Radioactivity In Blood Research Articles

The size of central vascular space in cirrhosis; position-induced redistribution of central blood volume

The aim of this study was to determine the relative size of central blood volume (CBV) and its redistribution after taking up the erect posture. In 19 patients with alcoholic or posthepatitic cirrhosis and 11 healthy controls the whole-body imaging of the 99mTc-labeled red blood cell equilibrium distribution was performed and geometrical mean of counts in the anterior and posterior projection was used for calculations. In addition, thoraco-abdominal scintigrams were obtained in supine and erect postures. Regions of interest were outlined within the cardiopulmonary, splanchnic and renal area. Contribution of CBV to the total blood radioactivity was similar in both groups (21.6 versus 21.8%). By contrast, the relative size of the splanchnic vascular bed was greater in cirrhotic patients than in controls (31.6 versus 25.4%, P<0.005). In cirrhotic patients taking up the erect posture was accompanied by impaired redistribution of CBV to the noncentral vascular bed. In conclusion, this study demonstrates that in cirrhosis the blood is preferentially pooled in splanchnic circulation, but this phenomenon does not affect the size of CBV. CBV is not reduced in the erect posture either, since its gravitational shift to the noncentral vascular compartment is limited.

Absorption, Distribution, Metabolism, and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Dermally to Rats

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns at different time intervals following a single or multiple dermal administration of [Hexyl-1-14C] MGK 264 (N-octylbicycloheptene dicarboximide).Two groups of fasted rats were administered [14C] MGK 264 at a single dermal dose of 10 mg/kg or at a daily dermal dosage of 10 mg/ kg of nonradiolabeled compound for 14 days followed by a single dose of 14C-labeled compound at 10 mg/kg. Each animal was administered approximately 15 μCi radioactivity.Five male rats were used in each of two groups to determine the blood kinetics of administered radioactivity following a single or multipie dermal administration at 10 mg/kg. Radioactivity peaked at approximately 6 h after both single and multiple dermal dosing, indicating slow dermal absorption. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity for both groups was found to be 31 h.Twenty male rats were used in each of the other two experiments. Five animals were euthanized at each of the following time intervals following dose administration: peak blood radioactivity (12 h), blood half-life of radioactivity (43 h), second half-life (74 h), and 168 h. Urine and feces were collected from all animals at predetermined time intervals. At the predetermined times, the rats were euthanized and selected tissues and organs, including the treated skin, were harvested. Samples of urine, feces, and tissues were subsequently analyzed for 14C content.The animals excreted the majority of the absorbed radioactivity in the urine with a significant amount in the feces. At the 168 h time interval the animals excreted 46.27-51.48% of the dosed radioactivity in the urine and 30.37-35.92% in the feces. Tissue residues of 14C were the highest at the 1 h time interval and decreased at the subsequent time intervals. The level of radiolabeled compound was found to be highest in the lungs, stomach, intestine, kidneys, prostate, seminal vesicle, and liver. The total mean recovered radioactivity of the administered dose ranged between 85.35 and 101.52%.The results from the study clearly show that the absorption of MGK 264 from the skin is slow. After 12 h, 88.62 and 85.57% of the applied radioactivity was accounted for as unabsorbed radioactivity on the skin for the single and multiple dose, respectively, The surface radioactivity accounted for 60.06 and 59.15% after 43 h and 38.25 and 46.78% after 74 h for the single and multiple dose, respectively.The daily application of MGK 264 did not significantly affect the blood kinetics or blood half-life of radioactivity. Residual radioactivity on the treated skin for the multiple dose regimen was higher than for the single dose but the absorbed radioactivity was excreted in both the urine and the feces in a similar manner. The very low level of blood radioactivity indicates that the absorbed radioactivity is very quickly eliminated from the systemic circulation. With the exception of a higher amount of radioactivity present in the skin following multiple dose administration, the patterns of absorption, tissue distribution, and elimination between the single and multiple doses are equivalent.

Metabolism and excretion of citalopram in man: identification of O-acyl- and N-glucuronides

1. The antidepressant citalopram (CT), a selective serotonin uptake inhibitor, was given in its labelled form, [14C]-CT, as a single oral dose in 50 ml aqueous solution (0.1 mmol/30 μCi/1.1 MBq) to four healthy male volunteers. 2. Concentrations of radioactivity in whole blood and plasma were similar. The respective pharmacokinetic parameters were: Cmax=214±41 and 246±69 nmol eq./litre, Tmax=3 and 2 h, AUC=18289±2959 and 14537±2883 nmol eq.h/litre, and t1/2=90.2±22.5 and 79.5±14.9 h respectively. A mean of 85.2±10.4% of the radioactive dose was recovered after 17 days of collection of excreta. The majority of radioactivity was excreted in urine (74.7±8.9%) and the remaining part in faeces (10.5±2.3%). 3. The HPLC profile of urinary components showed that besides the known metabolites of citalopram, three glucuronides were present. The relative amounts of CT and its metabolites in urine collected for 7 days were: CT (26%), N-demethyl-CT (DCT, 19%), N,N-didemethyl-CT (DDCT, 9%), the N-oxide (7%), the quaternary ammonium glucuronide of CT (CT-GLN, 14%), the N-glucuronide of DDCT (DDCT-GLN, 6%), and the glucuronide of the acid metabolite (CT-acid-GLN, 12%) formed by N,N- dimethyl deamination of CT. CT-GLN was isolated using preparative chromatography and identified by LC-MS-MS and NMR. DDCT-GLN and CT-acid-GLN were identified by LC-MS. 4. This study shows that protracted renal excretion represents the major route of elimination, with a small fraction voided with faeces. A considerable portion of the urinary excreted dose consists of N-glucuronides of CT and DDCT together with the O-acyl glucuronide of CT-acid.

Absorption, Distribution and Excretion of 14C-labeled Tacrolimus(FK506) Ointment after a Single Dermal Application to the Rat.

The absorption, distribution, and excretion of radioactivity were studied in the male rat after a single dermal application of 14C-labeled FK506 ointment at an FK506 dose level of 1.6 mg/kg. The application period of the ointment was 24 hours. 1. Urinary and fecal excretion of radioactivity were 0.5 and 5.1% of the administered dose, respectively, over 168 hours after application to the intact skin under the non-occlusive dressing condition, 0.4 and 4.2% to the intact skin under the occlusive condition, and 2.4 and 53.8% to the damaged skin under the occlusive condition. Radioactivity remaining at the application site and in the animal body were respectively 14.6 and 0.3% at 168 hours after application to the intact skin under the non-occlusive condition, and were 4.7 and 0.4% after application to the damaged skin under the occlusive condition. 2. Radioactivity was not detected in the whole blood and plasma at any sampling points after ointment application to the intact dorsal skin under occlusive dressing condition. After application to the damaged dorsal skin under the occlusive condition, the pharmacokinetic parameters of radioactivity in the whole blood and plasma were respectively as follows: maximal concentration (Cmax), 42.7 and 37.9 ng eq./mL; time to reach Cmax, both 2 hours; area under the concentration-time curve, 559 and 457 ng eq.·h/mL; and half life, 9.0 and 9.3 hours. 3. After ointment application to the damaged dorsal skin under the occlusive dressing condition, rank order of radioactivity detected at 30 minutes after application was as follows: lung and adrenal gland>brown fat, heart, thyroid gland, kidney, liver and spleen>plasma, urinary bladder and eyeball>cerebrum and testis. The maximal level of radioactivity was observed between 1/2 and 2 hours after application in most tissues. The proportion of radioactivity at 72 hours after application of the maximal level was less than 0.1 in all tissues except the urinary bladder where the proportion was 0.94.

Metabolic Fate of YM992. Absorption, Distribution, Excretion and Metabolic Fingerprinting after a Single Oral Administration of 14C-YM992 to Rats.

The absorption, distribution, metabolism and excretion of radioactivity were investigated after a single oral administration of 30 mg/kg of 14C-YM992 to rats. 1. Blood and plasma radioactivity levels reached the Cmax at 30 min after administration, and then decreased bi-phasically with terminal half-lives (t1/2) of 7.2 and 5.5 hr, respectively. Plasma unchanged drug levels reached the Cmax 15 min after dosing, and then decreased bi-phasically with a t1/2 of 1.2 hr. The ratios of the unchanged drug to total radioactivity level in the plasma were 1.6% and 4.1% at 5 and 15 min after dosing, respectively, and subsequently decreased to 0.1% at 8 hr after dosing. 2. 14C-YM992 was well absorbed from the duodenum to the colon but not stomach. 3. Radioactivity was distributed quickly into various tissues, showing a peak level within 1 hr after dosing in most tissues. Radioactivity levels (excluding the gastrointestinal tract) at 1 hr after dosing were highest in the liver, followed by the kidney, lung, adrenal, bone marrow, spleen, submandibular gland, and pancreas. Radioactivity disappeared relatively rapidly from most tissues, reflecting a decrease in the plasma concentration. The ratio of the unchanged drug to total radioactivity level in the cerebrum was 62.8% at 15 min after dosing, and subsequently decreased time-dependently to 33.3% at 24 hr after dosing. 4. Within 168 hr after dosing, 61.3% and 37.7% of the dosed radioactivity were excreted in the urine and feces, respectively. In bile-duct cannulated rats, 58.0 % and 39.4% of the dosed radioactivity were excreted within 72 hr in the bile and urine, respectively. At least 70.6% of the radioactivity excreted in bile was reabsorbed. 5. At least 18 peaks of radioactivity were observed in the radio-chromatogram of plasma at 1 hr after dosing, and at least 10 peaks in the radio-chromatograms of urine and bile collected for 6 hr after dosing. Little or trace amount of unchanged drug was observed in these samples. In the radio-chromatogram of cerebrum at 1 hr after dosing, at least 9 peaks of radioactivity were observed, and the main peak corresponded to the unchanged drug.

Preparation, biodistribution, and dosimetry of 188Re-Labeled MoAb ior cea1 and its f(ab′) 2 fragments by avidin-biotin strategy

The biotinylated monoclonal antibody (MoAb) ior cea1 and its F(ab′) 2 fragments were labeled with Re-188 by combination of avidin-biotin strategy. 188Re-MoAb, 188Re-MoAb-biotin, 188Re-F(ab′) 2, and 188Re-F(ab′) 2-biotin preparations were produced for these studies with specific activities of 1.30 ± 0.18 GBq/mg and from instant freeze-dried kit formulations using ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) as a weak competing ligand. There were no significant differences ( p > 0.05) between the biodistribution in mice of biotinylated and unbiotinylated 188Re-labeled immunoconjugates. When avidin was injected as a chase after injection of 188Re-MoAb-biotin or 188Re-F(ab′) 2-biotin, the blood radioactivity level decreased approximately 75% (cumulated activity) and the effective dose decreased almost 25% with respect to that of the radioimmunoconjugates in which the chase effect was not used. Our results suggest that 188Re-labeled biotinylated MoAb ior cea1 and its F(ab′) 2 fragments prepared by this method are stable complexes in vivo.

Absorption, Distribution, Metabolism, and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

AbstractExperiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns at different time intervals following a single or multiple dermal administration of [Hexyl-1-14C] MGK 264 (N-octylbicycloheptene dicarboximide).Two groups of fasted rats were administered [14C] MGK 264 at a single dermal dose of 10 mg/kg or at a daily dermal dosage of 10 mg/ kg of nonradiolabeled compound for 14 days followed by a single dose of 14C-labeled compound at 10 mg/kg. Each animal was administered approximately 15 μCi radioactivity.Five male rats were used in each of two groups to determine the blood kinetics of administered radioactivity following a single or multipie dermal administration at 10 mg/kg. Radioactivity peaked at approximately 6 h after both single and multiple dermal dosing, indicating slow dermal absorption. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity for both grou...

Transient alteration in intestinal permeability to technetium Tc99m diethylenetriaminopentaacetate during the prodromal stages of alimentary laminitis in ponies

Abstract Objectives To determine whether mucosal permeability is altered during the prodromal stages of alimentary laminitis. Animals 15 healthy adult ponies. Procedures Intestinal permeability was evaluated for control ponies (n = 5) and for ponies 4 to 12 (n = 5) and 20 to 28 (n = 5) hours after administration of carbohydrate overload. Mucosal permeability was determined by measuring the percentage of orally administered technetium Tc99m diethylenetriaminopentaacetate (99mTc-DTPA) excreted in urine during an 8-hour period, then measuring blood radioactivity at hourly intervals. Plasma endotoxin-like activity was measured by use of a chromogenic Limulus amebocyte assay. Results Urinary excretion of 99mTc-DTPA was 2.45% of administered dose for control ponies, and was 16.67% of administered dose 4 to 12 hours and 3.57% of administered dose 20 to 28 hours after administration of carbohydrate. Conclusions A marked but transient increase in intestinal permeability was observed early in the prodromal stages of alimentary laminitis. Clinical Relevance Absorption of substances from the intestine may be an initiating event in alimentary laminitis. (Am J Vet Res 1998;59:1431–1434)

Wide distribution of [3H](-)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue.

The increasing recognition of green tea and tea polyphenols as cancer preventives has created a need for a study of their bioavailability. For this purpose, we synthesized [3H] (-)-epigallocatechin gallate ([3H]EGCG) with a specific activity of 48.1 GBq/mmol and directly administered the solution into the stomachs of CD-1 female or male mice. Radioactivity in the digestive tract, various organs, blood, urine and feces was measured with an oxidizer at various times after administration and significant radioactivity was found in the previously reported target organs of EGCG and green tea extract (digestive tract, liver, lung, pancreas, mammary gland and skin), as well as other organs (brain, kidney, uterus and ovary and testes) in both sexes. Incorporation of radioactivity in the cells was confirmed by microautoradiography. Within 24 h, 6.6 (females) and 6.4% (males) of total administered radioactivity was excreted in the urine and 37.7 and 33.1% in feces. HPLC analysis of urine from both sexes revealed that 0.03-0.59% of administered [3H]EGCG, along with at least five metabolites, was excreted. In addition, we found that a second, equal administration to female mice after a 6 h interval enhanced tissue levels of radioactivity in blood, brain, liver, pancreas, bladder and bone 4-6 times above those after a single administration. These results suggest that frequent consumption of green tea enables the body to maintain a high level of tea polyphenols and this paper is the first pharmacological evidence of a wide distribution of [3H]EGCG in mouse organs, indicating a similar wide range of target organs for cancer prevention in humans.

Clearance of [125I]-Tumor Necrosis Factor-α from the Brain into the Blood after Intracerebroventricular Injection in Rats

To test the hypothesis that brain to blood clearance is a mechanism by which brain inflammation and damage can increase circulating acute phase cytokines, rate of transfer of [¹²⁵I]-tumor necrosis factor-α ([¹²⁵I]-TNF) from brain to blood was determined. Acid precipitable [¹²⁵I]-TNF appeared in peripheral blood within 5 min of intracerebroventricular (i.c.v.) injection and was cleared from brain to blood following first order kinetics at a fractional rate of 0.01123 ± 0.0030/min, a value virtually identical with a previously determined clearance rate of [¹²⁵I]-IL-6. Area under blood concentration curve compared with that after intravenous injection shows that 31.6 ± 5.8% of the intracerebral dose reached peripheral blood in 4 h. Elevated ratios of superior sagittal sinus to aortic blood radioactivity concentration at 1 and 3 h (1.48 ± 0.26, p = 0.042; 1.95 ± 0.39, p = 0.026, respectively) indicate that TNF-α drains from brain at least in part via the sagittal sinus. Escherichia coli lipopolysaccharide i.c.v. injection increased the rate of brain efflux of TNF-α.

Hepatic and extrahepatic clearance of circulating human lactoferrin: an experimental study in rat.

Lactoferrin, unlabelled or 125I-labelled by 2 different methods, was given intravenously to rats. Blood, tissue and liver cell radioactivity was measured. Both of the radiolabelled preparations were eliminated by the liver, and some deposited extrahepatically. One preparation formed large aggregates--here 90% of the hepatic uptake occurred in the Kupffer cells. The other preparation, consisting mostly of protein monomers but also dimers/oligomers/microaggregates, was taken up by hepatocytes (63% of total liver uptake), liver endothelial cells (22%) and Kupffer cells (15%). On a per cell volume basis, lactoferrin uptake was much more efficient by nonparenchymal cells compared to hepatocytes, which explains why immunomorphological staining only revealed lactoferrin in the nonparenchymal liver cells. The study demonstrates that radio-iodination of lactoferrin can affect its properties and handling, which may be important regarding contradictory reports on hepatic lactoferrin uptake. We conclude that both hepatocytes and nonparenchymal liver cells are involved in the blood clearance of lactoferrin, probably to a great extent owing to nonspecific mechanisms. Extrahepatic deposition and exposure (for instance on vessel walls/glomeruli) suggests that lactoferrin can be available to circulating anti-lactoferrin autoantibodies in autoimmune disease.

Pharmacokinetic study in rats after single intravenous and oral administrations of [14C]-ITF-296.

Pharmacokinetics of [14C]-ITF-296 and its metabolites, ITF-1124 and ITF-1577, were studied in rats after a single intravenous (2.5 mg/kg) and oral (10 mg/kg) administration. Radioactivity was measured by LSC while unchanged drug and its metabolites in plasma were assayed by an HPLC-UV method. The absorption of [14C]-ITF-296 after oral administration is practically complete. Elimination of radioactivity occurs mainly in urine (higher than 80%) and the recovery of the dose (higher than 95%) takes place up to 96 h after both treatments. Both by i.v. and p.o. route the results show that the radioactivity is largely excreted in the bile and reabsorbed in the intestine. The tissue distribution study indicates that there is no accumulation or localization of radioactivity in the major organs or blood and no radioactivity levels are found 96 h after either treatment. In addition, whole body autoradiography confirms the tissue distribution pattern, showing no differences between albino and pigmented rats.

Chronic Exposure to Secoisolariciresinol Diglycoside Alters Lignan Disposition in Rats

Mammalian lignans from colonic bacterial action on secoisolariciresinol diglycoside (SDG) may mediate the anticarcinogenic effect of prolonged SDG feeding in rats. To elucidate lignan bioactivity, our objective was to determine 3H-SDG disposition in rats with acute or chronic SDG treatment over 48 h. After food deprivation overnight, female Sprague-Dawley rats (70–72 d old) were given a single gavage of 3H-SDG (3.7 kBq/g body weight) either immediately (acute, n = 12) or after 10 d of gavage with 1.5 mg unlabeled SDG/d (chronic, n = 12). Rats were killed at 12, 24, 36 and 48 h after gavage, and samples collected and analyzed for radioactivity by liquid scintillation counting. Radioactivity was 1- to 16-fold higher at 12 vs. 48 h for tissues, blood and gastrointestinal contents (P < 0.05). By 48 h, >80% of the recovered dose was excreted in both groups (feces > 50%, urine = 28–32%). Tissue radioactivity was highest (by 0.5- to 176-fold) in the cecum (P < 0.05). Levels in the liver, kidney and uterus (12 h) were 0.2- to 7.5-fold higher than in other nongastrointestinal tissues. At 12 h, fecal radioactivity was negligible, and cecal content, liver and adipose radioactivity were one- to threefold greater in rats with chronic SDG exposure than in those acutely exposed (P < 0.05). Blood radioactivity, present mostly in the plasma fraction (0.4% of dose), suggested that lignan concentrations could be 3000 times higher than peak estrogen levels in rats. Thus, SDG metabolites accumulated in the liver, kidney, intestinal tissues and uterus. Chronic SDG exposure delayed fecal excretion while increasing liver and adipose lignan levels.

Three-Step Tumor Imaging with Biotinylated Monoclonal Antibody, Streptavidin and 111In-DTPA–Biotin

The purpose of this study was to test the three-step targeting of tumors in mice using biotinylated antibody, streptavidin and radiolabeled biotin. Nude mice bearing subcutaneous LS180 human colon cancer xenografts were intravenously administered with 200 μg of the biotinylated anti-Tn monoclonal antibody MLS128, and 2 days later they got intravenous injection of 50 μg of streptavidin. They were intravenously injected 1, 4 or 7 days later with 0.5 μg of 111In-diethylenetriamine pentaacetic acid (DTPA)–biotin. The tumor uptake, determined 2 h later, was 1.4, 0.5 and 0.6% injected dose/gram of tissue (ID/g), respectively, and the blood radioactivity was 1.0, 0.2 and 0.2% ID/g, respectively. When the interval between the streptavidin and radiolabeled biotin injections was prolonged from 1 day to 7 days, the tumor-to-blood ratio 2 h after injection of 111In-labeled biotin increased from 1.5 to 4.0. Clear tumor images were obtained as early as 2 h after injection of radiolabeled biotin. In conclusion, these preliminary data suggested that the three-step method using the streptavidin–biotin system would be applicable in an experimental mouse tumor model and provides images of tumors rapidly and clearly after injection of radiolabeled biotin.

Metabolic Fate of NKH477. (1). Blood and Plasma Concentrations, Distribution and Excretion in Rats and Dogs after a Single Intravenous Administration.

The pharmacokinetics, distribution and excretion of NKH477, a novel water-soluble forskolin derivative, improving acute cardiac failure, were investigated in rats and dogs after a single intravenous administration of 14C-labeled NKH477 and unlabeled NKH477. 1. After intravenous bolus administration of 14C-NKH477 (0.011 ?? 0.3 mg/kg) to male rats, the elimination half life of radioactivity in the blood ranged from 70.67 to 118.23 hr. The elimination half life of radioactivity in the blood was prolonged compared with that in the plasma, which should be attributed to binding of the radioactivity to blood cells. 2. After intravenous bolus dosing of NKH477 to male rats, plasma concentrations of unchanged NKH477 and active metabolite, M-1, declined rapidly with half lives of 0.23 and 0.25 hr, respectively. The AUC of M-1 was markedly lower than that of unchanged NKH477. 3. In dogs, the radioactivity levels in the blood and plasma declined two-exponentially following administration, and the slow elimination of the blood radioactivity, but less compared to rats, was also observed. 4. Following intravenous infusion of NKH477 for 2 hours to male dogs under anesthesia at doses ranging from 0.15 to 0.60 mg/kg/min, plasma concentrations of unchanged NKH477 and M-1 decreased with the elimination half lives of 1.57 ?? 2.36 hr. The AUC of M-1 was half as much as that of unchanged NKH477. 5. After administration to male rats, the radioactivity was rapidly and extensively distributed to the tissues except those belonging to the central nervous system. The liver showed much higher concentration of radioactivity than the other tissues. The radioactivity declined rapidly from most tissues, except the heart, blood, spleen and adrenal gland. 6. After dosing to male rats, excretion of the radioactivity in urine and feces within 144 hr was 6.4 and 90.2% of dose, respectively. In bile duct-cannulated rats, biliary and urinary excretion of radioactivity was 77.1 and 7.8% of the dose, respectively within 72 hr after administration, suggesting that the main excretory route of 14C-NKH477 is feces through bile. 7. In dogs, 78.2% of the dose was excreted into feces during 144 hr after dosing.

Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs

SUMMARY Objective To determine plasma clearance kinetics and imaging biodistribution of indium 111-labeled transferrin (111In-TF) in dogs. Animals 7 adult dogs. Procedure After 30 minutes’ incubation of 18.5 MBq (0.5 mCi) of 111InCl3 with 1 ml of serum (n = 3) or 1 ml of plasma (n = 4) at 37 C, dogs were given autologous 111In-TF IV, and serial blood samples and right lateral and dorsal scintigraphic images were obtained immediately and 1, 3, 5, 9, 22, and 48 hours later. Blood and plasma clearance kinetics were determined from a least-squares, nonlinear fit of the sample radioactivity data. Blood radioactivity was compared with plasma radioactivity to determine the extent of cellular labeling. Imaging biodistribution was characterized by subjective and objective assessment of blood pool, liver, gastrointestinal (abdomen) tract, kidney, and bone marrow activity. Results 111In-TF plasma clearance was best described by a biexponential fit, with early and late clearance half-times of 6 and 49 hours, respectively. The 111In was not redistributed between transferrin (plasma proteins) and blood cells. Imaging studies documented progressive liver and bone marrow uptake of the 111In-TF over 48 hours. Some radioactivity was evident in the colon of 1 dog on 48-hour images. Decay-corrected count rates (counts/pixel/mCi/kg/min) within the abdominal region of interest increased over the 48-hour imaging period and exceeded the blood pool (cardiac) activity at 20 hours after injection. Conclusion 111In-TF has a biexponential plasma clearance in clinically normal dogs, with early and late clearance half-time of 6 and 49 hours, respectively. Scintigraphically, 111In-TF localizes to sites of iron storage (bone marrow and liver) over time. Some loss of 111In-TF via the gastrointestinal tract may be seen on late 48-hour images. Clinical Relevance 111In-TF appears to be a viable radiopharmaceutical for use in dogs, with specific application for identifying those with protein-losing enteropathy. (Am J Vet Res 1997;58:1188–1192)

Distribution studies in CD-1 mice administered [14C]muconaldehyde.

Trans,trans-muconaldehyde (muconaldehyde, MUC), a microsomal hematotoxic ring-opened metabolite of benzene, has been proposed to play a role in benzene hematotoxicity. In the present study, [14C]muconaldehyde was administered to CD-1 mice and the distribution of [14C]muconaldehyde equivalents was investigated. The study was carried out to evaluate whether [14C]muconaldehyde equivalents could reach the bone marrow. [14C]Muconaldehyde at a dose of 2 mg/kg was administered intraperitoneally (3.4 microCi/mouse) and by intravenous injection (2.7 microCi/mouse). The amount of [14C]muconaldehyde equivalents was measured in the bone marrow, blood, liver, lung, kidney and spleen at 0.25, 0.5, 1, 2, 4, and 24 h after [14C]MUC administration. The results indicate that 0.044% or 0.018% of the total dose administered when given i.v. or i.p., respectively, reached the bone marrow. The elimination of the radioactivity in all organs had at least two phases. The bone marrow, kidney, and lung had a rapid first phase (t1/2 0.5-1.2 h) and a slower second phase (t1/2 2.8-15.7 h). In the liver, a slow first phase (t1/2 3.7 h) was followed by a more rapid second phase (t1/2 1.5 h). The level of radioactivity in blood and bone marrow was significantly higher when [14C]muconaldehyde was administered intravenously compared with intraperitoneally, demonstrating that the route of administration affects the distribution of [14C]muconaldehyde equivalents.

Neuroimaging of vessel amyloid in Alzheimer's disease.

Despite extensive recent advances in understanding Alzheimer's disease (AD) we are unable to noninvasively establish a definite diagnosis during life and cannot monitor the cerebral deposition of amyloid beta protein (A beta) in living patients. We evaluated the use of 10H3, a monoclonal antibody Fab targeting A beta protein 1-28 labeled with Tc-99m. Six subjects with probable AD were studied using single-photon emission computed tomography (SPECT) at times from 0-24 hours following injection. Curves of radioactivity in blood demonstrate a half-life of the injected Fab of 2-3 hours. Images show uptake around the head in the scalp or bone marrow in all subjects. There is no evidence of cerebral uptake of the antibody. Scalp biopsies in all six patients demonstrate diffuse staining with 10H3 of the scalp, a pattern indistinguishable from that found in controls. Evidence of amyloid deposition in the scalp in AD is not seen with other anti-A beta antibodies, suggesting that 10H3 is cross-reacting with another protein. Further studies with anti-A beta antibodies will require longer-lived radionuclides to detect cerebral uptake at later times after injection to allow for complete clearance from the blood. Alternately, imaging using labeled A beta itself may provide a means for noninvasive targeting of cerebral amyloid.

Cerebral benzodiazepine receptor binding in vivo in patients with recurrent hepatic encephalopathy.

Increased activation of the central benzodiazepine receptor (BZR) appears to play an important role in hepatic encephalopathy (HE). However, there is controversy regarding whether the density or affinity of BZRs is altered. A previous positron emission tomography (PET) study using the BZR antagonist [11C]flumazenil (FMZ) found two- to threefold greater cerebral cortical tracer uptake in recurrent HE, but did not account for impaired FMZ metabolism due to liver disease or assess the relative contributions of tracer delivery versus BZR binding. We hypothesized that correcting for these factors would affect estimations of BZR binding in HE. Nine patients with recurrent HE and 13 age-comparable controls were studied with [11C]FMZ PET. After intravenous administration of [11C]FMZ, arterial blood samples were collected, and PET images were acquired over 60 minutes. FMZ transport and binding maps were calculated for each subject by using a physiological tracer kinetic model. In agreement with the previous report, we found that FMZ reached a much higher level and was retained longer in the HE cerebral cortex despite similar total blood radioactivity levels in the two groups. However, the patients showed impaired hepatic metabolism of FMZ. After physiological modeling incorporating these data, significant increases in BZR binding were found in the thalamus (13%), cerebellum (20%), and pons (23%). There were minor, statistically insignificant increases in cerebral cortical (10%), putamen (12%), and whole brain (12%) BZR binding in patients with recurrent HE. These findings are in general agreement with results of autopsy studies, confirming a lack of major increases in cortical or basal ganglial BZR binding in HE. They emphasize that physiological tracer modeling should be used and altered peripheral radioligand metabolism considered in future PET studies of HE.

Regional distribution of 11C-labeled lidocaine, bupivacaine, and ropivacaine in the heart, lungs, and skeletal muscle of pigs studied with positron emission tomography.

The regional myocardial uptake and kinetics of 11C-lidocaine, 11C-bupivacaine, and 11C-ropivacaine were examined in the pig, utilizing positron emission tomography to determine whether disproportionate distribution exists among these agents. The three drugs were rapidly distributed to the myocardium and lung with mean peak radioactivities occurring between 0.35 and 0.48 min post-injection in myocardium and 0.35 and 0.65 min in lung. Radioactivities peaked later in skeletal muscle than in the myocardium and lung, occurring between 1.1 and 2.7 min post-end injection. Blood radioactivities for bupivacaine and ropivacaine were significantly higher than those of lidocaine, whereas myocardial, lung, and muscle uptakes for the three agents were not significantly different. Myocardium-blood partition coefficients were similar for bupivacaine and ropivacaine (0.55 and 0.49 respectively), while it was three times higher for lidocaine (1.4). A similar relationship existed for skeletal muscle- and lung-blood partition coefficients. Bupivacaine and ropivacaine t1/2z in skeletal muscle were significantly longer than those of lidocaine. The results of this study indicate that the increased cardiotoxicity associated with bupivacaine does not appear to be related to disproportionate distribution in the myocardium when compared to lidocaine and ropivacaine.