Pharmacokinetics and biotransformation of rifamycins in the body of experimental animals]

The study on distribution of 14C-rifampicin and 14C-rifamycin S in experimental animals after intramuscular administration of the drugs showed that concentrations of rifampicin in the organs and blood were higher than those of rifamycin S. Biotransformation products of both antibiotics, such as 25-deacetylrifampicin, N-oxide of rifampicin, 3-phormylrifamycin SV, rifamycin SV and others were found in the liver, kidneys, bile and urine. No products of the antibiotic metabolism were found in the blood, lungs and spleen.     

The effect of murine B16F10 melanoma on the biodistribution of 99mTc-MDP in male C57BL/6J mice.

The biodistribution of radiopharmaceuticals used in diagnostic imaging can be altered by a wide variety of factors. We studied the effect of murine B16F10 melanoma on the biodistribution in mice of 99mTechnetium-methylenediphosphonic acid (99mTc-MDP). Viable B16-F10 cell lines (1 x 10(5)) were inoculated subcutaneously in the dorsal region of 8-12 week-old male isogenic C57BV/6j mice. 14-16 days after inoculation, 99mTc-MDP was injected in the ocular plexus and after 0.5 hr the animals were rapidly sacrificed. The organs and tumor were isolated, the mass determined and the percentage per gram of injected activity (%ATI/g) calculated. The results shown that the %ATI/g:i/ has not been altered in inguinal lymph nodes, prostate, pancreas, testis, seminal vesicle, bladder, kidney, stomach, small intestine, spleen, thymus, heart, lung, brain and muscle; but ii/ significantly decreased in thyroid, bone, blood and liver. In conclusion, the B16F10 melanoma can alter the 99mTc-MDP uptakes in some organs.     

Study of the distribution of C14-variamycin and C14-mitramycim after intravenous administration to mice]

Distribution of antitumor antibiotics, i.e. C14-variamycin and C14-mitramycin in the organs of albino mice after their intravenous administration in single doses was studied. Similarity in the distribution dynamics of both the antibiotics with respect to the animal organs was found. However, the level of variamycin as compared to that of mitramycin was much higher in the liver and especially the spleen. In the experiments with variamycin the radioactivity of the kidney tissue decreased more rapidly than in the experiments with mitramycin. Chromatographic analysis of the urine of the mice treated with C14-variamycin was performed. The labeled Variamycin was detected in the animal urine within 48 hours from the moment of the antibiotic administration. Its portion in the total amount of the radioactive products in the urine was 30 to 40% at various stages of the study.     

Changes in protein synthesis due to an inflammatory challenge

Rates of protein synthesis in various chick tissues were examined 16 hr after an inflammatory challenge. Protein synthetic rates were calculated from the rate at which [14C]leucine was incorporated into protein and the specific activity of [14C]leucine in the precursor pool. An injection of either Escherichia coli or sheep red blood cells (SRBC) decreased the rate of protein synthesis in the gastrocnemius muscle, and increased the rate in liver, bursa, spleen, and thymus. E. coli, but not SRBC, decreased protein synthesis in the pectoralis muscle. E. coli significantly decreased the aggregation of pectoralis muscle polysomes and increased the aggregation of polysomes in the thymus, bursa, and spleen. E. coli increased the aggregation of free, but not bound, polysomes in liver, suggesting an increase in synthesis of export proteins. SRBC significantly increased polysomal aggregation in bursa and spleen only. A crude preparation of leukocyte endogenous mediator, isolated from peritoneal macrophages, decreased muscle-polysomal aggregation. These studies indicate that tissue-specific changes in protein synthesis occur after a noninfectious inflammatory challenge. These changes may be part of a homeostatic mechanism which supports the immune response.     

Incorporation of orotic acid into nucleotides and RNA in mouse organs during 60 minutes.

Mouse kidney and liver were found to increase their levels of radioactivity above that of serum from 2 to 60 min after administration of [6-14C]orotic acid. In spleen, thymus and brain, the radioactivity level reached a maximum soon after the injection and then decreased, as did that in serum. Sixty minutes after the injection, 44% of the administered isotope dose was found in the kidneys, 22% in the liver and 0.75% in the spleen. The 14C activity in liver UTP increased rapidly and then remained constant for 60 min. The ratio between the activities in uridine phosphates and UDP-sugars was 3:4 from 10- 60 min after injection. In the liver and kidneys, the RNA 14C activities at 60 min after injection were 15% of the activity in their acid-soluble fractions. Intraperitoneal administration was found to be preferable to intravenous administration for studies on nucleotides and RNA in mouse liver, due to the delayed incorporation of the [14C]orotic acid activity into the nucleotide pool.     

Immunohistochemical localization of thymosin beta 9 in bovine tissues

Using an indirect fluorescent antibody technique with frozen sections, the localization of thymosin beta 9 was investigated for the first time in bovine thymus, spleen, lung, muscle and liver. The antibodies used have been raised against the N-terminal fragment 1-14 of thymosin beta 9 in order to minimize the cross-reactivity with thymosin beta 4 which was found to be also present in bovine tissues. The specific antibodies against thymosin beta 9 raised in our laboratory allowed us to localize this peptide in presence of the highly homologous and always accompanying thymosin beta 4 in different tissues. Although thymosin beta 9 was first isolated from calf thymus, it could be also detected in other bovine organs. The highest density of positive immunoreaction was found to be in spleen sections. In the muscle tissue a pronounced fluorescence intensity was present in the region of the sarcolemma.     

14C] Alanine incorporation into proteins and their contents in the tissue of intact and adrenalectomized rabbits after hydrocortisone and cortitropin administration

A single administration of hydrocortisone to intact rabbits increases the incorporation of [14C] alanine into proteins of the brain and liver tissue homogenates and soluble fractions as well as in blood plasma proteins and reduces the label incorporation into the brain tissue proteins and reduces its incorporation into the blood plasma proteins. Adrenalcetomy is followed by an increase in the incorporation of [14C] alanine into proteins of the brain and muscle tissue homogenates and soluble fraction and into proteins of blood plasma and liver tissue homogenates as well as by reducing the label incorporation into the spleen soluble fraction proteins. ACTH administered to adrenalectomized rabbits reduces incorporation of [14C] alanine into the brain and muscle tissue proteins, total proteins of liver tissue homogenate and increases it into the proteins of the spleen tissue soluble fraction. Multiple administration of the soluble fraction hormones both to intact and adrenalectomized rabbits inhibits the label incorporation into the studied tissue proteins. Parallel with the change in [14C] alanine incorporation into proteins under the hormones effect certain shifts in their contents were also established.     

The effect of dietary lipid hydroperoxide on lymphoid tissues in mice

Effects of dietary lipid hydroperoxides on lymphoid tissue were studied in mice. When graded amounts (190, 270 and 310 mg) of methyl linoleate hydroperoxide (MLHPO) were orally administered to male C57BL/6 mice (6 weeks old), necrosis was observed in lymphocytes located among the reticular network in the thymus, and thymus weight was significantly decreased 24 h after the treatment. The spleen weight of mice given MLHPO tended to decrease. Spontaneous chemiluminescence of the thymus was remarkably increased after the dose. Thiobarbituric acid reactants in the liver, thymus and blood were also increased after the dose of MLHPO. At intervals of 3, 6, 12 and 24 h after a dose of 14C-labeled MLHPO, 14C was detected in the blood and liver. Fatty infiltration of the liver was found after the treatment with MLHPO. These findings indicate that oral intake of lipid hydroperoxides causes significant damage to lymphoid tissues of mice.     

Distribution of the 14C-hydrated analog of phenazepam in the organs and tissues of mice

The absorption kinetics of hydrated phenazepam analog into the liver, spleen, brain, kidney, blood, lungs, heart, skeletal and fat tissues is studied at 0.25-24 hour intervals after its intraperitoneal (i/p) administration to mice. Drug concentration in the above mentioned organs was maximal 0.5-1 hour later. The decrease of the drug and its metabolite level in the organs under study is a biexponential process, consisting of "quick" (1-6 hours) and "slow" phases. The rate of absorption of hydrated phenazepam analog into the organs and tissues and its elimination is lower than that of phenanzepam.     

Comparative in vitro and in vivo assessment of genotoxic effects of etoposide and chlorothalonil by the comet assay.

The alkaline single cell gel electrophoresis (comet) assay was used to assess in vitro and in vivo genotoxicity of etoposide, a topoisomerase II inhibitor known to induce DNA strand breaks, and chlorothalonil, a fungicide widely used in agriculture. For in vivo studies, rats were sacrificed at various times after treatment and the induction of DNA strand breaks was assessed in whole blood, bone marrow, thymus, liver, kidney cortex and in the distal part of the intestine. One hour after injection, etoposide induced DNA damage in all organs studied except kidney, especially in bone marrow, thymus (presence of HDC) and whole blood. As observed during in vitro comet assay on Chinese hamster ovary (CHO) cells, dose- and time-dependent DNA effects occurred in vivo with a complete disappearance of damage 24 h after administration. Even though apoptotic cells were detected in vitro 48 h after cell exposure to etoposide, such a result was not found in vivo. After chlorothalonil treatment, no DNA strand breaks were observed in rat organs whereas a clear dose-related DNA damage was observed in vitro. The discrepancy between in vivo and in vitro models could be explained by metabolic and mechanistic reasons. Our results show that the in vivo comet assay is able to detect the target organs of etoposide and suggest that chlorothalonil is devoid of appreciable in vivo genotoxic activity under the protocol used.     

57Co-bleomycetin pharmacokinetics in the body of mice with LIO-1 lymphosarcoma

Pharmacokinetics of 57Co-bleomycetin was studied on mice with lymphosarcoma LIO-1. It was found that at early periods of intravenous administration of the labeled antibiotic, i.e. within the period from 5 minutes to 1 hour its higher levels are detected in the liver, kidneys, blood serum, lungs, intestine and tumor. At later periods the drug levels in the organs and tissues gradually decrease and by the 72nd hour the concentration of 57Co-bleomycetin in the blood serum appears to be 30 times lower as that after 5 minutes. In the muscles and tumor its concentrations by that period are 15 and 2 times lower respectively. Radiometry of the animals showed that within the first 24 hours more than 85 per cent of 57Co-bleomycetin was excreted from the mice.     

Stimulation of ornithine decarboxylase activity in rat tissues by growth hormone and by serum growth factor from rats infested with spargana of Spirometra mansonoides

Ornithine decarboxylase activity was studied in heart, kidney, liver, thymus, lung, spleen, skeletal muscle and fat of hypophysectomized rats after growth hormone treatment. A marked increase in enzyme activity was observed in kidney and liver, and a significant increase in heart and thymus at 4 h after injection of growth hormone. The kidney was the most responsive organ with an increase in activity of about 100 fold. The enzyme activity in kidney responded to a dose of 10 μg of growth hormone. Daily injection for 12 days raised activity only in the heart. Infestation for 6–13 days with spargana of Spirometra mansonoides, which also causes growth of hypophysectomized rats, increased enzyme activity in the heart and thymus. Intravenous injection of serum of hypophysectomized rats infested with spargana of Spirometra mansonoides caused a significant increase in the enzyme activity in liver and kidney after 4 h. Growth hormone and the serum growth factor of sparganosis seem to share the characteristic of causing an early increase in ornithine decarboxylase activity in rat tissues. The marked response in kidney and liver raises the possibility that these organs are the primary targets of both substances.     

Myelotoxicity of epirubicin]

Epirubicin (pharmorubicin, India), an antitumor antibiotic of the anthracycline group, was studied in regard to its effect on peripheral blood, bone marrow and lymphoid organs (the thymus and spleen) of CBA mice after its intraperitoneal administration in a single dose equal to the MIC (7.8 mg/kg) and in a course dose (1/5 of the MIC 5 times a day). The cytogenetic impairments induced by the cytostatic were estimated on metaphase plates with the bone marrow specimens and by counting the peripheral blood erythrocytes with micronuclei (the micronuclear test). It was shown that epirubicin induced cytogenetic disturbances in the hemopoietic cells within the first 72 hours. The antibiotic had a marked reversible effect on the erythroid population and lymphoid tissues and a moderate toxic action on the granulocyte population. The antibiotic did not affect thrombocytopoiesis. The single administrations had a more pronounced and prolonged myelotoxic and lymphotropic effect.     

Ganglioside expression in tissues of mice lacking the tumor necrosis factor receptor 1

This study presents a comparative analysis of gangliosides from lymphoid (spleen and thymus) and other tissues (brain, liver, lung, muscle) of C57BL/6 mice homozygous (-/-) and heterozygous (+/-) for the tumor necrosis factor receptor 1 (TNFRp55). Quantitative and qualitative differences in the expression of the lipid-bound N-acetylneuraminic (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) and of various ganglioside biosynthesis pathways were detected between the tissues of the TNFRp55 -/- and the control TNFRp55 +/- mice. Sialic acid profiles showed a strong decrease in the absolute amount of sialic acids (Neu5Ac + Neu5Gc) in the lungs and thymus of homozygous (1.41 and 0.3 ng/mg wet weight, respectively) compared with control heterozygous animals (7.18 and 2.05 ng/mg wet weight, respectively). Considerable differences of Neu5Ac/Neu5Gc ratios in the lungs, muscle, spleen, and thymus were also detected. The gangliosides GM3(Neu5Ac) and GM3(Neu5Gc) were the dominant gangliosides in the lungs of the control animals, whereas the knockout mice almost completely lacked these structures in this organ. Reduced expression of GM1b-type gangliosides (GM1b and GalNAc-GM1b) was also found in the lungs, spleen, and thymus of the TNFRp55 knockout mice. On the other hand, neolacto-series gangliosides were more abundant in the lungs, brain, and muscle of the knockout mice, whereas their expression in the liver, spleen, and thymus was similar in both groups of animals. This study provides in vivo evidence that TNF signaling via the TNFRp55 is involved in the acquisition of a distinct ganglioside assembly in different mouse organs. TNFRp55 signaling seems to be especially important for the activation of the GM1b-type ganglioside biosynthetic pathway that is a unique characteristic of the mouse lymphoid tissues.     

Comparison of the distribution kinetics and metabolism to acid end-products of corticosterone and 11-deoxycorticosterone in BALB/c mice

The conversion of [4 14C]corticosterone[( 14C]B) and 11-deoxy-[1,2-3H]corticosterone [( 3H]DOC) to steroidal carboxylic acids was studied in the BALB/c mouse. There was rapid and preferential excretion of [3H]DOC metabolites into the gastrointestinal tract. Excretion of 14C through the kidney was higher than 3H excretion. Within minutes of intraperitoneal injection, levels of 3H and 14C in most organs reached their maximal levels and subsequently decreased in an exponential pattern. The majority of the organs took up 14C to a greater extent than 3H. Using tissue blood ratio of tracer (T/B) as criterion, it was found that liver, gall bladder, intestine, and kidney concentrated 3H and 14C-labeled steroid from blood. T/B for 3H exceeded that for 14C in the gastrointestinal tract. Abdominal fat preferentially took up [3H]DOC tracer, whereas [14C]B tracer was not taken up by this tissue. T/B was less than 1 for 3H and 14C in heart, thymus, spleen, brain, skeletal muscle and skin. In these organs uptake of B and its metabolites was greater than that of DOC and its metabolites. In liver, [14C]B and [3H]DOC were converted to carboxylic acid metabolites which accumulated in the intestine. The most abundant acid was 11 beta,20 alpha-dihydroxy-3-oxo-pregn-4-en-21-oic acid from B. The acid metabolites of DOC were not identified. For both steroids, acids were major metabolic end-products.     

A new fluorescent viability test for fungi cells

Examination of the distribution of radioactivity in rat tissues during the first 24 hr after administration of ochratoxin A-¹⁴C demonstrated maximum accumulation in stomach and kidney. The highest counts were observed in stomach, lung, kidney, thymus, spleen and heart during the first 6 hr after treatment, whereas the brain, liver muscle, duodenum, jejenum, ileum, and cecum exhibited the greatest counts at 18 hr after toxin exposure.The mention of firm names or trade products does not imply that they are endorsed or recommended by the U.S. Department of Agriculture over other firms or similar products not mentioned.     

Expression of mRNAs for alpha-fetoprotein (AFP) and albumin and incorporation of AFP and docosahexaenoic acid in baboon fetuses.

alpha-Fetoprotein and albumin, two members of a multigene family, reversibly bind fatty acids with high affinity. The origin of alpha-fetoprotein (AFP) and albumin present in fetal tissues other than the liver and yolk sac is a subject of controversy. In this work, we have searched for the presence of the albumin and AFP mRNA molecules in different fetal organs of the baboon (Papio cinocephalus), using a highly sensitive gel-blot hybridization assay with human albumin and AFP cDNA probes. Large amounts of albumin and AFP mRNA molecules were found in the fetal liver; significant quantities were also present in the gastrointestinal tract and in the kidney. No detectable levels were found in the other tissues examined (brain, skin, spleen, pancreas, muscle, heart, thymus, placenta, and amnion). After injection of radiolabeled AFP into pregnant baboons, all fetal tissues took up the protein. White adipose tissue, kidney, intestine, lung, liver, and cerebral cortex showed a great uptake of exogenous AFP. [14C]Docosahexaenoic acid (22:6, n-3), injected at the same time, was actively transferred from the maternal compartment across the placenta and incorporated into cellular lipids by all fetal tissues and particularly by liver (around 70% of total incorporation). The levels of [14C]docosahexaenoic acid per gram of tissue increased in the order: maternal blood less than placenta less than fetal liver, indicating a selective accumulation of this fatty acid by the fetus. These results indicate that intracellular AFP in non-hepatic tissues of the developing baboon is, for the most part, of plasma origin.     

Changes in fatty acid composition of thymus cells, liver, blood plasma, and muscle tissue in mice with solid Ehrlich carcinoma

The fatty acid composition of thymus cells, liver, blood plasma, muscle tissue, and tumor focus has been studied in mice with solid Ehrlich carcinoma. The tumor growth in the mice was associated with an increase in the total content of monounsaturated fatty acids in all organs and tissues studied and with a decrease in the total amount of polyunsaturated fatty acids in all tissues except blood plasma. The tumor tissue was characterized by increased levels of monounsaturated fatty acids in comparison with their levels in organs and tissues of intact animals. In the thymus of tumor-bearing mice, the contents of myristic and palmitic saturated fatty acids, which are associated with activation of the T-cell immunity, were increased. The most expressed and considerable changes in the fatty acid composition during tumor growth were observed in the muscle tissue of the animals. A possible role of changes in the fatty acid composition in the investigated organs and tissues of tumor-bearing mice in the organism’s response to tumor growth is discussed.     

Comparative study of cephalexin and cephradine distribution in the body of rats]

Distribution regularities of cephalexin and cephradine, 2 semisynthetic cephalospor in antibiotics for oral use were studied on rats. It was found that the cephalosporins had a capacity for satisfactory penetration through the histochematological barriers. The drugs were rather rapidly absorbed from the gastrointestinal tract of the rats into the blood. Their maximum blood levels were determined 1 hour after the administration. The highest cephalosporin concentrations were detected in the kidneys and liver. Still, the level of cephradine in the kidneys was lower and that in the liver was higher than the levels of cephalexin. The lowest concentrations were found in the skeletal muscles. The character of cephradine distribution in the lungs, heart and spleen differed from that of cephalexin; the maximum concentrations of cephradine in these organs were achieved 1 hour after its administration, while those of cephalexin were achieved in 30 minutes. The antibiotics were not detected in the brain tissue. No increase in the concentration gradient with time was observed.