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PubMed2002

Trypanosoma cruzi: role of host genetic background in the differential tissue distribution of parasite clonal populations.

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, has quite a variable clinical presentation, ranging from asymptomatic to severe chronic cardiac and/or gastrointestinal disease. The reason for that is not completely understood, but both parasite and host genetic traits are certainly involved. Recently, we have demonstrated clinically and experimentally that the genetic variability of T. cruzi is one of the determinants of the pattern of tissue involvement in Chagas' disease. We then decided to turn our attention to the role of host genetic background. To study this, we compared the infection of four lineages of mice [three inbred (BALB/c, DBA-2, and c57Black/6) and one outbred (Swiss)] with two T. cruzi clonal populations, the Col1.7G2 clone and the JG monoclonal strain. The tissue distribution of T. cruzi strains was identical for BALB/c and DBA-2 mice, but very different in C57BL/6 (H-2(b)) and outbred Swiss mice. This result clearly demonstrates the importance of host genetic aspects in the process. Since BALB/c and DBA-2 have the same H-2 haplotype (H-2(d)) and C57BL/6 does not (H-2(b)), it is possible that MHC variability may be involved in influencing the tissue distribution of involvement in experimental Chagas' disease of the mouse.

Animals↗

PubMed1990

Autoradiographic study of tissue distribution of [3H]ubenimex in IMC carcinoma-bearing mice.

[3H]Ubenimex was administered to IMC carcinoma-bearing mice, and the tissue distribution of the radioactivity was examined at various times after drug injection by autoradiography of glutaraldehyde-fixed tissues. Silver grains were concentrated on some of the macrophages present around the solid tumor and in thymic medulla, splenic red pulp, and mesenteric lymph node medulla. The grains were also seen at a similar concentration on some nurse cell-like cells in the thymic cortex and on some reticular cells in splenic red pulp. In the liver, grains were concentrated on the hepatocytes and bile duct epithelium. The grains were most densely concentrated on kidney proximal straight tubules, in which strong leucine aminopeptidase activity was also observed.

Animals↗

PubMed1993

Skin proteasomes (high-molecular-weight protease): purification, enzymologic properties, gross structure, and tissue distribution.

Proteasomes (high-molecular-weight protease) were purified from rat skin, and their enzymologic properties, gross structure, and tissue distribution were investigated. Skin proteasomes were purified by successive (NH4)2SO4 fractionation and by phenyl Sepharose CL-4B and HPLC gel filtration chromatography. The molecular weights of the proteasomes were estimated from gel filtration to be 750 kD. On sodium dodecylsulfate-polyacrylamide gel electrophoresis, the purified enzymes dissociated into several bands, the majority falling into the range of 36-20 kD. Two-dimensional electrophoretic analysis demonstrated approximately 10-15 separate protein spots with pl values varying between 3 and 10. As analyzed by electron microscopy, the gross structure of the enzymes showed an almost symmetrical ring-shaped particle with a small hole in the center. Succinyl-leucyl-leucyl-valyl-tyrosine-4-methylcoumaryl-7-amide, a fluorogenic substrate for serine proteinases, demonstrated the highest activity in terms of substrate specificity. Sodium dodecylsulfate, Ca++, and some free fatty acids activated enzyme activity. Activity was inhibited by diisopropylfluorophosphate, leupeptin, N-ethylmaleimide, iodoacetamide, and chymostatin. These results show that both serine and cysteine residues are related to the enzyme activity of proteasomes. Total and specific enzyme activities in the epidermis were, respectively, 10 and 20 times higher than in the dermis. Immunohistochemical studies utilizing the avidin-biotin complex method with monoclonal antibody revealed that the enzyme is distributed throughout the epidermis. These findings indicate the epidermal localization of proteasomes.

Animals↗

PubMed1999

[The time course and tissue distribution of endotoxin in rats after thermal injury].

OBJECTIVE: To observe the time course and tissue distribution of endotoxin, and to evaluate the potential role of local endotoxin in mediating multiple organ damage following burns. METHODS: Wistar rats were subjected to a 35 percent full-thickness scald injury. They were grouped according to time of sacrifice: no burn, and 12, 24, 48, 72 hours postburn. Tissue specimens from liver, kidneys, lungs and intestine were aseptically harvested to determine tissue endotoxin levels. In addition, blood samples were obtained for measurement of organ function parameters. RESULTS: It was found that endotoxin levels in liver, spleen and lungs increased markedly after thermal injury, with the highest level in liver. Meanwhile, serum GPT, GOT, CK-MB levels, and pulmonary myeloperoxidase(MPO) activities markedly elevated after scald injury, reaching a maximum between 12 and 24 hours. Intestinal diamine oxidase(DAO) activities tended to decrease at various time points postburn. In addition, there were highly positive correlations between pulmonary endotoxin levels and MPO activities, and also between renal endotoxin levels and serum Cr values. CONCLUSION: Burn injury per se can result in gut-derived endotoxin translocation which is mainly distributed to the liver, spleen and lungs. Endotoxin accumulated in local sites may play an important role in mediating multiple organ damage secondary to major burns.

Animals↗

PubMedDate not supplied

[Kinetics of the organ and tissue distribution of D-alpha-(5 methyl-3H)-tocopherol as a function of the age of animals].

Principles of an intertissue distribution of D-alpha(5 methyl-3H)tocopherol were studied depending on ontogenesis of animals. The tissues were divided into three groups via kinetics of the label distribution: tissues responsible for transport and recirculation of the vitamin, tissues-consumers from which the third group was derived--endocrine glands with the maximal rate of the label incorporation within a week. In preadolescent rats the rate of the vitamin consumption was high due to increase in hepato-intestinal recirculation and to optimal conditions of tocopherol intestinal absorption. In ageing rats the rate of the vitamin utilization was decreased as a result of lowering of its absorption in intestine but the vitamin E metabolism was increased in the tissue-consumers considering that the label content was decreased in tissues, the intestinal phase was prolonged two-fold and more as compared with young animals and that excretion of the vitamin metabolites with urine was increased. High level of radioactivity in feces appears to occur because of presence of tocopherol nonabsorbed in intestine.

Aging↗

PubMed2004

Differential involvement of multidrug resistance-associated protein 1 and P-glycoprotein in tissue distribution and excretion of grepafloxacin in mice.

The involvement of multidrug resistance-associated protein 1 (Mrp1) and P-glycoprotein (mdr1) in the tissue distribution and excretion of grepafloxacin (GPFX), a fluoroquinolone antibiotic, was investigated using gene-deficient mice [mdr1a(-/-), mdr1a/1b(-/-), and mrp1(-/-)]. The plasma concentration-time profile of GPFX in mrp1(-/-) was nearly identical to that in mrp1(+/+), whereas that in mdr1a/1b(-/-) was higher than that in mdr1a/1b(+/+). The urinary clearance of GPFX in mdr1a/1b(-/-) was lower than that in mdr1a/1b(+/+), suggesting that the urinary excretion of GPFX is at least partially mediated by mdr1. The tissue-to-plasma concentration ratios during the beta-phase (K(p beta),) was significantly higher in the heart, trachea, kidney, spleen, and brown fat of mrp1(-/-) than those in mrp1(+/+). In MRP1-transfected LLC-PK1 cells, the efflux of GPFX after preloading into the cells was higher than that observed in the parent cell lines. These results suggest that GPFX is a substrate of MRP1 and that its distribution to these tissues might be limited by Mrp1. On the other hand, a higher K(p beta), and of GPFX in mdr1a(-/-) mdr1a/1b(-/-) compared with mdr1a/1b(+/+) was observed only in the brain. GPFX was efficiently distributed to the lung parenchyma cells and pulmonary airspaces, including the epithelial lining fluid and macrophages that are the pharmacological target of GPFX, although the contribution of Mdr1 and Mrp1 to such distribution seems to be minor. Thus, the present findings reveal that the disposition of GPFX is at least in part governed by these two ABC transporters and that both Mrp1 and Mdr1 are involved in the limited distribution of GPFX to the distinct tissues, including pharmacological and/or toxicological targets by an active efflux mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

[Preparation of amylopectin modified dipyridamole liposome and its tissue distribution in mice].

AIM: To prepare amylopectin anchored dipyridamole (DIP) liposome and to study its tissue distribution in mice. METHODS: The regular DIP liposomes were prepared by film-scatter method. The amphiphilic O-palmitoyl amylopectin was synthesized and added to modify the surface of liposome. The entrapping efficiency, zeta potential, mean diameter, span of modified and regular liposomes were assayed. The RP-HPLC was used for the determination of DIP concentration in mice tissue. RESULTS: After modification, the entrapping efficiency depressed, zeta potential was raised, mean diameter and span had no obvious change. The level of DIP in lung, liver and spleen for regular liposomes were higher than that of injections. Compared with regular liposomes, the modified liposomes increased the DIP level in lung, and decreased the DIP level in liver, spleen, moreover, lengthened the retention time of DIP in lung. CONCLUSION: The distribution of modified liposome in mice was markedly changed as compared with regular liposomes and injections. The modified liposomes had obvious lung targeting property.

Amylopectin↗

PubMed1990

The tissue distribution in rats of [195mPt]carboplatin following intravenous, intraperitoneal and oral administration.

[195mPt]carboplatin has been administered intravenously, intraperitoneally and orally to Wistar rats and the tissue distribution, metabolism, and pharmacokinetics of the drug investigated. The urinary and faecal excretion and toxicity following oral [195mPt]carboplatin administration has also been studied. Virtually identical results have been observed following i.v. and i.p. administration, indicating a rapid absorption of the unaltered compound from the abdominal cavity into the systemic circulation. Thus i.p. administered drug should produce a similar therapeutic response as i.v. administration, but may produce an additional local effect within the peritoneal cavity. Orally administered compound shows a pattern of distribution which is similar to that following parenteral injection for all tissues (except for the increased relative concentration in the stomach tissue), the concentration being lower by a factor of 4-5. However, the overall fraction of the dose retained within the body at 24 h is similar to that following i.v. administration. The toxicity is considerably lower for the orally administered drug compared with i.v. injection. These results clearly show that oral doses could be adjusted to produce a comparable therapeutic effect as i.v. or i.p. doses, and should also result in a higher efficacy against gastric carcinomas than achievable with parenteral administration.

Administration, Oral↗

PubMed2002

Molecular cloning and tissue distribution of mRNA encoding porcine 5-HT7 receptor and its comparison with the structure of other species.

The effects of 5-hydroxytriptamine (5-HT, serotonin) are mediated via five main receptor types of which the 5-HT7 receptor is the most recently characterised member. The 5-HT7 receptor has been shown to participate in mediating cranial blood vessels dilatation that may result in migraine headache. We report here the cDNA cloning, sequencing and tissue distribution of porcine 5-HT7 receptor and illustrate its comparison with corresponding receptor of known species. Employing a combination of reverse transcriptase and inverse polymerase chain reaction we amplified and sequenced a full length cDNA from the porcine cerebral cortex. The deduced amino acid sequence comparison confirmed that the cloned porcine receptor belongs to 5-HT7 receptor as described for human and other species and showing overall homology of 92-96%. The expression of 5-HT7 receptor mRNA was observed in porcine central (cerebral cortex, trigeminal ganglion and cerebellum) as well as in peripheral (pulmonary and coronary arteries, superior vena cava and saphenous vein) tissues. The established cDNA sequence and tissue distribution of porcine 5-HT7 receptor will be helpful in exploring the role of this receptor in pathophysiological processes and to predict as a potential therapeutic target for antimigraine drug development.

Amino Acid Sequence↗

PubMed1992

Maternal and fetal tissue distribution of L-carnitine in pregnant mice: low accumulation in the brain.

The distribution of L-carnitine was studied by whole-body autoradiography in pregnant CD-1 mice at 1, 2, 3, and 6 hr after receiving L-[14C]carnitine. Highest concentrations of carnitine were found in maternal tissues including liver, placenta, kidney, myocardium, and choroid plexus. High retention of tissue carnitine in excess of blood levels suggests the existence of concentrative uptake mechanism. Labeled carnitine was not detectable in either maternal or fetal brain. This suggests that the brain barrier systems limit the access of L-carnitine to the brain. In fetus, the level of carnitine was less than that seen in the maternal tissues, however, the tissue distribution was similar. The fetal tissue carnitine concentration increased with time. These findings suggest that relief of encephalopathy due to toxic organic anions in metabolic disorders following L-carnitine supplementation appears to be peripheral metabolic effects rather than direct access to the central nervous system. However, the physiological role for the concentrative uptake of L-carnitine by the choroid plexus remains to be determined. Transport of carnitine into fetal tissues via placenta further suggests the possibility of prenatal therapy in pregnancies at risk for certain inherited metabolic disorders.

Animals↗

PubMed2006

[Pharmacokinetics and tissue distribution of atractylenolide III in rats].

OBJECTIVE: [corrected] To establish an HPLC method for the analysis of pharmacokinetics and tissue distribution of atractylenolide III in rats. METHODS: The biological samples were extracted with ether. The chromatographic conditions were as follows: Hypersil ODS column (150 mm x 4.6 mm, 5 microm) was used. The mobile phase was methnol/warter (67 : 33) with a flow rate of 1.0 ml/min under the column temperature of 25 degrees C, and the detection wavelength was set at 220 nm. RESULTS: The recovery of the method was 85.12% (RSD = 5.57%). The linear range was 0.2 microg/ml - 18.5 microg/ml (r = 0.9996) in rat plasma. The Lowest Limit of detection was 0.10 microg/ ml (S/N > 3). The within-day and between-day precision were from 0.98% to 6.19% and 12.95% to 15.48%, respectively. After oral administration of atractylenolide III (100 mg/kg), the concentration-time profiles of atractylenonlide III fit a two compartment model. In main effect tissues, the atractylenolide III concentration was followed as in order C(lung) > C(cerebellum) > C(heart) > C(cerebrum), and that was C(spleen) > C(liver) > C(kidney) in eliminated tissues. CONCLUSION: The method is accurate, stable and reliable, and can be used for the investigation of atractylenolide III in plasma and tissues of rats.

Animals↗

PubMed2005

Mitoxantrone-loaded BSA nanospheres and chitosan nanospheres for local injection against breast cancer and its lymph node metastases. II: Tissue distribution and pharmacodynamics.

Bovine serum albumin (BSA) and chitosan (CS) nanospheres of mitoxantrone (MTO) were comparatively evaluated in terms of tissue distribution, acute toxicity and therapeutic efficiency against breast cancer and its lymph node metastases. After local injection in rats, MTO nanospheres showed a slower elimination rate and a much higher drug concentration in lymph nodes compared with MTO solution, and a lower drug concentration in other tissues. There was no observed acute toxicity to the main tissues of Kunming mice after local injection of MTO-BSA-NS. Mild toxicity to liver and lung was observed for MTO-CS-NS, but, for MTO solution, severe toxicity to liver and lung and much lower number of white blood cells were observed. Human MCF-7 breast cancer in nude mice and animal model of P388 lymph node metastases in Kunming mice were applied to investigate the therapeutic efficiency. The inhibition rate of the nanospheres against breast cancer was much higher than that of MTO solution, and lymph node metastases were efficiently inhibited by the nanospheres, especially MTO-BSA-NS.

Animals↗

PubMed2000

Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: interaction with cyclosporine.

We report the tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD ¿40-O-(2-hydroxyethyl)-rapamycin and its metabolites in monkey lung transplant recipients as well as its interaction with cyclosporine as the Neoral formulation. After left unilateral lung transplantation, cynomolgus monkeys received by oral administration either 1) 1.5 mg/kg/day SDZ-RAD (n = 4); 2) 100 mg/kg/day cyclosporine (n = 4); 3) 0.3 mg/kg/day SDZ-RAD + 100 mg/kg/day cyclosporine (n = 6); 4) 1.5 mg/kg/day SDZ-RAD + 50 mg/kg/day cyclosporine (n = 5); or 5) SDZ-RAD and cyclosporine doses adjusted according to trough blood concentration measurements (n = 6). At the end of the observation period (usually 29 days after transplantation), and 24 h after the last doses, tissue samples were collected and analyzed with HPLC/mass spectrometry. Gall bladder, pancreas, the transplant lung, cerebellum, kidneys, and spleen had the highest SDZ-RAD concentrations. Coadministration of cyclosporine increased SDZ-RAD concentrations in most tissues as well as tissue-to-blood distribution coefficients. In contrast, SDZ-RAD had only a small effect on cyclosporine blood and tissue concentrations. Rejection in lung grafts in monkeys treated with either of the cyclosporine/SDZ-RAD combinations was significantly less than in the monotherapy groups (P <.002). Histological rejection scores were inversely correlated with SDZ-RAD concentrations in blood (r = -0. 68; P <.001; n = 24), lymph nodes (P = -0.58; P <.003; n = 24), thymus (r = -0.63; P <.001; n = 23) and transplant lung tissue (r = -0.58; P <.003; n = 24). We conclude that, in addition to the synergistic pharmacodynamic interaction, a pharmacokinetic interaction resulting in higher SDZ-RAD tissue concentrations contributed to the significantly better immunosuppressive efficacy when both drugs were combined compared with monotherapy.

Animals↗

PubMed1990

Tissue distribution of 131I radiolabeled transferrin in the athymic nude mouse: localization of a human colon adenocarcinoma HT-29 xenograft.

The tissue distribution of 131I-transferrin (131I-Tf) was studied in athymic nude mice having s.c. human colonic adenocarcinoma HT-29 xenografts. Four days after 131I-Tf injection, the 131I-specific activity measured in the HT-29 tumor, i.e. amount of radioactivity per gram of fresh tissue, represented 0.31 +/- 0.09% of the injected radioactivity and was 1.90 fold more than that measured in the murine colon (P less than 0.05). After correction for intravascular 131I-Tf as estimated by means of 99mTc-Sn in vivo labeling of red blood cells, the 131I specific activity observed in the HT-29 tumor was 7.21 fold more than that observed in the murine colon. This subtracting method enabled us to localize a HT-29 tumor xenograft by gamma scintigraphy of the entire animal and demonstrated that 131I-Tf could be a non-specific but potent marker for human colon cancer.

Adenocarcinoma↗

PubMed1995

Supplementing ferrets with canthaxanthin affects the tissue distributions of canthaxanthin, other carotenoids, vitamin A and vitamin E.

To study the effects of canthaxanthin supplementation on the tissue distribution of canthaxanthin, other carotenoids, vitamin A and vitamin E, 26 spayed female ferrets (2 mo of age) were used. Ferrets were assigned to receive a commercial ferret diet and a gavage of canthaxanthin [50 mg/(kg body wt.d)] or a gavage of placebo beadlets (0 mg canthaxanthin) 5 d/wk. Serum canthaxanthin concentrations in the canthaxanthin-fed group increased from 0 at baseline to 37.76 +/- 5.34 nmol/L trans and 77.10 +/- 12.60 nmol/L cis canthaxanthin at 12 mo. Further accumulation of canthaxanthin did not occur with continuous dosing. After 2 y of receiving canthaxanthin beadlets by gavage, the ferrets did not show a detectable concentration of canthaxanthin in the eyes, nor did they have clinical signs of toxicity. Canthaxanthin concentrations were highest in liver, with high concentrations also seen in fat, lung and small intestine. The sum of alpha and beta-carotene concentrations detected in livers was significantly higher in the canthaxanthin-fed group than in the placebo-fed group, but not significantly higher when individual carotenes were compared. However, alpha-tocopherol concentrations in the livers and lungs and lutein/zeaxanthin in the fats of the ferrets fed canthaxanthin were significantly lower than in those fed the placebo. Retinoid concentrations in tissues of the ferrets fed canthaxanthin were not different from those of the placebo-fed group. The effects of canthaxanthin supplementation on other antioxidants and vitamin A nutrients demonstrate either a synergistic or antagonistic relationship, depending on the specific tissue assayed.

Adipose Tissue↗

PubMed1988

Tissue distribution of the novel antitussive compound vadocaine hydrochloride in white female mice studied by whole-body autoradiography.

The tissue distribution of tritium-labelled vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) was studied in female mice by whole-body autoradiography at different times (15 min - 24 h) after intravenous injection. Radioactivity disappeared rapidly from blood and was fairly selectively localized in the liver, the gall bladder and the intestinal contents. Vadocaine is evidently metabolized in the liver and a remarkable part of the drug and its metabolites are excreted into the bile. Accumulation of radioactivity in the kidneys shows that also renal elimination is important. A considerable accumulation into the lungs supports the peripheral anaesthetizing mechanism in the antitussive action of vadocaine. No detectable penetration into the brain was seen. At 24 h, only traces of the radioactivity could be detected in the liver and lungs.

Animals↗

PubMedDate not supplied

Influence of dietary restriction and protein deficiency on plasma half-life and tissue distribution of tetracycline in rats.

1. The effects of dietary restriction and protein deficiency on plasma half-life and tissue distribution of tetracycline were studied in rats by feeding either a 20% protein diet in restricted quantity or a 9% protein diet ad lib and compared with rats given a 20% protein diet ad lib (control group). 2. It was observed that half-life of tetracycline was shortened and that plasma and tissue Cmin levels at steady-state were lower in undernourished rats. Tissue concentrations in liver, kidney, muscle and bone correlated well with plasma levels. A high degree of correlation was also observed between plasma and tonsillar concentrations of tetracycline in human subjects. 3. These studies indicate that undernourished subjects may require an altered dosage regimen of tetracycline to maintain effective steady-state concentrations of the drug.

Adolescent↗

PubMedDate not supplied

The pharmacokinetics, tissue distribution, and biotransformation of a new class of antitumor agents: mitonafide and pinafide.

The pharmacokinetics, biotransformation, protein binding and tissue distribution of mitonafide and pinafide were studied after single i.v. and oral administration of each drug (20 mg/Kg) in female rats. In pregnant rats a study of cross placental-barrier after i.v. administration of the two drugs was also performed. The drugs were absorbed fairly rapidly with a mean peak plasma level of 7.63 +/- 0.70 micrograms eq/ml for the 3H-mitonafide and with 6.16 +/- 0.77 micrograms eq/ml for the 3H-pinafide between 30 minutes and 1 hour after oral dosing. For both drugs, the pharmacokinetics can be described by a two-compartment open model. The mean elimination half-lives were 17.8 h and 47.5 h for 3H-mitonafide and 3H-pinafide, respectively. Two metabolites for each compound as well as unchanged drugs were identified in urine by TLC and GC/MS by comparison of their chromatographic properties with a number of reference compounds. Approximately 30% of the radioactive drug was excreted over a 48 h period for 3H-mitonafide and 24% for 3H-pinafide in urine, after i.v. administration. The cross placental-barrier studies showed that both 3H-mitonafide and 3H-pinafide were present in the 14-day fetuses.

Animals↗