Absorption of 233U, 237Np, 238Pu, 241Am and 244Cm from the gastrointestinal tracts of rats fed an iron-deficient diet.

Absorption of U, Np, Am and Cm was increased by factors of 3.4, 7.1, 2.7 and 1.7, respectively, when nitrate solutions of these actinides were gavaged to adult rats fed an iron-deficient diet. Retention increased proportionately in liver, kidney and carcass. The concentration of the actinides excreted also increased substantially (over that of controls) in the urine of iron-deficient rats gavaged with 233U and 237Np, but not in those with 241Am or 244Cm. Weanling rats on an iron-deficient diet, gavaged with ferric nitrate immediately before administration of 238Pu nitrate, retained between 4% and 12% of the 238Pu retained by litter mates that were not treated intragastrically with iron.

Effect of excess Fe on Cd or Pb absorption by rats.

Absorption of cadmium and lead from the gastrointestinal (GI) tract of adult rats was measured after gavage with solutions of 109Cd or 210Pb. Before the radionuclide gavage, animals were either fed or fasted for 24 h, or fasted and given a supplemental gavage of ferric or ferrous iron. Fasting caused a slight increase in 109Cd absorption that was not statistically significant; ferrous iron caused a three-fold increase; and ferric iron increased absorption 14-fold. In contrast, fasting increased 210Pb absorption fivefold, and the oxidizing agents ferric iron and quinhydrone blocked the effect of fasting. Gavage of 8-d-old rats with 109Cd and either ferric or ferrous iron doubled the amount of cadmium retained in the carcass and substantially decreased the amount retained in the GI tract. Some of the large fraction (60-70%) of 109Cd stored in the mucosa of the intestine was absorbed into the body with time. An excess of ferric iron had an opposite effect on the retention of lead in the carcasses of 8-d-old rats, decreasing it from 53% of the gavaged dose to 3%; the effect on the amount retained in the intestine was similar, decreasing it from 16% to 8%. These results suggest that the mechanisms for transport of cadmium and iron across the intestine may be similar in the adult and neonatal rat, but that the oxidizing effect of ferric iron on cadmium absorption is much greater in the adult.

Neptunium-237 inhalation in rats.

Groups of rats were exposed to aerosols of 237Np nitrate to determine clearance rates, retention and distribution at various intervals after inhalation. Initial lung burdens (ILB) after 237Np inhalation by three treatment groups were 0.12, 0.19 and 0.37 mu Ci/kg, respectively. Radiochemical analyses of animals killed at 4, 8, 14, 28 and 90 d, as well as data for others maintained until they became moribund, showed that their lung clearance followed a three-compartment model, clearance half-times for which were 1, 35, and 10,000 d, respectively. Only 3% of the ILB was retained after 90 d; 12% of that burden had translocated to the skeleton at 750 d; the half-time for skeletal retention was 2500 d. A single tumor was the only malignancy detected in the lungs of the 35 animals allowed to survive the early phase of the study.

Effectiveness of DTPA therapy when administered intragastrically or intraperitoneally to remove Pu from adult or neonatal rats.

Adult and neonatal rats were given 238Pu by gavage or parenterally and treated with 0.5 mmoles/kg of calcium diethylenetriaminepentaacetate (DTPA), by gavage or parenterally, to determine its effectiveness for removing Pu. Parenteral administration of DTPA to adult rats 2 h after an intravenous 238Pu injection was much more effective than intragastric treatment, removing nearly 70% of the retained dose. When 238Pu was given to adults intragastrically (IG), followed by DTPA given either intraperitoneally (IP) or IG 2 h later, 238Pu absorption increased while retention remained either unchanged, or increased. When neonates were given 238Pu IG and treated 2 h later with intraperitoneal or intragastric DTPA, removal of 238Pu was better than in adults: more than 80% of the 238Pu that was absorbed and retained was removed by intragastric DTPA. When neonates were injected IP with 238Pu, treatment with intraperitoneal DTPA was more effective for 238Pu removal than intragastric treatment.

Influence of iron on plutonium absorption by the adult and neonatal rat.

To determine how iron affects plutonium absorption, adult rats were gavaged with 238Pu nitrate (pH 2) after they had been fed an iron-deficient diet or treated with iron supplements. Neonatal rats born to dams on an iron-deficient diet were also gavaged with 238Pu. An iron-deficient diet resulted in enhanced 238Pu absorption both in the adults and in neonates born to iron-deficient dams. Ferric iron increased 238Pu absorption 12-fold in adult rats; injected iron-dextran reduced that increase; gavaged ferrous iron reduced 238Pu absorption to one-third of the control value. Rat neonates absorbed 30 to 40 times as much 238Pu as adults; absorption was lowered in groups that received iron supplements: Iron-dextran caused a 50% reduction; ferric iron, 95%; and ferrous iron, greater than 95%. The results demonstrate an effect of the oxidation state of iron on plutonium absorption in adult rats different from that observed in suckling rats. The results suggest that the high rate of 238Pu absorption by neonatal animals is due not only to the permeability of their intestines but also to their high demand for iron.

Influence of oxidizing or reducing agents on gastrointestinal absorption of U, Pu, Am, Cm and Pm by rats.

Absorption of 233U, 238Pu, 241Am, and 244Cm from the gastrointestinal (GI) tract was measured in rats, fed ad libitum or fasted, that were gavaged with solutions containing ferric iron, ferrous iron, iron powder, quinhydrone or ascorbic acid. Absorption and retention of all of these actinides was increased substantially by fasting and by the addition of mild oxidizing agents, ferric iron and quinhydrone. In contrast, absorption and retention were decreased to below the fasted level by all the reducing agents except ascorbic acid, which caused diarrhea and an increase in absorption. Absorption of the lanthanide element 147Pm from the intestine of fasted rats was also increased by ferric iron. Some of these actinide elements are polyvalent and are, in some cases, known to be absorbed from the GI tract more readily in their higher oxidation states. This suggested an oxidation-reduction mechanism for the effect of fasting and the action of the chemical agents used. However, the improbability that either 241Am(III) 244Cm(III) or 147Pm is converted to a different oxidation state under these conditions makes that mechanism unlikely. Other explanations are suggested.

Further studies on the influence of chemical form and dose on absorptions of Np, Pu, Am and Cm from the gastrointestinal tracts of adult and neonatal rodents.

Absorption of isotopes of the actinide elements Np, Pu, Am and Cm from various organic media and/or in combination with plant or animal ligands or tissue is compared with their absorption from an inorganic nitrate medium. Gastrointestinal (GI) transport of 238Pu, 239Pu, 241Am and 244Cm at high concentrations from citrate medium by adult rats and/or mice was higher than from nitric acid medium. Neptunium-237 absorption, however, was not increased by citrate; probably because its oxidation state was reduced from 237Np(V) to 237Np(IV) by the medium and by the GI content. Increasing the mass of the 237Np dose resulted in increased absorption. Neither incorporation of 238Pu in rat liver nor retention of 238Pu oxide in rat lungs enhanced absorption when those Pu-containing tissues were administered intragastrically to either adult or neonatal rats. Ranking of GI absorption of the various forms of Pu gavaged in these studies suggests that transport is in the order: Pu citrate greater than Pu phytate greater than biologically incorporated Pu greater than Pu nitrate.

Effects of fasting and/or oxidizing and reducing agents on absorption of neptunium from the gastrointestinal tract of mice and adult or neonatal rats.

Neptunium-237(V) nitrate was administered by gavage to groups of fed or fasted adult and 5-day-old rats. Some groups also received the oxidants quinhydrone or ferric iron, and others received the reducing agent ferrous iron. Adult mice received ferric or ferrous iron and 235Np. When the adult rats were killed at 7 days after gavage, measurements showed that, compared with rats that were fed, a 24-hr fast caused a fivefold increase in 237Np absorption and retention. Both quinhydrone and ferric iron caused an even greater increase in absorption in both fed and fasted rats. Ferrous iron, on the other hand, decreased absorption in fasted rats to values lower than those obtained in fed rats. Similar results were obtained in mice treated with 235Np and either ferric or ferrous iron. The highest absorption obtained after gavage of ferric iron to fasted rats and mice was about two orders of magnitude higher than the value obtained in animals that were fed before gavage. The effects of ferric and ferrous iron on neptunium absorption by neonatal rats were similar to their effects on adult animals but of lesser magnitude. These results are consistent with the hypothesis that Np(V), when given in small mass quantities to fed animals, is reduced in the gastrointestinal tract to Np(IV), which is less well absorbed than Np(V).

Sustained administration of cyclazocine for antagonism of morphine.

The plasma levels, distribution and excretion of tritium were determined after administration of a single or sustained dose of 3H-cyclazocine to naive and morphine-addicted rats. The plasma levels reached and maintainat animals tolerant to morphine were cross-tolerant to cyclazocine. Although only half the administered radioactivity was excreted after either a single dose or a continuous administration, no appreciable concentration was found in any of the organs studied. The behavior of a single or sustained dose of cyclazocine was also determined in rabbits to evaluate the effect of the implant site on the drugs release rate and tissue biocompatibility. The release-rate of 3H-cyclazocine from a glyceride matrix implanted subcutaneously or intramuscularly could be controlled by modification of the matrix itself or by manipulation of the drug concentration within the matrix. Durations of action between a few days and a month were obtained by these means from devices that were both biodegradable and tissue compatible. The results indicate that the procedures used here may provide a practical means for administering narcotic antagonists to addicts.