma cholecystokinin (CCK) determined at 6, 18, 30 and 39 weeks of age, and serum amylase activity with gross and histopathological analyses of major organs at 6 and 39 weeks of age are reported. TI had no effect on plasma CCK, serum amylase activity, or numerous clinical chemistry values. TI-fed piglets had a larger relative liver weight at 6 weeks of age. Relative pancreas weight decreased with age but was not affected by TI. Gross and histopathological analyses of major organs, except the spleen, were within normal limits. Increased incidence of extramedullary hematopoiesis was noted in the spleen of the TI group at 6 but not at 39 weeks of age. There was no consistent pattern in immunohistochemical foci for secretin, gastrin releasing polypeptide or CCK, and no change in DNA, RNA, mitotic index or nuclear density of pancreatic cells. At 6 weeks of age, TI increased pancreatic protein and amylase activity but not trypsin or chymotrypsin activity. None of the effects suggested that this dose of TI was toxic to either the neonatal or sexually mature miniature male swine.

Body and organ growth of the developing Hormel-Hanford strain of male miniature swine.

As part of a larger study designed to characterize the early developmental stages of the Hormel-Hanford strain miniature pig, whole body, brain, kidney, liver, pancreas and spleen from male animals were examined for weight increases from one to 196 days, the approximate age of maturity. At 196 days, body weights had increased to 82.5 times the weight at day 1; increases in organ weights were greatest for spleen, less and similar for kidney, liver and pancreas, and the least for brain. Little change in relative organ weights was noted, except for the brain where an almost steady decrease occurred starting from 7 days after birth.

Ornithine decarboxylase, fatty acid synthetase, and lipid levels in selected organs of the postnatal developing male miniature pig.

Ornithine decarboxylase (ODC) and fatty acid synthetase (FAS) activities were determined in tissues from male neonate and juvenile miniature swine (Hormel-Hanford strain) at various ages. ODC activity was measured in liver, brain, kidney, pancreas, and spleen at one day and at 1, 4, 8, 12 and between 24 and 32 weeks. Hepatic FAS activity, total lipid, triglyceride, and total cholesterol were measured at 2, 8, 16, and 32 weeks. Generally, tissue ODC activity was highest in the spleen at all ages. Three postnatal patterns of ODC activity were observed for the different organs. The mean values of FAS activity, total lipid, and cholesterol were highest at 8 weeks compared to other sampling periods.

Excretion and tissue distribution of 14C-labelled 8-methoxypsoralen in beagle dogs and miniature pigs.

Male beagle dogs and miniature swine were given 14C-labelled 8-methoxypsoralen (8-MOP) as a single oral dose (10 mg/kg body weight). In dogs, there appeared to be wide variability in 8-MOP absorption as indicated by the broad range of percentages of radioactivity recovered from urine and faeces over a 4-day period (3.6-24.7% in urine; 47.3-94.9% in faeces); mean recovery values were 13.6% in the urine and 68.6% in the faeces. In pigs, considerable variability in absorption was also evident, but not to the extent of that seen in dogs. Based on the fraction of the dose recovered in the urine, the absorption of 8-MOP was greater in pigs; the proportion of the dose recovered in urine over a 7-day period ranged from 25.8 to 57.8%. Faecal recovery ranged from 15.4 to 49.0% of the dose. Mean recovery values in pigs were 45.4% in urine and 35.6% in faeces. Most of the 8-MOP was cleared from the bodies of dogs and pigs in a few days, and little 8-MOP residue was sequestered in any of the tissues examined in either species. Small amounts of an 8-MOP-related substance remained in the liver and blood for as long as 4 days in dogs and 7 days in pigs.

The beagle dog as an animal model for a bioavailability study of controlled-release theophylline under the influence of food.

Beagle dogs were evaluated as an animal model to study the effect of food on the bioavailability of two commercially available oral controlled-release theophylline products. The products were administered with and without food in single doses, and the bioavailability parameters were compared with those following an i.v. aminophylline dose. The total plasma theophylline clearance in dogs following an i.v. dose was 0.128 liter/hr/kg and the volume of distribution was 0.8 liter/kg using a one-compartment model. The absolute bioavailabilities of these two products under fasting conditions were 31 and 48%, respectively. The food increased the bioavailability of one product and decreased the bioavailability of the other. The overall trends in relative bioavailability of these two products with and without food appeared to be similar to those reported in humans.

Capillary gas chromatographic (GC) analysis of nitroglycerin and its denitration products in plasma.

A convenient, specific, and sensitive capillary gas chromatographic (GC) assay for analyzing nanogram concentrations of nitroglycerin and its dinitro- and mononitrometabolites in plasma has been developed. Using a bonded-phase (DB-1) 30-m, 1-micron-thick film capillary column and a 1-m, 5-microns-thick film precolumn, separation of nitroglycerin and all four partially nitrated metabolites was achieved in less than 15 min. On-column injection, electron capture detection, and isothermal operation at 100 degrees C yielded a linear extraction curve over a 300-ng/ml range without any need to concentrate sample extracts. Using methyl t-butyl ether as extraction solvent and o-chloronitrobenzene as internal standard, recoveries from plasma spiked at levels greater than 10 ng/ml approximated 35% for the 1-monometabolite, 40% for the 2-monometabolite, and greater than 90% for all others. The method was employed in a pharmacokinetic study of nitroglycerin administered intravenously to beagle dogs. Plasma samples were collected at various time points and analyzed.

The effect of food on the absorption of controlled-release theophylline in mini-swine.

The effect of differing fat contents of food on the bioavailability of theophylline following a 400-mg single dose of Theo-24 was studied in mini-swine. The pharmacokinetics of theophylline, following the intravenous administration of aminophylline equivalent to 5 mg/kg as a single dose, were also studied in the same animals. The terminal plasma half-life of theophylline following an i.v. dose was found to be approximately 24 hr. The volume of distribution, Vdext, and clearance following the i.v. dose were approximately 0.7 liter/kg and 0.023 liter/hr/kg, respectively. The terminal half-life of theophylline following the administration of theophylline capsules under fasting conditions was 21 hr. The average bioavailability under fasting conditions was approximately 80% compared to the i.v. dose. Food appeared to have decreased the rate of absorption but no significant effect on the extent of absorption.

Maternal-foetal distribution studies in late pregnancy. II. Distribution of [1-14C]acrylamide in tissues of beagle dogs and miniature pigs.

[carbonyl-14C]Acrylamide was administered iv as a single dose (5 mg/kg) to pregnant beagle dogs and miniature pigs late in gestation. After a 2-hr equilibration period, the animals were killed and foetuses were removed for determination of the amount of radioactivity in maternal and foetal tissues. In total, six dog litters (33 foetuses) and seven pig litters (45 foetuses) were examined. In dogs, acrylamide was distributed readily to both maternal and foetal tissues with a placental distribution factor of 17.7%. The blood/brain distribution factor was insignificant (5.9%) in maternal dogs and 0% in the foetuses. Maternal liver was the largest depot of the administered acrylamide in the dog, followed by the maternal kidney. In pigs, the placental distribution factor was 31%, and the blood/brain distribution factor was insignificant in both maternal and foetal pigs. Liver and kidney of maternal pigs also contained the greatest amount of radioactivity. Although there appears to be some placental protection of the foetuses from the xenobiotic in the maternal circulation, foetal brain would be exposed to the effect of any acrylamide present in the foetal circulation, since the foetuses of both species had blood/brain distribution factors that were either small or zero, reflecting the absence of a blood-brain barrier.

Maternal-foetal distribution studies in late pregnancy. I. Distribution of [N-methyl-14C]betaine in tissues of beagle dogs and miniature pigs.

[N-Me-14C]Betaine was administered iv as a single dose (5 mg/kg) to pregnant beagle dogs and miniature pigs late in gestation. Two hr after administration of the radiolabel, when the compound was in equilibrium, the dams were killed and the foetuses were removed for determination of the radioactivity in maternal and foetal tissues. Eight litters of dogs (56 foetuses) and four litters of pigs (30 foetuses) were examined. The distribution of betaine in both species showed distinct differences between maternal and foetal tissues, indicating definite placental barriers; the placental distribution factor was estimated to be 52.3% in dogs and 97.8% in pigs. The blood/brain distribution factor was 84.6% in maternal dogs, 89% in maternal pigs, 65.7% in foetal dogs and 0% in foetal pigs. In the dog, maternal liver was the largest depot of the administered betaine, followed by foetal liver. Foetal heart, lung and kidney tissues also incorporated radiolabelled betaine. The highest concentrations of betaine in the pig were found in maternal kidney and liver.