Radioactivity In Carcass Research Articles

ADME studies of [5-(3)H]-2'-O-methyluridine nucleoside in mice: a building block in siRNA therapeutics.

The chemical modification 2′‐O‐methyl of nucleosides is often used to increase siRNA stability towards nuclease activities. However, the metabolic fate of modified nucleosides remains unclear. Therefore, the aim of this study was to determine the mass balance, pharmacokinetic, and absorption, distribution, metabolism, and excretion (ADME)‐properties of tritium‐labeled 2′‐O‐methyluridine, following a single intravenous dose to male CD‐1 mice. The single intravenous administration of [5‐3H]‐2′‐O‐methyluridine was well tolerated in mice. Radioactivity was rapidly and widely distributed throughout the body and remained detectable in all tissues investigated throughout the observation period of 48 h. After an initial rapid decline, blood concentrations of total radiolabeled components declined at a much slower rate. [3H]‐2′‐O‐Methyluridine represented a minor component of the radioactivity in plasma (5.89% of [3H]‐AUC 0‐48 h). Three [3H]‐2′‐O‐methyluridine metabolites namely uridine (M1), cytidine (M2), and uracil (M3) were the major circulating components representing 32.8%, 8.11%, and 23.6% of radioactivity area under the curve, respectively. The highest concentrations of total radiolabeled components and exposures were observed in kidney, spleen, pineal body, and lymph nodes. The mass balance, which is the sum of external recovery of radioactivity in excreta and remaining radioactivity in carcass and cage wash, was complete. Renal excretion accounted for about 52.7% of the dose with direct renal excretion of the parent in combination with metabolism to the endogenous compounds cytidine, uracil, cytosine, and cytidine.

Pharmacokinetics of SNI-2011. (1): Absorption, Distribution, Metabolism and Excretion of 14C-SNI-2011 in Rats.

The absorption, distribution, metabolism, excretion and plasma protein binding of SNI-2011, a novel muscarinic acetylcholine receptor agonist developed as an agent improving the symptoms of dry mouth or dry eye caused by Sjogren's syndrome, were studied in rats. 1. After a single oral administration of 14C-SNI-2011 to male rats, plasma level of radioactivity reached the maximum at approximately 30 minutes, and declined by the bi-exponential manner. Oral absorption rate of radioactivity was 94%. Plasma level and pharmacokinetic parameters of radioactivity in female rats were comparable with those of male rats. 14C-SNI-2011 was considerably absorbed from duodenum, jejunum, ileum and colon. Plasma level of radioactivity at 8hr after daily oral administration of 14C-SNI-2011 increased with the number of dosing, and reached a steady state by the 3rd day. 2. After a single oral administration of 14C-SNI-2011 to male or female rats, radioactivity was distributed rapidly in whole body, and then eliminated rapidly. Tissue levels of radioactivity in male rats at 8hr after daily oral administration increased with the number of doses reaching approximately 4 times higher levels than those after the 1st administration. In pregnant rats on the 18th day of gestation, radioactivity was transferred into fetal tissues, and then decreased similarly as from maternal plasma. 3. SNI-2011 trans-sulfoxide (SNI-t-SO), SNI-2011 cis-sulfoxide (SNI-c-SO), SNI-2011 sulfone (SNI-SO2) and SNI-2011 N-oxide (SNI-NO) were identified in rat urine. As judged from the result on TLC/ radioluminography of plasma and urine samples, SNI-t-SO appeared to be the main metabolite in rats. Plasma concentration and urinary excretion rates of the unchanged SNI-2011 in female rats were higher than those in male rats. Repeated administration of SNI-2011 had no effect on liver weight, microsomal protein contents and activities of hepatic drug-metabolizing enzymes. 4. Main excretion route of 14C-SNI-2011 was urine in both of male and female rats, and approximately 100% of the dose was excreted in urine within 168 hours after administration. Fecal excretion rate of radioactivity was below 1% of the administered dose. Residual radioactivity in carcass accounted only for 0.1% of the dose. Daily urinary and fecal excretion rates of radioactivity in the period and after repeated oral administration were almost constant, and these rates were similar to those after a single administration. Radioactivity in the milk was 3.0 to 4.7 times higher than that in plasma. 5. Plasma protein binding rates of 14C-SNI-2011 in rats, dogs and human in vitro were relatively low (15.2 to 20.6%), and the binding rate was not affected by drug concentration or test species.

Distribution, elimination, and residues of [14C]clenbuterol HCl in Holstein calves.

Clenbuterol HCl is a beta-adrenergic agonist that has been used illegally in Europe and the United States by some livestock producers to increase carcass leanness. The objectives of this study were to determine the metabolic disposition, distribution of radioactivity, and the concentrations of parent clenbuterol in tissues after a single oral dose of [14C] clenbuterol HCl in calves. [14C]Clenbuterol HCl (1.59 microCi/mg, 3 mg/kg BW) was administered to a 74- and a 96-kg Holstein bull calf as a single oral dose. Blood samples were taken at 1, 3, 6, 12, 24, 36, and 48 h after dosing; urine and feces were collected separately and placed into respective pools from 0 to 6, 6 to 12, 12 to 24, 24 to 36, and 36 to 48 h after dosing. At 48 h after dosing, calves were anesthetized and exsanguinated, and visceral organs, bile, eyes, brain, skeletal muscle, skin, adipose tissue, and the remainder of the carcass were collected. Tissues were processed by coarse grinding through a Hobart grinder, followed by homogenization on dry ice. Eyes were dissected and the various tissues and excreta were assayed for total radiocarbon content by combustion analysis and(or) liquid scintillation counting. Parent clenbuterol was measured in selected tissues by HPLC after solvent extraction. Urinary, fecal, and carcass radioactivity averaged 41.5 +/- 8.1, 2.4 +/- .4, and 52.3 +/- 8.7% of the dose, respectively (mean +/- SD.). Average total recovery of radiocarbon was 96.2 +/- .4%. Radioactive residues present in carcasses averaged (ppm; mean +/- SD.): blood, .6 +/- .2; heart, 1.4 +/- .0; lungs, 8.4 +/- 1.7; spleen, 2.6 +/- .3; liver, 5.0 +/- .4; kidney, 5.9 +/- .0; brain, 1.9 +/- .4; adipose tissue, 1.1 +/- .2; rumen, reticulum, omasum, abomasum, 2.3 +/- .4; small intestine, 3.2 +/- .3; large intestine, 4.0 +/- .4; skeletal muscle, 1.0 +/- .2; bile, 12.5 +/- 4.0; white skin, .7 +/- .1; black skin, 4.0 +/- .7; remainder of the carcass, 1.0 +/- .2. Ocular residues were as follows: aqueous humor, 6.3 +/- 1.2; cornea, 13.5 +/- 8.6; iris, 255.8 +/- 167.0; lens, 2.3 +/- 1.5; vitreous humor, 2.2 +/- .4; retina/choroid, 84.5 +/- 34.1; sclera, 11.1 +/- 2.1. Mean concentrations of parent clenbuterol in tissues were (ppm; mean +/- SD): lung, 6.8 +/- .9; liver, 2.2 +/- .5; kidney, 3.7 +/- .5; and heart, .9 +/- .1. Parent clenbuterol represented from 43.9% of the total residue in liver to 81.2% of the total residue in lung.

Studies on the metabolic fate of FO-1561 in rats. (II). Blood and plasma levels, distribution and excretion after intravenous administration of (CH3-14C)FO-1561.

The blood and plasma levels, distribution and excretion of S-adenosyl-L-methionine sulfate tosylate (FO-1561) were studied in rats afer intravenous administration of [CH3-14C] FO-1561. 1. After intravenous administration of 10 mg/kg to rats, the blood and plasma levels of radioactivity decreased biphasically until 2 hr, and then kept steady state until 24 hr. After intravenous administration of 100 mg/kg to rats, the blood and plasma levels of radioactivity decreased biphasically until 4 hr, increased slightly until 8 hr, and then decreased slowly. The biological half life of radioactivity at early time period after administration was slightly shorter in plasma than in blood. The dose dependence in the biological half life was not observed. 2. The main excretory route of radioactivity was in urine (31.30 %) and expired air (29.72 %) at a dose of 10 mg/kg, and in urine (74.39 %) at a dose of 100 mg/kg. The excretion of radioactivity in feces or bile was slight. At 120 hr after administration, the residual of radioactivity in carcass was 33.41 % of dose in the group administered at 10 mg/kg, and 11.39 % of dose in the group administered at 100 mg/kg. 3. At 6 hr after administration, the increase of radioactivity was observed in the gastro-intestinal wall and several tissues, and in the skeletal muscle at 48 hr. These results suggest that [CH3-14C] may be incorporated into endogenous substance. The high level of radioactivity in the kidney was observed during 120 hr after administration. 4. The binding of radioactivity to plasma protein increased gradually after 1 hr and at 24 hr later, more than 90 % of radioactivity was bound to protein. The binding of radioactivity to blood cell increased gradually after 6 hr, and the binding rate of radioactvity was 69.64 % at 120 hr.

Metabolism of liposomes prepared from a labelled ether analog of 1,2-dioleoyl- sn-glycero-3-phosphocholinein the rat

To synthesize the ether analog of 1,2-diacyl- sn-glycero-3-phosphocholine (PC), 1- O- cis-9′-octadecenyl-2- O- cis-9′-[9′10′(n)- 3H]octadecenyl- sn-glycero-3-phosphocholine, we have adapted ava methodology and have obtained a product of high specific activity and purity. The labelled dioleyl ether phosphatidylcholine (DOEPC) was used to prepare 250–350 Å unilamellar liposomes, which contained also PC and free cholesterol. Following intravenous injection into rats, labelled PC was cleared from the plasma at a faster rate than DOEPC. The uptake of both labelled compounds by the liver increased up to 3 h, at which time there was about 40% of injected PC and 60% of DOEPC. The PC disappeared more rapidly than the DOEPC, so that 17 and 48% of injected label were present in the liver 24 h after injection of PC and DOEPC, respectively. Ten days after injection of DOEPC, about 10% of the label was still present in the liver. During the first 5 days after injection of DOEPC, 10% of radioactivity was found in the gastrointestinal tract and about 20% in the carcass; no increase in carcass radioactivity occurred during the loss of label from the liver. 24 and 48 h after injection of DOEPC, 40% of liver radioactivity was present in a neutral lipid, which on TLC comigrated with triacylglycerol. Since after alkaline hydrolysis this compound comigrated with diacylglycerol, it appears that the ether bond of DOEPC was not hydrolyzed, but after removal of phosphocholine, presumably by phospholipase C, the diether glycerol was reacylated. In experiments in vitro, the rate of exchange of labelled PC with red blood cell phospholipids exceeded that of DOEPC. Incubation of cultured hepatocytes with liposomes containing PC and/or DOEPC resulted in uptake of both phospholipids and metabolism of DOEPC to neutral lipids. The present findings indicate that DOEPC undergoes slow metabolism and can be eliminated from the body. These properties could prove advantageous for the use of DOEPC as a carrier of drugs and possibly as a carrier of free cholesterol in reverse cholesterol transport.

Effect of age and diet on renal cadmium retention in rats.

The results of our previous and recent work on cadmium metabolism in relation to age and diet are presented. Experiments were performed on albino rats aged 1-26 weeks. In some experiments rats were given different foods (milk, meat, bread) instead of standard rat diet. Some animals received trisodium calcium salt of diethylenetriaminepentaacetate (DTPA) intraperitoneally to decrease cadmium retention. Radioactive cadmium (115mCd) was administered orally and intraperitoneally. Whole body (WB), carcass (C) and organ (kidney, liver and brain) retentions were determined 1 and 2 weeks after a single radioisotope administration. The results are expressed as percentages of the administered dose (% D) and as percentages of whole body (% WB) and carcass (% C) radioactivities. After oral administration whole-body cadmium retention was higher in sucklings than in weaned animals, primarily due to increased gut retention. The kidney retention of orally administered cadmium was about 5-7 times higher in sucklings than in older rats. Cadmium distribution (% C) was similar after oral and intraperitoneal administration. In sucklings, kidney retention made a lower fraction of the carcass radioactivity one week after 115mCd administration but reached adult values a week later. Liver retention in sucklings was a slightly lower fraction of the carcass radioactivity than in older rats at both time intervals. Brain retention (% C) was about 10 times higher in sucklings than in older rats throughout the experiment. Preliminary data on the influence of dietary treatments and treatment with DTPA indicate that some treatments which influence cadmium retention also influence cadmium distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

The distribution and metabolism of cyclotrimethylenetrinitramine (RDX) in the rat after subchronic administration

Rats were either dosed with unlabeled cyclotrimethylenetrinitramine (RDX) or [ 14C]RDX by gavage at 20 mg/kg/day for up to 90 days or allowed free access to unlabeled RDX or [ 14C]RDX-saturated drinking water (50–70 μg/ml) for up to 90 days. RDX did not accumulate in any tissue examined in these studies, nor were there any tendencies for plasma (RDX) to increase continuously with repeated dosing. In the 90-day drinking water study the daily recovery of the 14C label, estimated at the end of 1, 4, 8, and 13 weeks, varied between 54 and 89%. The majority of the label was excreted as exhaled 14CO 2 and as unidentified metabolites in the urine. Residual carcass radioactivity in the drinking water study did increase threefold from Week 1 to Week 13. While no overt neurological signs characteristic of RDX toxicity occurred in any of the treated rats, 8 of 30 rats dosed with 20 mg/kg/day died, apparently from exacerbation of chronic respiratory disease. Compared with results from other animal studies, these data support an ingestion limit of 0.1 mg of RDX/kg/day, or an acceptable level of 2 to 3 ppm in potable water.

Field Measurement of Cesium-137 in Deer

The U. S. Forest Service conducts yearly white-tailed deer hunts on the Savannah River Plant to help control the indigenous deer population. Successful hunters are permitted to retain their guarry after clearance by Forest Service personnel. To be sure that carcass radioactivity is similar to that found throughout the southeastern coastal region, each carcass is radioassayed on the spot with a single channel analyzer set to measure the cesium-137 photopeak (Figure 1). This paper describes the circuitry and performance of the instrument used for the field analyses. A sodium iodide crystal with photomultiplier tube provides electrical pulses proportional to the incident gamma radiation. An amplifier is tailored to compensate the temperature-induced gain changes of the detector system, and micropower digital logic is used to form control, pulse shaping, and scaling functions. The components are interconnected with wire-wrap techniques. The resulting instrument is compact and simple to operate, and its analyses are comparable in accuracy to laboratory analyses.