Gastrointestinal absorption of metals.

Estimating gastrointestinal absorption remains a significant challenge in the risk assessment of metals. This presentation reviews our current understanding of the gastrointestinal absorption of lead (Pb) to illustrate physiological mechanisms involved in metal absorption, new approaches that are being applied to the problem of estimating metal absorption in humans, and issues related to integrating this information into risk assessment. Absorption of metals can be highly variable in human populations because it is influenced by a variety of factors that include the chemical form of the metal, environmental matrix in which the ingested metal is contained, gastrointestinal tract contents, diet, nutritional status, age, and, in some cases, genotype. Thus, in risk assessment models, gastrointestinal absorption is best described as a variable whose distribution is determined in part by the above multiple influences. Although we cannot expect to evaluate empirically each of the above factors in human populations, we can expect to achieve a sufficiently detailed understanding of absorption mechanisms to develop conceptual and, eventually, quantitative models of absorption that account for some aspects of individual variability. A conceptual model is presented of the physiological processes involved in the transfer of ingested metals from the lumen of the gastrointestinal tract to the blood circulation. Components of the model include delivery to the site(s) of absorption; distribution among intracellular and extracellular ligands and transcellular and paracellular pathways of transfer across the gastrointestinal tract epithelium. The gastrointestinal absorption of Pb is discussed in the context of this model.

Cobalt 60 radiotherapy for treatment of squamous cell carcinoma of the nasal cavity and paranasal sinuses in three horses.

Three adult horses underwent aggressive treatment of squamous cell carcinoma of the nasal cavity and paranasal sinuses, using course-fractionated cobalt 60 radiotherapy. Squamous cell carcinoma of the nasal cavity and paranasal sinuses is not commonly diagnosed in horses. Historically, horses with this type of neoplasm have not been treated or have undergone some form of surgery. The prognosis for long-term survival or cure has been poor. Long-term results of cobalt 60 radiotherapy were good to excellent and exceeded those usually reported for horses treated surgically. On the basis of these results, use of radiotherapy for these neoplasms is recommended.

A scoring system for gastric ulcers in the horse.

Five investigators familiar with gastric ulcer disease in horses met to establish a scoring system that could be utilised in future studies. Slides of gastric lesions were viewed and discussed and a scoring system established that required the nonglandular and glandular portions of the stomach to be graded separately. Each portion of the stomach (glandular and nonglandular) received a score for number of ulcers present and a score for severity of ulcers which resulted in each stomach receiving 4 separate scores. After the grading system was developed, each investigator independently graded 16 horses with gastric ulcer disease that had been previously recorded on video tape. The results of each investigator's scores were then compared. There was a variability between observers in the scores for severity of both nonglandular and glandular lesions but the variability was not significant. The variability between observers for the number of glandular lesions was also not significant. This implied that there was consistency between the 5 observers in the way severity of lesions was scored and the number of glandular lesions. However, there was a significant variability between observers for the number of nonglandular lesions which implied agreement on this observation was more variable.

Plasma pharmacokinetics of ranitidine HCl in adult horses.

Plasma pharmacokinetics of ranitidine HCl were investigated after intravenous (i.v.) and oral (p.o.) administration of 2.2 mg/kg drug to six healthy adult horses. Concentrations of ranitidine were determined using normal-phase, high-performance liquid chromatography. Plasma concentrations of ranitidine HCl declined from a mean of 5175 ng/mL at 5 min to 37 ng/mL at 720 min after i.v. administration. A three-exponent equation, Cp = A1 x e-k1t + A2 x e-k2t + A3 x e-k3t, best described data for all horses. Mean values for model-independent values calculated from the last quantifiable time point were: apparent volume of distribution (Vdss) = 1.07 L/kg; area under the curve (AUC) = 231,000 ng.min/mL: area under the moment curve (AUMC) = 26,900,000 ng.min2/mL; mean residence time (MRT) = 113 min; and clearance (Cl) = 9.8 mL/min.kg. Following p.o. administration, a two-exponent equation, Cp = A1 x e-k1t + A2 x e-k2t, best described the data for five horses: data for the remaining horse were best described by a three-exponent equation. Mean values of pharmacokinetic values from the p.o. study include: AUC = 59,900 ng x min/mL; AUMC = 10,600,000 ng x min2/mL; mean absorption time (MAT) = 58.9 min: Tmax = 99.2 min; Cmax = 237 ng/mL: and F = 27%.

Plasma pharmacokinetics of ranitidine HCl in foals.

Plasma pharmacokinetics of ranitidine HCl were investigated after intravenous (i.v.) and oral (p.o.) administration of drug to six healthy foals. Twelve- to sixteen-week-old foals received 2.2 mg ranitidine/kg i.v. and 4.4 mg ranitidine/kg p.o. Concentrations of ranitidine were determined using normal phase high performance liquid chromatography. Plasma concentrations of ranitidine HCl declined from a mean of 3266 ng/mL at 5 min to 11 ng/mL at 720 min after administration. The profile of the plot of concentrations of ranitidine HCl vs. time was best described by a two-exponent equation for two foals; data for the remaining four foals were best described by a three-exponent equation. Mean values for model-independent values were: apparent volume of distribution (Vdss) = 1.46 L/kg; area under the curve (AUC) = 167,442 ng.min/mL; area under the moment curve (AUMC) = 18,068,221 ng.min2/mL; mean residence time (MRT) = 108.9 min; and clearance (Cl) = 13.3 mL/min.kg. Following p.o. administration, a two-exponent equation best described data for five foals; data for the remaining foal were best described by a three-exponent equation. Mean values of the pharmacokinetic values from the p.o. study include: AUC = 126,413 ng.min/mL; AUMC = 18,039,825 ng.min2/mL; mean absorption time (MAT) = 32.0 min; observed time to maximum plasma concentration (Tmax) = 57.2 min; maximum observed plasma concentration (Cmax) = 635.7 ng/mL; and bioavailability (F) = 38%.

Gastrointestinal absorption of metals.

Estimating gastrointestinal absorption remains a significant challenge in the risk assessment of metals. This presentation reviews our current understanding of the gastrointestinal absorption of lead (Pb) to illustrate physiological mechanisms involved in metal absorption, new approaches that are being applied to the problem of estimating metal absorption in humans, and issues related to integrating this information into risk assessment. Absorption of metals can be highly variable in human populations because it is influenced by a variety of factors that include the chemical form of the metal, environmental matrix in which the ingested metal is contained, gastrointestinal tract contents, diet, nutritional status, age, and, in some cases, genotype. Thus, in risk assessment models, gastrointestinal absorption is best described as a variable whose distribution is determined in part by the above multiple influences. Although we cannot expect to evaluate empirically each of the above factors in human populations, we can expect to achieve a sufficiently detailed understanding of absorption mechanisms to develop conceptual and, eventually, quantitative models of absorption that account for some aspects of individual variability. A conceptual model is presented of the physiological processes involved in the transfer of ingested metals from the lumen of the gastrointestinal tract to the blood circulation. Components of the model include delivery of the metal to the site(s) of absorption; distribution of metal among intracellular and extracellular ligands and transcellular and paracellular pathways of transfer across the gastrointestinal tract epithelium. The gastrointestinal absorption of Pb is discussed in the context of this model.

Indwelling cecal catheters for fluid administration in ponies.

Two different fluid solutions were infused through percutaneous cecal catheters in 6 healthy ponies to determine the effects on body weight; CBC; packed cell volume (PCV); total plasma protein concentration; plasma fibrinogen concentration; abdominal fluid analysis; concentrations of blood urea nitrogen (BUN), serum creatinine, Ca, total CO2 (TCO2), Na, Cl, K, and P; and fractional clearance (FC) of Na, Cl, K, and P. During intracecal administration of solution 1, FCNa and FCCl were significantly increased, whereas FCK and BUN were significantly decreased. During administration of solution 2, FCNa and serum P were significantly increased, while PCV was significantly decreased. All ponies developed peritonitis during the study. Complications included catheter-related problems, diarrhea, laminitis, and hypocalcemia. We concluded that hydration and electrolyte balance could be maintained by administration of crystalloid solutions intracecally, but that complications were associated with the procedure.

Bioavailability of cadmium in food and water: a case study on the derivation of relative bioavailability factors for inorganics and their relevance to the reference dose.

Published studies in which rats were exposed to CdCl2 in standard chow or drinking water were analyzed to compare the relative bioavailability of cadmium from the two media. Relative bioavailability was assessed from estimates of the rate of accumulation of cadmium in kidney cortex or liver. Data were grouped into tiers based on study design and reporting of data: Tier 1, identical experimental protocols and dosage can be estimated; Tier 2, very similar or identical protocols and dosage can be estimated; Tier 3, protocols may differ and dosage can be estimated; and Tier 4, protocols may differ and dosages cannot be estimated (but concentration of cadmium in food or water is reported). Tiers were nested, such that Tier 4 contained all relevant studies; Tier 3 included data sets from Tiers 1 and 2; and Tier 2 included the data set from Tier 1. Data within Tiers 1, 2, and 3 were subjected to a linear regression analysis with dosage as the independent variable and tissue accumulation rate as the dependent variable to determine whether bioavailability of cadmium was significantly different based on medium of administration. The results of this analysis show the following: (1) In rats receiving food and drinking water ad libitum, the bioavailability of cadmium in drinking water is not significantly different (P > 0.05) from the bioavailability of cadmium in food when dosages are less than 4 mg/kg body wt/day. (2) Cadmium decreases food and water consumption; therefore, assessments of relative bioavailability should be made based on actual dosage rather than exposure levels. (3) Diet composition and status of the gastrointestinal tract are probably a more important determinant of the bioavailability of cadmium than is the exposure medium. (4) Studies of the effect of total diet composition on bioavailability of cadmium may be more relevant than are studies of the effect of the exposure medium. It is concluded from this analysis that the bioavailability of cadmium in food is not different from that in water when diet is provided ad libitum. Therefore, we recommend that distinct RfDs for cadmium in food and drinking water should not be based on the assumption that the bioavailability of cadmium in drinking water is greater than that of cadmium in food.

Circulation of estrogens introduced into the rectum or duodenum in pigs.

To determine the absorption and metabolism of 17 beta-estradiol (E2) by the rectum of the pig, 10 mg of crystalline E2 was placed in the rectum of prepubertal gilts in Experiment 1. Blood samples were subsequently obtained from hepatic portal and jugular veins and plasma was assayed for E2, estrone (E1), 17 beta-estradiol-glucuronide (E2G), estrone-glucuronide (E1G) and estrone-sulfate (E1S). Concentrations of E2, E1, E2G, E1G, and E1S rose in the hepatic portal vein within 30 min and remained elevated for several hr. Concentrations of E2 in the hepatic portal vein represented 3% of the total estrogen detected in the hepatic portal vein during the 5 hr sampling period, indicating that most of the E2 was metabolized prior to entering the hepatic portal vein after absorption by the rectal mucosa. Concentrations of E2, E1, E2G, E1G, and E1S rose in the jugular vein and remained elevated for several hr. The rise in E2 and E1 in the jugular vein may have come from E2 and E1 in venous circulation from the rectum that entered the inferior vena cava bypassing the hepatic portal vein and liver. The net result of absorption of E2 from the rectum of gilts was a large rise in unconjugated and conjugated E2 and E1 in the peripheral circulation. In Experiment 2 prepubertal gilts fitted with jugular, hepatic portal, duodenal, and gall bladder catheters were infused into the duodenum with bile from pregnant gilts. Concentrations of E2, E1, E2G, and E1G were determined in gallbladder bile of gilts before infusion and at 470 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption and metabolism of estrogens from the stomach and duodenum of pigs.

To determine the absorption and metabolism of 17 beta-estradiol (E2) by the stomach and liver of the pig, crystalline E2 was placed in the stomach of prepubertal gilts. Blood samples were subsequently obtained from the hepatic portal and jugular veins and plasma was assayed for E2, estrone (E1), 17 beta-estradiol-glucuronide (E2G), estrone-glucuronide (E1G) and estrone-sulfate (E1S). Concentrations of E2, E1, E2G and E1S rose in the hepatic portal vein within five min and remained elevated for several hr. Concentration of E2 represented only 6% of the total estrogen detected in the hepatic portal vein during the sampling period, indicating that most of the E2 was converted or conjugated prior to entering the hepatic portal vein. The metabolism of E2 presumably occurred in the stomach mucosa because food had been withheld for 26 hr before infusion of E2. Concentrations of E2G, E1G and E1S, but not E2 and E1, rose in the jugular vein and remained elevated for several hr. The lack of a rise in E2 and E1 in the jugular vein indicates that the E2 and E1 from the hepatic portal vein were completely converted and/or removed by the liver. Most of E2 was converted to E1 and then to E1G. The infusion of bile containing normal estrogens from pregnant gilts into the duodenum of prepubertal gilts resulted in a peak of E1G and E2G in the hepatic portal and jugular veins within a few minutes. This was followed in about 180 min by a second sustained rise. The first peak was essentially abolished by extracting E1 and E2 from the bile before infusion. The second peak failed to occur in gilts given antibiotics orally to reduce gut bacteria before infusion of bile.

Urinary indices of horses after intravenous administration of crystalloid solutions.

Saline or glucose solution was infused for approximately 4 hours into six healthy mares in two separate experiments to determine the effect of infusion of crystalloid solutions on fractional excretion (FE) of sodium (Na), chloride (Cl), potassium (K), and phosphorus (P), ratio of urinary creatinine to serum creatinine (UCr/SCr), and ratio of urinary osmolality to serum osmolality (Uosm/Sosm). After intravenous infusion of either saline or glucose solution, FENa, FECl and FEP were significantly increased, whereas UCr/SCr and Uosm/Sosm were significantly decreased. In addition, FEK was significantly increased after infusion of glucose solution. It was concluded that urinary indices were altered by intravenous infusion of crystalloid solutions in healthy mares and that fluid therapy may interfere with the use of these indices for diagnostic purposes.

Idiopathic cecal rupture in foals after anesthesia for gastric endoscopy.

Cecal rupture has been reported as a complication of tape-worm infestation or parturition in horses. Often it occurs with no apparent predisposing factors. Spontaneous rupture on the medial surface of the cecum occurred in 2 of 19 foals, 12 to 24 hours after gastric endoscopy. The sites of rupture were identical in both foals. Rupture occurred despite prior deworming, withholding of food and water before anesthesia, and care in induction of anesthesia and recovery. Surgeons should be aware of the potential of cecal rupture in horses anesthetized for elective surgery.

Epidemiology of equine protozoal myeloencephalitis in North America based on histologically confirmed cases. A report.

Following a workshop on equine protozoal myeloencephalitis (EPM) convened at the Veterinary Medical Forum of the American College of Veterinary Internal Medicine in 1988, this survey of EPM in North America was developed. It is based upon 364 histologically confirmed case records from California, Florida, Illinois, Kentucky, New York, Ohio, Oklahoma, Ontario, Pennsylvania, and Texas up to 1988. The highest rate of infection was found in young Thoroughbred, Standardbred, and quarter horses. Differences in geographic location, sex, and month (season) of infection were not discernible. This report, the first comprehensive survey of EPM in North America, is intended to serve as a basis for evaluating future changes in prevalence and spread of EPM.

Pharmacokinetics and bioavailability of cephalothin in horse mares.

The pharmacokinetics and bioavailability of cephalothin given to 6 horse mares at a dosage level of 11 mg/kg of body weight IV or IM were investigated. The disposition of cephalothin given IV was characterized by a rapid disposition phase with a mean half-life of 2.89 minutes and a subsequent slower elimination phase with a mean half-life of only 14.7 minutes. The mean residence time of cephalothin was 10.6 +/- 2.11 minutes. The total plasma clearance of cephalothin averaged 13.6 ml/min/kg and was caused by metabolism and renal elimination. Renal clearance of cephalothin averaged 1.32 ml/min/kg and accounted for elimination of about 10.1% of the administered dose. The volume of distribution at steady state averaged 151 mg/kg. Plasma protein binding of cephalothin at a concentration of 10 micrograms/ml averaged 17.9 +/- 2.5%. Cephalothin was rapidly metabolized to desacetylcephalothin. Maximum plasma desacetylcephalothin concentrations were observed in the blood samples collected 5 minutes after IV doses and averaged 22.9 micrograms/ml. The apparent half-life of desacetylcephalothin in plasma was 41.6 minutes and its renal clearance averaged 4.49 +/- 2.43 ml/min/kg. An average of 33.9% of the dose was recovered in the urine as desacetylcephalothin. The maximum plasma cephalothin concentration after IM administration was 11.3 +/- 3.71 micrograms/ml. The terminal half-life was 47.0 minutes and was longer than the half-life after IV administration. The bioavailability of cephalothin given IM ranged from 38.3% to 93.1% and averaged 65.0 +/- 20.5%.

Pharmacokinetics and bioavailability of cefazolin in horses.

The pharmacokinetics and bioavailability of cefazolin given (IV, IM) to horses at the dosage of 11 mg/kg were investigated. The disposition of cefazolin given by IV route was characterized by a rapid disposition phase with a half-life of 5 to 10 minutes and a subsequent slower elimination phase with a half-life of 35 to 46 minutes. The total plasma clearance of cefazolin averaged 5.51 ml/min/kg and was due mainly to renal clearance (5.39 ml/min/kg) of unchanged drug. The volume of distribution at steady-state averaged 188 ml/kg. Plasma protein binding of cefazolin at a concentration of 10 micrograms/ml averaged 8.1 +/- 1.9%. Given by the IM route, cefazolin was rapidly absorbed; the extent of bioavailability was 78.4 +/- 18.8%, and the terminal half-life ranged from 49 to 99 minutes. Thus, cefazolin was extensively absorbed, but was eliminated more slowly than after IV administration.