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PubMed1995

Influence of endogenous biotin on the biodistribution of labelled biotin derivatives in mice.

Previously, this laboratory reported that in mice pre-targeted with unlabelled streptavidin, the biodistribution of 111In administered on one biotin derivative (EB1) was superior to that of another derivative (DB2). In addition, a Scatchard analysis showed that the affinity constant of 111In-EB1 is lower by seven orders of magnitude from that of 111In-DB2. Therefore, this paper considers the role that endogenous biotin may play in these observations. Both 111In-labelled EB1 and DB2 were bound to streptavidin and incubated at 37 degrees C in mouse blood with increasing concentrations of d-biotin. As determined by Sephadex G-50 chromatography, only an 8-fold molar excess of d-biotin relative to labelled streptavidin was required to displace 90% of label in the case of EB1, whereas even a 20-fold molar excess provided no detectable displacement of DB2. That this displacement was also occurring in vivo was established in a mouse model bearing an infected thigh: increasing the serum biotin level (by intraperitoneal administration of d-biotin) had no effect on the biodistribution of 111In when administered on DB2; however, the target to non-target ratio decreased in the case of EB1. We have also observed that the biodistribution is no longer favourable when EB1 is administered radiolabelled with 99Tcm. When 111In was substituted with 99Tcm on EB1, chromatography of blood samples showed that similar displacement was occurring; however, in this case, the displaced label bound to serum proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Biodistribution of 99Tcm-labelled 5-thio-D-glucose.

We studied the biodistribution and tumour localization of 99Tcm-labelled-5-thio-D-glucose (99Tcm-TG). 5-Thio-D-glucose was labelled with 99Tcm by direct stannous ion reduction. The biodistribution of 99Tcm-TG was investigated in normal rabbits and in mice bearing experimental tumours. In rabbits, the plasma and clearance of 99Tcm-TG was 14.5 +/- 2.0 and 11.3 +/- 3.0 ml.min-1 respectively. Urinary excretion at 1 h was 53 +/- 5%. 99Tcm-TG was injected intravenously in mice bearing MC26 colon carcinoma and tissue samples were analysed by gamma scintillation counting at various times. Uptake of 99Tcm-TG in tumour at 1 and 3 h was 1.6 +/- 0.3% and 1.2 +/- 0.3%; the tumour to muscle ratios were 2.7:1 and 4:1 respectively. The autoradiographic biodistribution of 99Tcm-TG in MX-1 human breast xenografted nude mice showed more persistent tumour uptake of 99Tcm-TG than 14C-2-deoxyglucose (14C-DG). 99Tcm-TG accumulated in the centre of the tumours; 14C-DG was decreased in this central region probably because of zones of infarction on necrosis. The discordance between the tumour uptake of 99Tcm-TG and 14C-DG indicates that 99Tcm-TG does not act like a glucose analog, suggesting 99Tcm-TG avidity for zones of infarction or necrosis. The further study of 99Tcm-TG in tumours and ischaemic injury is warranted.

Animals↗
PubMed2002

The effect of gadolinium-based MRI contrast agents on the biodistribution of (67)Ga.

It has been reported that administration of the paramagnetic contrast agent Gd-diethylenetriaminepentaacetic acid (Gd-DTPA, gadopentate) prior to 67Ga citrate could lead to poor quality scans, characterized by pronounced bone uptake and a loss of tumour avidity. Suggestions to account for this behaviour included in vivo dissociation or the presence of free DTPA in the formulation. The objective of this study was to assess this potential interference in 67Ga imaging using a mouse model. Commercial gadopentate and gadodiamide contrast agents at doses up to 5mmol*kg(-1) were injected into mature female Balb/c mice 4h before i.v. 67Ga citrate, then the biodistribution was determined at 24h. Gd-DTPA solutions containing excess Gd or DTPA were examined as well. The model was verified by identical studies using inactive Ga(III) or Fe(III) at 0.1mmol*kg(-1). The effects of Gd(III) or the DTPA ligand at this dose were also determined. Administration of Gd-DTPA was found to produce no marked changes in 67Ga biodistribution. Minor changes occurred after 0.1mmol*kg(-1) Gd(III) or the DTPA ligand, but could not account for the scan changes reported above. Inactive Ga(III) or Fe(III), as expected, caused a marked reduction of 67Ga uptake in all tissues except bone, leading to greatly increased total bone:total soft tissue ratios. It is concluded that Gd-DTPA or its constituents do not significantly alter the biodistribution of 67Ga citrate in mice. Extrapolating these findings to the human situation suggests that the previously reported scan changes may have been the result of other undetermined factors.

Animals↗
PubMed1998

Epitope blocking: positive and negative effects on the biodistribution of 125I-labeled anti-Tac disulfide-stabilized Fv fragment of two antibodies against different epitopes of the circulating antigen.

Prior in vivo studies using the 125I-labeled anti-Tac disulfide-stabilized variable region fragment (125I-anti-Tac dsFv) of monoclonal antibody in the presence of the circulating soluble alpha subunit of the interleukin-2 receptor (sIL-2R alpha) have shown formation of complexes which interfere with biodistribution. In this study we evaluated the effects of preinjecting HuTac and 7G7/B6, two immunoglobulin Gs (IgGs) that recognize different epitopes of sIL-2R alpha, on the biodistribution of 125I-anti-Tac dsFv in mice bearing SP2/Tac tumor xenografts, which produce sIL-2R alpha, or on nude mice injected with 500 ng of sIL-2R alpha. We also evaluated the biodistribution in mice of 125I-labeled sIL-2R alpha injected alone or with HuTac and 7G7/B6. Injection of either HuTac or 7G7/B6 resulted in complexes with the sIL-2R alpha in serum. Injection of HuTac before 125I-anti-Tac dsFv, in SP2/Tac tumor-bearing mice, resulted in faster clearance of the dsFv from the blood (7.6% ID/g at 30 min), compared to 23.2% ID/g for the no-antibody control; preinjection of 7G7/B6 prolonged the retention of 125I-anti-Tac dsFv to 35.3% ID/g, with more complexes in serum. In mice pre-injected with 7G7/B6 the concentration of 125I-anti-Tac dsFv in tumor was lower (5.2 +/- 0.3% ID/g) than in mice preinjected with HuTac (7.9 +/- 1.2% ID/g) or in the control group (5.6 +/- 0.7% ID/g). In conclusion, while both IgGs formed complexes with sIL-2R alpha and prolonged its retention, preinjection of 7G7/B6 was detrimental, because the increased circulating sIL-2R alpha still had the epitope recognized by the dsFv available for binding and neutralized the anti-Tac dsFv upon injection, whereas preinjection of HuTac blocked the epitope.

Animals↗
PubMed2000

In vivo biodistribution of 125IPIP and internal dosimetry of 123IPIP radioiodinated agents selective to the muscarinic acetylcholinergic receptor complex.

The development of new radioiodinated ligands for imaging the muscarinic acetylcholinergic complex (mAChR) using single photon emission computed tomography (SPECT) requires the evaluation of human organ doses prior to approval for human use. Animal biodistribution and excretion data were obtained and evaluated for IPIP, a new mAChR agent. Preliminary biodistribution studies were performed on four different stereoisomers of IPIP. A biokinetic model of the Z-(S)-IPIP stereoisomer was constructed for the rat and used to estimate the internal absorbed dose in humans based on an extrapolation of the rat model. The thyroid is the critical organ for this radiopharmaceutical, with an absorbed dose estimate of 2.4 mGy/MBq for both males and females, when labeled with 123I. Even when blocked, the thyroid is still the critical organ, yet with a 90% dose reduction. The heart and brain receive the next highest doses in both males and females. Effective dose estimates for the use of pure 123I-PIP in humans are 0.16 mSv/MBq for males and 0.14 mSv/MBq for females. The biodistribution studies of the Z-(S)-IPIP stereoisomer showed the most promise as a successful agent for imaging muscarinic receptor sites in the heart and brain. IPIP also demonstrated potential as a therapeutic radiopharmaceutical for some colon carcinomas where muscarinic receptor sites are expressed in the tumor cells. These results provide preliminary data for use of IPIP in clinical studies on humans.

Animals↗
PubMed1995

Contrast material-carrying liposomes: biodistribution, clearance, and imaging characteristics.

PURPOSE: To assess the biodistribution, clearance, and computed tomographic (CT) imaging characteristics of interdigitation-fusion (IF) liposomes that carry iotrolan in their aqueous phases. MATERIALS AND METHODS: Biodistribution and clearance of liposomes containing iotrolan produced with the IF method (IF vesicles) were assessed in rats. CT scans of rats and dogs were obtained after injection of IF vesicles at 100 and 250 mg of iodine per kilogram of body weight. RESULTS: A high initial uptake (63%-96% of the injected dose) was found in the liver and spleen. Liver elimination showed half-lives to be 12.9 days at 250 mg of iodine per kilogram, 10.9 days at 100 mg, and 8.7 days at 25 mg. At 250 mg of iodine per kilogram, the rats had an average of 96 HU of hepatic and 321 HU of splenic enhancement. The dogs had 116 HU of hepatic and 65 HU of splenic enhancement. CONCLUSION: IF liposomes have favorable biodistribution, clearance, and imaging characteristics as hepatosplenic contrast agents.

Animals↗
PubMedDate not supplied

A potential Dubin-Johnson syndrome imaging agent: synthesis, biodistribution, and microPET imaging.

Dubin-Johnson syndrome (DJS) is caused by a deficiency of the human canalicular multispecific organic anion transporter (cMOAT). A new lipophilic copper-64 complex of 1,4,7-tris(carboxymethyl)-10-(tetradecyl)-1,4,7,10-tetraazadodecane (5) was prepared and evaluated for potential as a diagnostic tool for DJS. The prepared ligand was labeled with (64)Cu citrate in high radiochemical purity. In vivo uptake and clearance of the complex was determined through biodistribution studies using normal Sprague-Dawley rats and mutant cMOAT-deficient (TR(-)) rats. In normal rats, the radioactive copper complex was cleared quickly from the body exclusively through the hepatic pathway. The (64)Cu complex was taken up rapidly by the liver and quickly excreted into the small intestine and then the upper large intestine, whereas <1% ID/organ was found in the kidney at all time points post injection. Whereas activity was accumulated continuously in the liver of TR(-) rats, it was not excreted into the small intestine. MicroPET studies of normal and TR(-) rats were consistent with biodistribution data and showed dramatically different images. This study strongly suggests that cMOAT is involved in excretion of (64)Cu-5. The significant difference between the biodistribution data and microPET images of the normal and TR(-) rats demonstrates that this new (64)Cu complex may allow noninvasive diagnosis of DJS in humans.

Acetates↗
PubMed2004

(99m)Tc-labeled murine ior C5 monoclonal antibody in colorectal carcinoma patients: pharmacokinetics, biodistribution, absorbed radiation doses to normal organs and tissues and tumor localization.

Monoclonal Antibody (mAb) ior C5 is a murine IgG(1) that recognizes the tumor associated antigen (TAA) ior C2, a cell surface O-linked glycoprotein carbohydrate chain not present in most normal tissues and homogeneously expressed in the cytoplasm of normal colon epithelium and heterogeneously expressed in more than 83% of primary colorectal carcinomas. This study was designed to investigate the pharmacokinetics, biodistribution and the absorbed radiation doses of (99m)Tc-labeled mAb ior C5 antibody in colorectal tumor patients. Ten patients were administered 3 mg of anti-O-linked glycoprotein carbohydrate chain TAA ior C2 murine monoclonal antibody ior C5 radiolabeled with (99m)Tc activity of 1435.0 +/- 123 MBq by intravenous (i.v.) bolus infusion. Blood and urine samples were collected from 4 out of 10 patients at timed intervals from 10 min and up to 24 h after injection of the (99m)Tc-labeled mAb ior C5 for pharmacokinetic studies. Whole body images were taken in 5 out of 10 patients for quantitative normal organ biodistribution and dosimetry studies and planar anterior and posterior and SPECT images were taken in 5 out of 10 patients for tumor localization. Mean absorbed doses were estimated using the methods developed by the Medical Internal Radiation Dose (MIRD) committee. The effective dose equivalent (EDE) and effective dose (ED) were calculated as prescribed in International Commission on Radiological Protection (ICRP) publications 30 and 60. Plasma disappearance curves of (99m)Tc-labeled murine antibody ior C5 were best fit by a two-compartment model in all patients with (t(1/2alpha)) of 4.32 +/- 2.18 h and (t(1/2beta) of 32.6 +/- 3.82 h. Among the main target organs, accumulation of the radiolabeled antibody was found in liver (9.38 +/- 0.80%), heart (8.92 +/- 0.94%) and spleen (1.37 +/- 0.30%) at 5 min post-administration. These values were reduced at 24 h to (5.91 +/- 0.73%) and (0.62 +/- 0.22%), respectively, for the heart and spleen and increased to (9.78 +/- 1.99%) for liver. Estimates of radiation absorbed dose to normal organs in rad/mCi administered were: whole body, 0.0181 +/- 0.0017; heart wall, 0.0768 +/- 0.0090; kidneys, 0.0530 +/- 0.0260; liver, 0.0565 +/- 0.0109 and spleen, 0.0540 +/- 0.0128. The effective dose equivalent and effective dose estimates for adults were 0.0314 +/- 0.0031 and 0.0249 +/- 0.0027 rem/mCi administered. This feasibility study indicates that the O-linked glycoprotein carbohydrate chain TAA ior C2 is expressed in primary and metastatic colorectal carcinomas and shows very limited expression in normal adult tissues. The very good pattern of biodistribution of (99m)Tc-labeled mAb ior C5 in patients will allow imaging of colorectal carcinoma lesions.

Aged↗
PubMed1999

MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.

This report describes recommended techniques for radiopharmaceutical biodistribution data acquisition and analysis in human subjects to estimate radiation absorbed dose using the Medical Internal Radiation Dose (MIRD) schema. The document has been prepared in a format to address two audiences: individuals with a primary interest in designing clinical trials who are not experts in dosimetry and individuals with extensive experience with dosimetry-based protocols and calculational methodology. For the first group, the general concepts involved in biodistribution data acquisition are presented, with guidance provided for the number of measurements (data points) required. For those with expertise in dosimetry, highlighted sections, examples and appendices have been included to provide calculational details, as well as references, for the techniques involved. This document is intended also to serve as a guide for the investigator in choosing the appropriate methodologies when acquiring and preparing product data for review by national regulatory agencies. The emphasis is on planar imaging techniques commonly available in most nuclear medicine departments and laboratories. The measurement of the biodistribution of radiopharmaceuticals is an important aspect in calculating absorbed dose from internally deposited radionuclides. Three phases are presented: data collection, data analysis and data processing. In the first phase, data collection, the identification of source regions, the determination of their appropriate temporal sampling and the acquisition of data are discussed. In the second phase, quantitative measurement techniques involving imaging by planar scintillation camera, SPECT and PET for the calculation of activity in source regions as a function of time are discussed. In addition, nonimaging measurement techniques, including external radiation monitoring, tissue-sample counting (blood and biopsy) and excreta counting are also considered. The third phase, data processing, involves curve-fitting techniques to integrate the source time-activity curves (determining the area under these curves). For some applications, compartmental modeling procedures may be used. Last, appendices are included that provide a table of symbols and definitions, a checklist for study protocol design, example formats for quantitative imaging protocols, temporal sampling error analysis techniques and selected calculational examples. The utilization of the presented approach should aid in the standardization of protocol design for collecting kinetic data and in the calculation of absorbed dose estimates.

Humans↗
PubMed1999

Biodistribution study of 188Re-labeled trisuccin-HuCC49 and trisuccin-HuCC49deltaCh2 conjugates in athymic nude mice bearing intraperitoneal colon cancer xenografts.

The trihydroxamate bifunctional chelating agent (BCA), trisuccin, has been shown to be a potential ligand for radiolabeling of monoclonal antibodies (MAbs) with rhenium radioisotopes, through an indirect postconjugation approach. The use of this trihydroxamate BCA made it possible to prepare stable BCA-MAb conjugates in pure form that could be radiolabeled with carrier-free 188Re. The anti-TAG-72 murine MAb, CC49, and its humanized derivatives are promising agents in the treatment of a number of malignancies with the CH2 domain-deleted MAb (HuCC49deltaCH2), which is of particular interest due to its rapid blood clearance. The biodistribution of 188Re-labeled conjugates of trisuccin with both humanized CC49 (HuCC49) and HuCC49deltaCH2 in athymic nude mice implanted i.p. with LS174T human colon carcinoma was studied. Trisuccin-MAb conjugates were synthesized at different BCA:MAb ratios by the 6-oxoheptanoic acid method using trisuccin hydrazide. The conjugates were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy for the number of incorporated trisuccin molecules. The conjugates were radiolabeled with carrier-free, generator-produced 188Re and purified by gel filtration on Sephadex G-25. Labeling yields and homogeneity of the labeled conjugates were analyzed by high-pressure liquid chromatography and instant TLC. Athymic nude mice were injected i.p. with LS174T human colon carcinoma cells, 7 days prior to injection of the labeled antibodies. 188Re-labeled MAbs were injected i.p., and the mice were sacrificed 24 h postinjection. Matrix-assisted laser desorption/ionization time-of-flight analyses showed stable incorporation of trisuccin into each MAb, with the measured ligand:MAb values positively correlating with the theoretical ratios. Labeling of the conjugates with 188Re proceeded with high yields, producing homogeneous 188Re-MAbs with good stabilities as shown by instant TLC and biodistribution analyses. Biodistribution of the radiolabeled MAbs at 24 h after injection showed median tumor uptake values of 23.5%ID/g and 17.6%ID/g for the 188Re-HuCC49deltaCH2 and 188Re-HuCC49, respectively. The blood clearance of the domain-deleted MAb was faster than that of the intact antibody. The blood values at 24 h after injection were 0.7%ID/g for 188Re-HuCC49deltaCH2 and 3.2%ID/g for 188Re-HuCC49. The results indicate that trisuccin is a promising agent for postconjugation labeling of antibodies with 188Re. Additionally, these results illustrate the potential of 188Re-HuCC49deltaCH2 in radioimmunodiagnosis and radioimmunotherapy of cancer.

Animals↗
PubMed2000

Effects of insulinlike growth factor binding proteins on insulinlike growth factor-I biodistribution in tumor-bearing nude mice.

UNLABELLED: This study evaluated the biodistribution and tumor targeting ability of radiolabeled insulinlike growth factor (IGF)-I. Because IGF binding proteins (IGFBPs) play a critical role in modulating IGF activity, the binding properties of 125I-labeled IGF-I to IGFBPs were investigated in vitro and in vivo. Because a large amount of the IGF-I was catabolized in vivo, we also studied the catabolism of IGF-I by tumor cells in vitro. METHODS: 125I-labeled-IGF-I was prepared using the chloramine T method. The biodistribution of 125I-labeled-IGF-I in tumor-bearing nude mice was compared between groups injected with 125I-labeled IGF-I alone or coinjected with unlabeled peptide. In vitro and in vivo chromatography studies were performed to evaluate the binding profile to IGFBPs and the degree of catabolites in serum as well as urine. RESULTS: Data indicated that the binding of radiolabeled IGF-I to IGFBPs in vitro was dose dependent. However, there was a difference in complex formation between the serum and the heparinized plasma. In heparinized plasma, the radioactivity shifted from a 30- to 50-kDa complex to a 150-kDa complex and to a free ligand, because the binding of heparin with IGFBPs decreased its affinity for IGF-I. In plasma prepared with acid citrate dextrose a binding pattern identical to that of serum was observed. Moreover, there was a binding difference between mouse and rat. The 125I-labeled IGF-I catabolized very quickly when incubated at 37 degrees C but not at all at 4 degrees C. In tumor-bearing nude mice, the uptake of radioactivity in normal tissues decreased quickly, particularly in the kidneys. In mice coinjected with unlabeled carrier, the radioactivity in most normal tissues was lower and the tumor uptake higher than in the mice without carrier. CONCLUSION: These data confirm that 125I-labeled IGF-I is avidly bound to IGFBPs, both in vitro and in vivo. By partially saturating this binding with unlabeled peptides, a favorable biodistribution was achieved, including faster clearance from normal tissue and higher tumor uptake, which resulted in better tumor-to-nontumor ratios. Nevertheless, the rapid catabolism and release of the radiolabel from tumor tissue result in a suboptimal targeting agent.

Animals↗
PubMed2000

Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15.

Interleukin-2 (IL-2) and interleukin-15 (IL-15) are T-cell tropic factors that share beta and gammac subunits of their receptors on T/NK-cells. Although these two cytokines share receptor components, the IL-15Ralpha molecule is expressed constitutively by various tissue cells, whereas the IL-2Ralpha expression is mostly restricted to activated mononuclear cells. Consequently, we postulated that the biodistribution of IL-15 might be different from that of IL-2 and that individual alpha chains play an important role in this respect. This study investigated the differences between IL-2 and IL-15 in pharmacokinetics, biodistribution, and their tumor-targeting abilities. It found that only IL-2 showed specific binding to a protein, alpha2-macroglobulin, which may be the reason that IL-2 displays longer blood clearance than IL-15. Upon injection of these cytokines into mice, we observed that IL-15 accumulated significantly more than IL-2 in kidney, spleen, and bone. These are all tissues that express IL-15 receptor alpha but not IL-2 receptor alpha. To evaluate the tumor-targeting ability of each cytokine, we used nude mice xenografted with three A431 tumors, parental and cells transfected with alpha subunit of the receptor for either IL-2 or IL-15. When examined using radioiodinated IL-2 or IL-15, each cytokine accumulated on the target cells, expressing its respective alpha chain, suggesting that the expression of the alpha chains is sufficient to define specific biodistribution of IL-2 and IL-15, although these cytokines share the beta and yc molecules of their receptors. IL-15 displayed better target-specific accumulation and more rapid clearance from the circulation than did IL-2, and thus it can be considered to be a novel and unique therapeutic agent.

Animals↗
PubMed2002

Biodistribution of 99mTc-O4Na changes in adult rats whose mothers were malnourished during lactation.

UNLABELLED: 99mTc-O4Na biodistribution changes in malnourished adults rats. We evaluated this biodistribution in rats whose mothers were malnourished during lactation. METHODS: On the first day of lactation the mothers were separated into 3 groups: control (C) group, protein-restricted (PR) group, and energy-restricted (ER) group. After weaning all pups received a control diet until 60 d, when they were injected with 99mTc-O4Na and killed after 30 min. We evaluated the absolute percentage injected dose (%ID) and the %ID per gram (%ID/g) in thyroid, stomach, heart, bone, kidney, lung, liver, brain, and testes. RESULTS: In the PR group, the %ID and %ID/g were significantly higher in the stomach and lower in the thyroid than in the C group. In the ER pups, the %ID and %ID/g were higher in the liver, stomach, and testes than in the C group. CONCLUSION: The mother's nutritional status during lactation affects the biodistribution of 99mTc-O4Na in the offspring, and this condition must be considered when nuclear medicine examinations are indicated.

Animals↗
PubMed2002

Effects of the glucantime on the kinetic of biodistribution of radiopharmaceuticals in Wistar rats.

There are evidences that some drugs used for the human diseases can modify the biodistribution of radiopharmaceuticals. The N-methyl meglumine antimoniate, commercially known as glucantime (Rhodia, Brazil), is the elected drug for the treatment of all the clinical forms of leishmaniasis. As therapeutic drugs can present important toxic effects, we studied the effects of the glucantime on the kinetic of biodistribution of radiopharmaceuticals. To study the glucantime effect on the biodistribution of technetium-99m-methylenediphosphonic acid (99mTc-MDP), glucantime IM (80 mg/kg/day) was administered into male Wistar rats (3 months old age) in single dose during 7 days. 99mTc-MDP was injected 1 hr after the last dose. The animals (n = 24) were divided into two groups: treated (n = 12) and control (n = 12) and they were rapidly sacrificed, respectively, in 3 periods (5, 30 and 120 min) after administration of the 99mTc-MDP. The organs were isolated (brain, heart, thyroid, lungs, kidneys, testis, stomach, intestines, pancreas, spleen, liver, muscle, bone and bladder) and the percentages of radioactivity (%ATI) in each organ were calculated. The results were analyzed by the Wilcoxon test (p < 0.05). The analysis of the results has shown a significant increase of the %ATI after 5 min administration of the 99mTc-MDP in spleen, kidneys, testis, heart, liver and a reduction of %ATI in bladder. Thirty minutes after administration of the 99mTc-MDP, the analysis ofthe results reveals a significant reduction of the %ATI in femur, kidneys, thin bowel, lungs, heart, liver and an increase in abdominal muscle and stout bowel. One hundred-twenty min after administration of the 99mTc-MDP, the analysis of the results shows a significant reduction of the %ATI in spleen, thyroid, blood, femur, kidneys, liver and an increase in bladder, pancreas and lungs. Biochemical dosages were also performed before (control group, n = 12) and after (treated group, n = 12) treatment with glucantime. There was a significant (p < 0.05) decrease to the biochemical levels after the treatment with glucantime in following dosages: blood urea nitrogen, creatinine, alkaline phosphatase, lactic dehydrogenase, aspartate amino transferase, total creatine kinase, total protein, globulin and albumin. These results were compared with the control group, without glucantime, and statistical analyses were performed (t-student test, p < 0.05). These results could be associated with the biological effects and/or metabolization of the studied drug.

Animals↗
PubMed2002

Effect of eggplant (Solanum melongena) extract on the in vitro labeling of blood elements with technetium-99m and on the biodistribution of sodium pertechnetate in rats.

The use of eggplant has been suggested to treat different diseases. We studied the effect of eggplant extract on the labeling of red blood cells (RBC) and plasma proteins with technetium-99m (Tc-99m) and on biodistribution of sodium pertechnetate (Tc-99m) in rats. Blood was incubated with an eggplant extract (final concentrations 3.12 to 250.00 mg/ml) for 60 min. Then, stannous chloride (SnCl2) (0.06 or 1.2 microg/ml) and Tc-99m, as sodium pertechnetate, were added. Samples of RBC and plasma (P) were separated and also precipitated and soluble (SF) and insoluble (IF) fractions were isolated. The percent of radioactivity (%ATI) in the fractions was calculated. In the biodistribution study, Wistar rats were treated with eggplant extract (300 mg/ml) for 4 weeks, in drinking water. Tc-99m was administered in the rats, after 90 min they were sacrificed and organs and blood were isolated. When 0.06 microg/ml SnCl2 was used, eggplant extract: i/ inhibited the label of RBC (97.14 +/- 2.01 to 52.21 +/- 3.97%ATI), ii/ decreased the labeling in IF-P from 38.79 +/- 11.73 to 5.49 +/- 2.65%ATI, and iii/ diminished the labeling in IF-RBC from 90.04 +/- 2.65 to 46.17 +/- 9.49%ATI. This inhibitory effect was not observed with SnCl2 1.2 microg/ml. In the biodistribution study, the %ATI: i/ increased in the liver from 2.15 +/- 0.54 to 3.11 +/- 1.29 and ii/ in the other organs the Tc-99m uptake was not modified. The uptake of Tc-99m in red blood cells protein (IF-RBC) decreased from 66.62 +/- 19.67 to 31.66 +/- 8.84%. It is possible to suggest that some components of the eggplant extract present an oxidation power able to alter the fixation of the Tc-99m on the blood elements. Moreover, as eggplant is metabolized in the liver, this fact could justify the alteration of the uptake in this organ.

Animals↗
PubMed2003

An artificial amino acid, 4-iodo-L-meta-tyrosine: biodistribution and excretion via kidney.

UNLABELLED: We evaluated the use of radiolabeled 4-iodo-L-meta-tyrosine as an amino acid transport marker. The pharmacologic features of this compound, particularly the biodistribution and excretion, were examined by conducting in vivo and in vitro studies using 4-(125)I-iodo-L-meta-tyrosine (4-(125)I-mTyr). Results obtained for L-(14)C-Tyr and 3-(125)I-iodo-alpha-methyl-L-tyrosine ((125)I-IMT) were used for comparison. METHODS: In vivo biodistribution studies of 4-(125)I-mTyr were performed in male ddY mice. Urinary excretion of 4-(125)I-mTyr and (125)I-IMT with administration of probenecid was studied. Local distribution of 4-(125)I-mTyr and (125)I-IMT in kidney was visualized by autoradiography. We performed metabolite analysis of 4-(125)I-mTyr in mice. For in vitro studies, reabsorption mechanisms of 4-(125)I-mTyr were compared with those of (125)I-IMT and the parent L-(14)C-Tyr using superconfluent monolayers of the porcine kidney epithelial cell line LLC-PK(1) in medium containing inhibitor (L-Tyr, D-Tyr, and 2,4-dinitrophenol), in Na(+)-free medium, and at 4 degrees C. RESULTS: 4-(125)I-mTyr demonstrated high accumulation in the pancreas and kidney and comparable brain uptake to that of (125)I-IMT. Blood clearance of 4-(125)I-mTyr was faster than that of (125)I-IMT. Three hours after administration, >70% of 4-(125)I-mTyr was excreted via the urine, whereas <5% was found in the feces. Renal autoradiography revealed moderate accumulation of 4-(125)I-mTyr and high accumulation of (125)I-IMT in the renal cortex. Probenecid further reduced accumulation of 4-(125)I-mTyr and (125)I-IMT in the kidney as well as urinary excretion. At 30 min after tracer injection, intact free 4-(125)I-mTyr accounted for >98.1% of the total present in kidney and >96.3% in urine. Protein incorporation was not observed. Uptake of 4-(125)I-mTyr into LLC-PK(1) cell monolayers was remarkably reduced by 5 mmol/L L-Tyr (4.6%) and incubation at 4 degrees C (15.6%) but was reduced by 5 mmol/L D-Tyr (50.0%). L-(14)C-Tyr and (125)I-IMT showed similar results; however, uptake of (125)I-IMT was enhanced by 0.1 mmol/L 2,4-dinitrophenol (165.1%), an inhibitor of generation of energy-rich phosphates. CONCLUSION: The artificial amino acid 4-(125)I-mTyr demonstrated high metabolic stability, rapid blood clearance, rapid urinary excretion, and similar biodistribution to other radiolabeled L-Tyr analogs. 4-(125)I-mTyr can be a competitive substrate of L-Tyr reabsorption. However, 4-(125)I-mTyr demonstrates different pharmacologic features than those of (125)I-IMT, particularly in renal handling. 4-(125)I-mTyr may potentially be applied as a new amino acid transport marker.

Amino Acids↗
PubMed2003

Pharmacokinetics and Biodistribution of (86)Y-Trastuzumab for (90)Y dosimetry in an ovarian carcinoma model: correlative MicroPET and MRI.

UNLABELLED: Preclinical biodistribution and pharmacokinetics of investigational radiopharmaceuticals are typically obtained by longitudinal animal studies. These have required the sacrifice of multiple animals at each time point. Advances in small-animal imaging have made it possible to evaluate the biodistribution of radiopharmaceuticals across time in individual animals, in vivo. MicroPET and MRI-based preclinical biodistribution and localization data were obtained and used to assess the therapeutic potential of (90)Y-trastuzumab monoclonal antibody (mAb) (anti-HER2/neu) against ovarian carcinoma. METHODS: Female nude mice were inoculated intraperitoneally with 5.10(6) ovarian carcinoma cells (SKOV3). Fourteen days after inoculation, 12-18 MBq (86)Y-labeled trastuzumab mAb was injected intraperitoneally. Tumor-free mice, injected with (86)Y-trastuzumab, and tumor-bearing mice injected with labeled, irrelevant mAb or (86)Y-trastuzumab + 100-fold excess unlabeled trastuzumab were used as controls. Eight microPET studies per animal were collected over 72 h. Standard and background images were collected for calibration. MicroPET images were registered with MR images acquired on a 1.5-T whole-body MR scanner. For selected time points, 4.7-T small-animal MR images were also obtained. Images were analyzed and registered using software developed in-house. At completion of imaging, suspected tumor lesions were dissected for histopathologic confirmation. Blood, excised normal organs, and tumor nodules were measured by gamma-counting. Tissue uptake was expressed relative to the blood concentration (percentage of injected activity per gram of tissue [%IA/g]/%IA/g blood). (86)Y-Trastuzumab pharmacokinetics were used to perform (90)Y-trastuzumab dosimetry. RESULTS: Intraperitoneal injection of mAb led to rapid blood-pool uptake (5-9 h) followed by tumor localization (26-32 h), as confirmed by registered MR images. Tumor uptake was greatest for (86)Y-trastuzumab (7 +/- 1); excess unlabeled trastuzumab yielded a 70% reduction. Tumor uptake for the irrelevant mAb was 0.4 +/- 0.1. The concentration in normal organs relative to blood ranged from 0 to 1.4 across all studies, with maximum uptake in spleen. The absorbed dose to the kidneys was 0.31 Gy/MBq (90)Y-trastuzumab. The liver received 0.48 Gy/MBq, and the spleen received 0.56 Gy/MBq. Absorbed dose to tumors varied from 0.10 Gy/MBq for radius = 0.1 mm to 3.7 Gy/MBq for radius = 5 mm. CONCLUSION: For all injected compounds, the relative microPET image intensity of the tumor matched the subsequently determined (86)Y uptake. Coregistration with MR images confirmed the position of (86)Y uptake relative to various organs. Radiolabeled trastuzumab mAb was shown to localize to sites of disease with minimal normal organ uptake. Dosimetry calculations showed a strong dependence on tumor size. These results demonstrate the usefulness of combined microPET and MRI for the evaluation of novel therapeutics.

Animals↗
PubMed2003

Biodistribution of 131I-BSA loaded gelatin microspheres after peroral application to BALB/c mice--particle size study.

Biodistribution studies of radiolabelled 131I-BSA loaded gelatin microspheres were carried out on BALB/c mice after peroral administration. To two groups, radiolabelled 131I-BSA gelatin microspheres of different particle size, 1.2 +/- 1.1 microm and 7.0 +/- 1.2 microm, were administered orally. To the control group, a solution of 131I-BSA was administered orally as well. Biodistribution was followed periodically within 15 days as the percent of total radioactivity present in the stomach and small intestine with Peyer's patches and mesentery, in colon with Peyer's patches, appendix and mesentery, in liver, spleen, blood, kidney, lungs and heart. Preliminary in vitro biodegradation and drug release studies confirmed the potential of gelatin microspheres to protect the antigen of interest from enzymatic degradation in the gut, and to release it in a controlled manner. The biodistribution data confirmed that particle uptake into Peyer's patches and passage to the liver and spleen via the mesentery lymph supply and nodes increased with decreasing particle size.

Administration, Oral↗