Joseph C. Hutter

Distribution of bisphenol A in the neuroendocrine organs of female rats

The distribution of 14C-bisphenol A (BPA) in plasma and neuroendocrine organs was determined in Fischer 344 female rats following three oral doses (0.1, 10 or 100 mg/kg). Plasma and tissue maximum concentrations (Cmax) were reached within 15-30 min of dosing. Plasma areas-under-the-curve (AUC) ranged from 0.06 to 53.9 mg-h/mL. The AUCs of the pituitary gland and uterus/gonads were 16-21% higher than that of plasma. The AUCs of hypothalamus and the rest of the brain were 43.7% and 77% of the plasma AUCs, respectively. In the brain tissue, the exposure increased linearly with the oral dose, as the dose was increased from 0.1 to 10 and 100 mg/kg; the exposure in the brain relative to the plasma increased by factors of 1, 1.19 and 1.24. This indicates that the brain barrier systems do not limit the access of the lipophilic BPA to the brain. The increases of the uterus/gonads relative to the plasma were 1, 1.07 and 1.04. Tissue partitioning was also examined in vitro by the uptake of 14C-BPA. The BPA tissue/blood partition coefficients were as follows: heart, 7.5; liver, 6.1; kidney, 6.4; fat, 3.6; muscle, 2.6; breast, 3.6; ovaries, 9.1; uterus, 5.9; stomach, 5.1; and small intestine, 6.7. The tissue/cerebrospinal fluid partition coefficients were as follows: pituitary gland, 12.8; brain stem, 6.1; cerebellum, 6.4; hippocampus, 7.1; hypothalamus, 6.1; frontal cortex, 4.9; and caudate nucleus, 6.8.

A biological model of tamponade gases following pneumatic retinopexy

Purpose. Predict the persistence and expansion of intraocular tamponade gases used in retinal detachment surgery. Quantify factors that contribute to elevations in the intraocular pressure. Methods. We developed a non-equilibrium physiological model of intraocular gas transfer in vitreoretinal surgery. The model was calibrated using published volumetric decay measurements for four perfluorocarbon gases (CF 4, C 2 F 6, C 3 F 8, C 4 F 10) injected into the New Zealand red rabbit. We validated the model by comparing predicted and experimental results at different conditions in the rabbit. Using the rabbit results, the model was scaled up to humans. Results. Predictions of gas expansion, half-life, and intraocular pressure in humans were found to correlate very well with clinical results. Gas transfer in the eye was controlled by diffusion through plasma and membranes. Although intraocular pressure depended on several complicating factors such as the physiological condition of the eye as well as the medications being used, prediction of conditions that favor elevations in intraocular pressure were identified based on the transport and thermodynamic properties of the gases. Conclusions. The biological model accurately predicted the dynamics of intraocular gases in the human eye. The major factor affecting the intraocular pressure was the aqueous humor dynamics, which is highly dependent on the physiological conditions in the eye. However, for long duration gases such as perfluoropropane, elevations in intraocular pressure are possible following an increase in volume and/or purity of the injected gas. By injecting a mixture of air with an expansive gas, it is possible to reduce elevations in intraocular pressure in patients with the trade off of a reduced longevity of the gas bubble. For gases that diffuse faster than perfluoropropane, there are minimal effects on intraocular pressure due to these changes.

A dynamic simulation of bisphenol A dosimetry in neuroendocrine organs.

Bisphenol A (BPA) is a known xenoestrogen with similar properties to 17b-estradiol. BPA and estrogen are hydrophobic compounds, and this affects the pharmacokinetics of both compounds in mammals. In a previous study we measured the distribution of BPA in female F344 rats exposed to oral doses of 0.1, 10 and 100 mg/kg. The results showed distribution to target neuroendocrine organs at all doses tested. Using these results, we developed a pharmacokinetic model to predict the dynamic uptake and excretion of BPA by various routes of exposure (po, iv, sc, ip). The model was able to simulate the entire time course (48 h) following various routes of exposure in rats over the dose ranges tested. The model indicated that the ultimate tissue uptake of BPA was established by the rapid initial transfer of free BPA into tissues. After free BPA enters the systemic circulation, metabolism and excretion reactions cause a relatively short duration and rapid decline. This period is followed by a slower long-term decline characteristic of BPA’s biphasic pharmacokinetics. Plasma protein and tissue binding reactions established the long-term half-life of BPA in the body. Route differences in tissue uptake were directly related to the competition between transfer and binding reactions during the absorption phase.

Distribution and pharmacokinetics of double-radiolabeled endotoxin in the rat brain and peripheral organs

The endotoxin, lipopolysaccharide (LPS), of Salmonella typhimurium was biosynthetically labeled with 3H and 14C incorporated into the fatty acyl chains and glucosamine residues, respectively. The radio-labeled LPS was isolated from the bacteria and then injected into Sprague-Dawley rats. The distribution of 14C and 3H-LPS in plasma and other organs was determined following intraperitoneal (IP) doses of 14C and 3H-LPS (200 μg/kg). Plasma concentrations of both fatty acyl chains and glucosamine residues were biphasic, with a relatively rapid decay followed by a slow decline for 48 h. Similar biphasic results were found in the peripheral organs (kidney and heart) and brain barrier tissues (meninges and choroid plexus). In other brain tissues (brain stem, caudate nucleus, hypothalamus, frontal cortex, cerebellum and hippocampus), the glucosamine residue was biphasic, whereas the fatty acyl chains showed accumulation. Highest concentrations of LPS were found in the plasma, spleen and the liver. In addition, in the liver, sustained elevations of 14C-glucosamine and 3H-fatty acyl chains were observed. This indicates LPS accumulation in the liver. By contrast, the spleen showed biphasic decay of glucosamine residues and accumulation of fatty acyl chains. In the brain barrier tissues, peak LPS concentrations were significantly reduced (about 70%) and were further reduced (about 95%) in other brain tissues. The high elevation of LPS in the spleen is considered indicative of an immune response. Our findings highlight the potential significant role of lipid A as shown with the sustained elevation of 3H-fatty acyl chains in the brain.

Prediction of the shelf life of cellulose acetate hemodialyzers by Monte Carlo simulation.

A previous investigation by our laboratory linked cellulose acetate degradation with adverse health effects in hemodialysis patients. 1 To establish the accumulation of degradation products with time, a Monte Carlo model of degradation kinetics was developed. The model tracks changes in a population of molecules representative of the dialyzer membrane during the degradation process. The degradation calculation is a two step process: First, the model uses a random number to select an individual polymer molecule out of the population, and then a second random number is used to identify a site on the selected molecule for the degradation reaction to occur. After the reaction calculation, the resulting degraded molecules are redistributed into the population. The course of the reaction is determined by recalculating the molecular weight averages in the changing population as the calculations proceed. The model was validated using gel permeation chromatography molecular weight results and total acetyl content measurements on dialyzers stored up to 13.3 years after manufacture. It was found that the degradation reactions can be accurately modeled as random events and that the chain scissions and deacetylation events occur at constant rates. The shelf life of these devices was estimated using the model predictions and animal test results.

Physiological-based pharmacokinetic modeling of endotoxin in the rat:

We have previously measured the distribution and pharmacokinetics of biosynthetically radiolabeled endotoxin of Salmonella typhimurium following intraperitoneal (IP) dosing (200 μg/kg) in Sprague-Dawley rats. In our experiments, the fatty acid residues were labeled with 3H and the glucosamine residues were labeled with 14C. To predict the dynamics of endotoxin exposure, we developed a physiological-based pharmacokinetic model using our measured distribution results. The model was validated with published low-dose (30 μg/kg) IP exposure results in rats. Endotoxin pharmacokinetics depended on dose and route. At high IP doses, absorption was followed by biphasic decay over 48 h in plasma. There were tissue accumulations of the fatty acid and glucosamine residues in various target organs, including the brain. We also found that the glucosamine and fatty acid components separated in vivo about 3 h after IP injection. At the lower IP dose, a smaller fraction of the dose was distributed to the tissues, with most of the dose remaining in the blood. Each component had its own dynamic behavior and target tissue distribution in the rat. The fatty acid components tended to remain in the brain stem, caudate nucleus, cerebellum, frontal cortex, hippocampus, and hypothalamus. Other organs (spleen, kidney, meninges, and choroid plexus) had similar biphasic distribution. The liver had the unique accumulation of both glucosamine and fatty acid residues.