Determination of the rat tissue partitioning of endotoxin <i>in vitro</i> for physiologically‐based pharmacokinetic (PBPK) modeling

Ross, Ivan A.; Sapienza, P.P.; Hanes, Darcy E.; Johnson, Widmark; Kim, Chung S.

doi:10.1002/jat.956

Cited by 5 publications

(4 citation statements)

References 16 publications

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“…Three hundred milliliter of S. typhimurium culture yields approximately 37.3 mg of bacteria (dry weight) that produce 1.32 mg of LPS. The LPS contained 0.028 mCi of 3 H per microgram and 0.002 mCi of 14 C per microgram (Ross et al, 2004).…”

Section: Specific Activity Of the Harvested Endotoxin Productmentioning

confidence: 99%

“…To incorporate the radiolabel, S. typhimurium was incubated with radiolabeled precursors of LPS as described above (Ross et al, 2004). Briefly, an initial inoculum of bacteria of 10 8 -10 10 /100 ml, at an OD 540 value of 0, produced a rapid increase to OD 540 values (log) of 0.3-0.4, indicating robust bacterial multiplication.…”

Section: Whole-cell Incubation and Incorporation Of Radiolabels Into Endotoxinmentioning

confidence: 99%

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

et al. 2012

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The endotoxin, lipopolysaccharide (LPS), of Salmonella typhimurium was biosynthetically labeled with (3)H and (14)C 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 (14)C and (3)H-LPS in plasma and other organs was determined following intraperitoneal (IP) doses of (14)C and (3)H-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 (14)C-glucosamine and (3)H-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 (3)H-fatty acyl chains in the brain.

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Section: Specific Activity Of the Harvested Endotoxin Productmentioning

confidence: 99%

Section: Whole-cell Incubation and Incorporation Of Radiolabels Into Endotoxinmentioning

confidence: 99%

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

et al. 2012

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“…After reaching steady state (90 min), each tissue was removed from the medium, rapidly blotted, weighed and analysed for radioactivity of BPA in a scintillation counter. The tissue partitioning of BPA in both artificial CSF and Krebs phosphate buffer was measured by using the ratio of in vitro tissue to medium at the steadystate as previously described (Kim et al, 1996;Ross et al, 2004).…”

Section: In Vitro Studiesmentioning

confidence: 99%

Distribution of bisphenol A in the neuroendocrine organs of female rats

et al. 2004

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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 100mg/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 microg-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.

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“…The structure of the lipid A component of endotoxin. N-acetyl-D-1-14 C-glucosamine and 3 H sodium acetate precursors were used to incorporate radiolabels in endotoxin harvested from Salmonella typhimurium (Ross et al, 2004).…”

Section: Pharmacokinetic Model Developmentmentioning

confidence: 99%

Physiological-based pharmacokinetic modeling of endotoxin in the rat

Hutter

Kim

2012

Toxicol Ind Health

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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 (3)H and the glucosamine residues were labeled with (14)C. 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.

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Determination of the rat tissue partitioning of endotoxin in vitro for physiologically‐based pharmacokinetic (PBPK) modeling

Cited by 5 publications

References 16 publications

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

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

Distribution of bisphenol A in the neuroendocrine organs of female rats

Physiological-based pharmacokinetic modeling of endotoxin in the rat

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