Radioactivity In Blood Research Articles

THE EVALUATION OF RADIOLABELED ARTESUNATE ON TISSUE DISTRIBUTION IN RATS AND PROTEIN BINDING IN HUMANS

The present study reports the tissue distribution, pharmacokinetics, mass balance, and elimination of [(14)C] artesunate (AS) following single intravenous administration in rats. Protein binding was performed with rat and human plasma. Radioactivity and drug levels in blood, plasma, tissues, urine, and feces up to 192 hours were collected and measured. The mean terminal half-life of plasma (76 h) and blood (105 h) radioactivity was prolonged compared with that of unchanged AS (0.43 h) and dihydroartemisinin (0.75 h), an active metabolite of AS. Drug was widely distributed after 1 hour in select tissues. After 24 hours, the radioactivity rapidly declined in all tissues except spleen until 96 hours. Only 1% of total radioactivity was detected in brain tissue. AS revealed a higher binding capacity with human and rat plasma proteins (73-81%). The radioactivity in whole blood was higher (two to fourfold) than that in plasma throughout the period of the treatment, suggesting that AS binding to RBCs may relate to its powerful antimalarial activity.

Evaluation of Reference Tissue Models for the Analysis of [11C](R)-PK11195 Studies

[(11)C](R)-PK11195 is a marker of activated microglia, which can be used to measure inflammation in neurologic disorders. The purpose of the present study was to define the optimal reference tissue model based on a comparison with a validated plasma input model and using clinical studies and Monte Carlo simulations. Accuracy and reproducibility of reference tissue models were evaluated using Monte Carlo simulations. The effects of noise and variation in specific binding, nonspecific binding and blood volume were evaluated. Dynamic positron emission tomography scans were performed on 13 subjects, and radioactivity in arterial blood was monitored online. In addition, blood samples were taken to generate a metabolite corrected plasma input function. Both a (validated) two-tissue reversible compartment model with K(1)/k(2) fixed to whole cortex and various reference tissue models were fitted to the data. Finally, a simplified reference tissue model (SRTM) corrected for nonspecific binding using plasma input data (SRTM(pl_corr)) was investigated. Correlations between reference tissue models (including SRTM(pl_corr)) and the plasma input model were calculated. Monte Carlo simulations indicated that low-specific binding results in decreased accuracy and reproducibility. In this respect, the SRTM and SRTM(pl_corr) performed relatively well. Varying blood volume had no effect on performance. In the clinical evaluation, SRTM(pl_corr) and SRTM had the highest correlations with the plasma input model (R(2)=0.82 and 0.78, respectively). SRTM(pl_corr) is optimal when an arterial plasma input curve is available. Simplified reference tissue model is the best alternative when no plasma input is available.

Pharmacokinetics, metabolism, excretion and plasma protein binding of 14C-levofloxacin after a single oral administration in the Rhesus monkey

Levofloxacin's metabolism, excretion, and in vitro plasma protein binding, together with its pharmacokinetics, were studied in the Rhesus monkey in support of an anthrax efficacy study in this species. Three males and three female Rhesus monkeys were dosed with a single oral dose of 14C-levofloxacin at 15 mg kg−1 (2 MBq kg−1). Following dose administration, blood samples were collected up to 48 h post-dose, and urine and faeces were quantitatively collected up to 168 h post-dose. Blood, plasma, urine, and faeces were analysed for total radioactivity. Metabolite profiling and identification was performed using radio-high-performance liquid chromatography (HPLC) and liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS). Additionally, the plasma protein binding of levofloxacin was determined in vitro by means of equilibrium dialysis. Peak plasma levels of total radioactivity and levofloxacin were rapidly reached after oral administration with a total radioactivity blood: plasma ratio close to unity. The elimination half-life of levofloxacin was estimated at about 2 h. Total radioactivity was mainly excreted in urine (about 57–86% of the dose) with faecal excretion accounting for only a minor fraction of the total amount of excreted radioactivity (about 7.4–14.7%). In the plasma, the majority of total radioactivity was accounted for by levofloxacin. In addition, two minor metabolites, i.e. levofloxacin n-oxide and presumably a glucuronide conjugate of levofloxacin, were detected. In the urine, five components were found, with levofloxacin being the major component. Minor metabolites included desmethyl levofloxacin, levofloxacin n-oxide, and a glucuronide conjugate of levofloxacin. In the faeces, the major analyte was a polar metabolite, tentatively identified as a levofloxacin glucuronide. The in vitro plasma protein binding was low (on average 11.2%) and independent of concentration (1.0–10.0 µg ml−1). No sex differences were noted in any of the investigations. The present data indicated that the metabolism and excretion pattern, and also the in vitro plasma protein binding of levofloxacin in the Rhesus monkey, were comparable with those previously reported in man, hereby supporting the use of this animal species in the efficacy evaluation of levofloxacin against inhalation anthrax. The shorter half-life of levofloxacin in the Rhesus monkey relative to man (2 versus 7 h) prompted the development of an alternative dosing strategy for use in the efficacy study.

Uptake and metabolism of plasma-derived erucic acid by rat brain

We examined the ability of erucic acid (22:1n-9) to cross the blood-brain barrier (BBB) by infusing [14-14C]22:1n-9 (170 microCi/kg, iv and icv) into awake, male rats. [1-14C]arachidonic acid (20:4n-6) [intravenous (i.v.)] was the positive control. After i.v. infusion, 0.011% of the plasma [14-14C]22:1n-9 was extracted by the brain, compared with 0.055% of the plasma [1-14C]20:4n-6. The [14-14C]22:1n-9 was extensively beta-oxidized (60%), compared with 30% for [1-14C]20:4n-6. Although 20:4n-6 was targeted primarily to phospholipid pools, 22:1n-9 was targeted to cholesteryl esters, triglycerides, and phospholipids. When [14-14C]22:1n-9 was infused directly into the fourth ventricle of the brain [intracerebroventricular (i.c.v.)] for 7 days, 60% of the tracer entered the phospholipid pools, similar to the distribution observed for [1-14C]20:4n-6. This demonstrates plasticity in the ability of the brain to esterify 22:1n-9 in an exposure-dependent manner. In i.v. and i.c.v. infused rats, a significant amount of tracer found in the phospholipid pools underwent sequential rounds of chain shortening and was found as [12-14C]20:1n-9 and [10-14C]oleic acid. These results demonstrate for the first time that intact 22:1n-9 crosses the BBB, is incorporated into specific lipid pools, and is chain-shortened.

Translocation of Ultrafine Particles

We read with great interest the article by Geiser et al. (2005) on the mechanism of translocation of ultrafine particles (UFPs) across cellular membranes in vivo in rats following inhalation and in vitro using porcine pulmonary macrophages and human red blood cells.

Intratissular Lymphaticovenous Anastomoses Demonstrated by Perioperative Intramuscular Injection of 99mTc-Colloids

The existence of intratissular lymphaticovenous anastomoses has often been suggested, but it has never been demonstrated. This study aims at demonstrating the presence of such anastomoses. The free flap model was used to investigate the drainage of radiolabeled colloid particles whose size prevents direct passage to the blood vessels. The tracer was injected into the muscle or the skin during the surgical procedure. Blood samples were sequentially drawn from the venous pedicle over the 30 minutes that followed the tracer injection. The blood samples were counted using a gamma well-counter. In all 14 patients, the venous blood radioactivity steadily increased over time. Radiochemical analyses performed on the blood samples demonstrated that the radioactivity is related to the labeled colloids and not to free pertechnetate. Planar imaging performed 24 hours after the surgical procedure showed a significant liver uptake, and no accumulation in the area of normal lymphatic relays. As, in the free flap model, there is no lymphatic drainage through the classical pathways whatsoever, and since the size of the radiolabeled particles prevents them from directly entering the blood stream, the results strongly suggest the presence of functional intratissular lymphovenous anastomoses.

PIMECROLIMUS: ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION IN HEALTHY VOLUNTEERS AFTER A SINGLE ORAL DOSE AND SUPPLEMENTARY INVESTIGATIONS IN VITRO

The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [(3)H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After t(max) (1-3 h), its blood concentrations fell quickly to 3% of C(max) at 24 h, followed by a slow terminal elimination phase (average t(1/2) 62 h). Radioactivity in blood decreased more slowly (8% of C(max) at 24 h). The tissue and blood cell distribution of pimecrolimus was high. The metabolism of pimecrolimus in vivo, which could be well reproduced in vitro (human liver microsomes), was highly complex and involved multiple oxidative O-demethylations and hydroxylations. In blood, pimecrolimus was the major radiolabeled component up to 24 h (49% of radioactivity area under the concentration-time curve(0-24) h), accompanied by a large number of minor metabolites. The average fecal excretion of radioactivity between 0 and 240 h amounted to 78% of dose and represented predominantly a complex mixture of metabolites. In urine, 0 to 240 h, only about 2.5% of the dose and no parent drug was excreted. Hence, pimecrolimus was eliminated almost exclusively by oxidative metabolism. The biotransformation of pimecrolimus was largely catalyzed by CYP3A4/5. Metabolite pools generated in vitro showed low activity in a calcineurin-dependent T-cell activation assay. Hence, metabolites do not seem to contribute significantly to the pharmacological activity of pimecrolimus.

Pharmacokinetics and Metabolic Disposition of Sirolimus in Healthy Male Volunteers After a Single Oral Dose

The pharmacokinetics and metabolic disposition of sirolimus (rapamycin, Rapamune), a macrocyclic immunosuppressive agent for the prevention of allograft rejection in organ transplantation, were investigated in 6 healthy male volunteers after a single nominal 40-mg oral dose of the C-radiolabeled drug, with the added aim of assessing the potential role of sirolimus metabolites in the clinical pharmacology of the parent drug. The absorption of parent drug and derived materials was rapid (tmax 1.3 +/- 0.5 hours, mean +/- SD), and the elimination of sirolimus was slow (t(1/2) 60 +/- 10 hours, mean +/- SD) in whole blood. The high whole blood to plasma (B/P) concentration ratio of sirolimus (142 +/- 39) was consistent with its extensive partitioning into formed blood elements. The markedly lower B/P value based on radioactivity (2.7 +/- 0.4) suggested that drug-derived products partitioned into formed blood elements to a much lesser extent. Based on AUC0-144h values, unchanged sirolimus represented an average 35% of total radioactivity in whole blood. Drug-derived products in whole blood were characterized by HPLC, LC/MS, and LC/MS/MS as 41-O-demethyl, 7-O-demethyl, and several hydroxy, dihydroxy, hydroxy-demethyl and didemethyl sirolimus metabolites. The percentage distribution of sirolimus metabolites in whole blood ranged from 3%-10% at 1 hour to 6%-17% at 24 hours after drug administration. Based on their low immunosuppressive activities and relative abundance in whole blood of humans after sirolimus administration, metabolites of sirolimus do not appear to play a major role in the clinical pharmacology of the parent drug. A majority of the administered radioactivity (91.0 +/- 8.0%) was recovered from feces, and only 2.2% +/- 0.9% was renally excreted.

Preparation and Characterization of a DOTA−Lysine−Biotin Conjugate as an Effector Molecule for Pretargeted Radionuclide Therapy

Pretargeted radionuclide therapy depends on the establishment of a high concentration of secondary binding sites at a tumor to which low-molecular weight radiolabeled effector molecules can be directed. This study describes the simple synthesis of an effector molecule and its subsequent characterization to determine the extent to which it complied with the ideal requirements of such a compound. (Epsilon)-DOTA-(alpha)-biotinamidolysine (DLB) was synthesized in high yield and purity using conventional SPPS methodology. High radiochemical purities were obtained when labeled with several potentially useful radionuclides. The radiolabeled analogue bound to streptavidin efficiently with a stoichiometry similar to that of native biotin and showed high stability in serum and upon challenge with acid conditions. Biodistribution studies in normal animals showed a rapid rate of clearance from the blood and low retention of radioactivity by normal tissues. This design of effector molecule therefore shows promise for further pretargeted radionuclide therapy studies.

Toxicokinetics of 14C‐endosulfan in male Sprague–Dawley rats following oral administration of single or repeated doses

Endosulfan (ES), an organochlorine (OC) insecticide that belongs to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. The toxicokinetics of 14C-endosulfan following oral administration of a single dose of 5 mg/kg body weight was investigated in male Sprague-Dawley rats. Three rats were sacrificed 30 min, 1 h, 2 h, 4 h, and 8 h after dosing. 14C-endosulfan radioactivity was detected in all tissues at each time point. In a separate experiment urine and feces were collected for 96 h. The total radioactivity recovered in the excreta for 4 days was 106.8% +/- 26.2%, with fecal elimination the major route of elimination route (94.4% +/- 21.4%). The cumulative excretion in the urine for 4 days was 12.4% +/- 4.8%. Radioactivity 8 h after administration was highest in gastrointestinal (GI) tract tissue (20.28 +/- 16.35 mg ES eq./L) and lowest in muscle (0.18 +/- 0.06 mg ES eq./L). The toxicokinetic parameters obtained from 14C-endosulfan-derived radioactivity in blood were distribution half-life (T1/2 x) = 31 min and terminal elimination half-life (T1/2 y) = 193 h. Blood concentration reached its maximum (Cmax) of 0.36 +/- 0.08 mg ES eq./L 2 h after the oral dose. Endosulfan was rapidly absorbed into the GI tract in rats, with an absorption rate constant (ka) of 3.07 h(-1).

Primaquine-Induced Hemolytic Anemia: Role of Splenic Macrophages in the Fate of 5-Hydroxyprimaquine-Treated Rat Erythrocytes

Primaquine-induced hemolytic anemia is known to result from premature sequestration of damaged (but intact) erythrocytes by the spleen. We have shown previously that a phenolic metabolite, 5-hydroxyprimaquine (5-HPQ), is a direct-acting hemolytic agent in rats, suggesting that 5-HPQ is a mediator of the hemolytic response to primaquine. To investigate the fate of erythrocytes in vivo after in vitro exposure to 5-HPQ, rat (51)Cr-labeled erythrocytes were incubated with hemolytic concentrations of 5-HPQ and then readministered intravenously to rats. The time course of loss of radioactivity from blood and uptake into the spleen and liver was measured. In rats given 5-HPQ-treated erythrocytes, an increased rate of removal of radioactivity from the circulation was observed as compared with the vehicle control. The loss of blood radioactivity was accompanied by a corresponding increase in radioactivity appearing in the spleen but not in the liver. When rats were pretreated with clodronate-loaded liposomes to deplete splenic macrophages, there was a decreased rate of removal of radioactivity from the circulation and a markedly diminished uptake into the spleen. A role for phagocytic removal of 5-HPQ-treated red cells was confirmed in vitro using the J774A.1 macrophage cell line. Furthermore, depletion of red cell GSH with diethyl maleate significantly enhanced in vitro phagocytosis of 5-HPQ-treated red cells. The data indicate that splenic macrophages are responsible for removing 5-HPQ-treated red cells and support the postulate that this metabolite is a contributor to the hemolytic anemia induced after administration of the parent compound.

Evaluation of reference tissue models for analysing [11C](R)-PK11195 studies

[11C](R)-PK11195 is a marker of activated microglia, which can be used to measure inflammation in neurologic disorders. The purpose of the present study was to define the optimal reference tissue model based on a comparison with a validated plasma input model and using clinical studies and Monte Carlo simulations. Accuracy and reproducibility of reference tissue models were evaluated using Monte Carlo simulations. The effects of noise and variation in specific binding, nonspecific binding and blood volume were evaluated. Dynamic positron emission tomography scans were performed on 13 subjects, and radioactivity in arterial blood was monitored online. In addition, blood samples were taken to generate a metabolite corrected plasma input function. Both a (validated) two-tissue reversible compartment model with K1/k2 fixed to whole cortex and various reference tissue models were fitted to the data. Finally, a simplified reference tissue model (SRTM) corrected for nonspecific binding using plasma input data (SRTMpl_corr) was investigated. Correlations between reference tissue models (including SRTMpl_corr) and the plasma input model were calculated. Monte Carlo simulations indicated that low-specific binding results in decreased accuracy and reproducibility. In this respect, the SRTM and SRTMpl_corr performed relatively well. Varying blood volume had no effect on performance. In the clinical evaluation, SRTMpl_corr and SRTM had the highest correlations with the plasma input model (R2=0.82 and 0.78, respectively). SRTMpl_corr is optimal when an arterial plasma input curve is available. Simplified reference tissue model is the best alternative when no plasma input is available.

Development of a Tracer Kinetic Plasma Input Model for (R)-[11C]PK11195 Brain Studies

(R)-[(11)C]PK11195 ([1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl]-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor, which, in the brain, is mainly expressed on activated microglia. Using both clinical studies and Monte Carlo simulations, the aim of this study was to determine which tracer kinetic plasma input model best describes (R)-[(11)C]PK11195 kinetics. Dynamic positron emission tomography (PET) scans were performed on 13 subjects while radioactivity in arterial blood was monitored online. Discrete blood samples were taken to generate a metabolite corrected plasma input function. One-tissue, two-tissue irreversible, and two-tissue reversible compartment models, with and without fixing K(1)/k(2) ratio, k(4) or blood volume to whole cortex values, were fitted to the data. The effects of fixing parameters to incorrect values were investigated by varying them over a physiologic range and determining accuracy and reproducibility of binding potential and volume of distribution using Monte Carlo simulations. Clinical data showed that a two-tissue reversible compartment model was optimal for analyzing (R)-[(11)C]PK11195 PET brain studies. Simulations showed that fixing the K(1)/k(2) ratio of this model provided the optimal trade-off between accuracy and reproducibility. It was concluded that a two-tissue reversible compartment model with K(1)/k(2) fixed to whole cortex value is optimal for analyzing (R)-[(11)C]PK11195 PET brain studies.

A unique method by which to quantitate synchrony with equilibrium radionuclide angiography

Cardiac resynchronization therapy (CRT) improves symptoms and the survival rate in patients with advanced heart failure by improving synchrony. However, CRT is not always successful, is costly, and is applied without individualization. There is no specific measure of synchrony. The goal of this study was to analyze new quantitative parameters of synchrony and compare them with established measures. Equilibrium radionuclide angiography, phase angle (Ø), and amplitude quantitate regional contraction timing and magnitude and are the basis for new synchrony (S) and entropy (E) parameters. S is the vector sum of all amplitudes based on the angular distribution of Ø divided by the scalar sum of the length of all vectors. Complete S equals 1, and its absence equals 0. E measures the disorder in the region of interest, is 1 with random contraction and 0 with full synchrony, and differentiates among differing contraction patterns. Left ventricular S and E were measured in 22 normal equilibrium radionuclide angiography studies, where regions of interest were drawn from the left ventricle, left atrium, and background to analyze model ventricles with normal wall motion (N), ventricles with aneurysm (An), ventricles with severe diffuse dysfunction (Diff), and ventricles with severe regional dysfunction (Reg). The new S and E parameters were highly reproducible and well differentiated among N, An, Diff, and Reg, which were not separated by SD Ø (SD of ventricular phase), which has gained popularity as a measure of synchrony. Unique scintigraphic parameters for the evaluation of ventricular synchrony were derived, and their added value was determine compared with established measures. Indications for pacemaker therapy now include the treatment of severe congestive heart failure (CHF). Atrial triggered biventricular pacemakers reduce CHF symptoms and prolong life in patients with cardiomyopathy, severe CHF, left ventricular (LV) ejection fraction (EF) lower than 35%, and QRS greater than 120 milliseconds. Such pacing, or cardiac resynchronization therapy (CRT), seeks to reduce the heterogeneity and increase the synchrony of ventricular activation, conduction, and contraction. CRT has improved hemodynamics, increased exercise tolerance, reduced symptoms and the need for hospitalization, reversed ventricular remodeling, and reduced the all-cause mortality rate in CHF. However, CRT is costly, fails to improve symptoms or activity level in more than 30% of patients, and is applied blindly without individualization or consideration of lead placement sight. A variety of echocardiographic methods have sought to measure synchrony and its serial changes with CRT. A recent study presented evidence of the poor reproducibility of several widely applied echocardiographic measurements by which to determine ventricular synchrony. Magnetic resonance imaging has excellent resolution of regional wall motion and has been applied to assess ventricular synchrony and its response to pacing therapy. However, these methods are complex and are not well established or widely available, and magnetic resonance imaging has not been widely applied after pacing. An accurate and reproducible method is needed by which to objectively measure regional ventricular synchrony. Phase image analysis, a functional method based on the first Fourier harmonic fit of the gated blood pool time versus radioactivity curve, generates the parameters of amplitude (A), which parallels the extent of regional ventricular contraction or stroke volume, and phase angle (Ø), which represents the timing of regional contraction. It was applied early with demonstrated reproducibility to show the linkage between electrical and mechanical dyssynchrony and to characterize the contraction pattern in heart failure and its alteration with CRT. The SD of ventricular Ø, applied as a marker of synchrony, has been shown to demonstrate the beneficial effects of biventricular pacing, and its strong prognostic value has been shown in patients with congestive cardiomyopathy and CHF, superior to LVEF. The SD Ø may not be optimal for synchrony evaluation. We sought improved, more sensitive parameters to better differentiate synchrony among the spectrum of possible patterns of dyssynergy. We derived, initially evaluated, and here present new synchrony (S) and entropy (E) parameters, based on the phase method, to quantitate regional and global ventricular synchrony and applied them in simulation and clinical protocols.

An animal model for venous thrombosis and spontaneous pulmonary embolism

An animal model. To test the natural sequence of venous thrombosis and pulmonary thromboembolism experimentally. Veterans Administration Hospital, USA. In dogs, a venous thrombosis was induced in a isolated segment of the internal jugular vein by a 5 min exposure to sodium morrhuate and then re-establishing venous patency. A tracer, (125)I human fibrinogen, was administered through another vein 1 h prior to the end of each experiment when a blood sample, the venous thrombus, and the lungs were removed. Thrombi were described by age, weight, histology, and fibrin uptake (thrombus to blood radioactivity ratio, g/g). Pulmonary emboli (PE) were identified by autoradiography of lung slices or by microscopic examination of lung sections. Venous thrombosis developed in all experiments, duration 1-64, median 5 h (n=12). Histologically, younger thrombi were characterized by platelet aggregates surrounded by polymorphonuclear leukocytes (PMN), and uniform fibrin deposit; the older thrombi by platelet ghost cells, fewer PMN leukocytes, and broken fibrin strands and loops (n=6). Pulmonary thromboemboli were imaged as 'hot spots' in six of six experiments in which lung slices were autoradiographed and were identified microscopically in six of six experiments in which lung sections were taken. The number of PE diagnosed microscopically did not correlate with the age of the corresponding thrombus but was directly related to fibrin uptake (n=5, r=0.99, P<0.01). An animal model for venous thrombosis that generates pulmonary thromboembolism has been described.

Detection of cerebrospinal fluid leakage in intracranial hypotension with radionuclide cisternography and blood activity monitoring

Radionuclide cisternography is an indispensable examination to detect cerebrospinal fluid (CSF) leakage in patients suspected of having spontaneous intracranial hypotension (SIH). However, it sometimes fails to demonstrate the site of CSF leakage, and in such cases, early bladder visualization is utilized for the diagnosis of SIH as an indirect finding. The aim of this work is to improve the diagnostic ability of radionuclide cisternography and to reevaluate the reliability of early bladder visualization as an indirect finding of CSF leakage. We obtained serial images during the first hour after injection as well as the following time points in 4 patients with SIH and 5 with normal pressure hydrocephalus (NPH) as a control. We also performed blood sampling over time to measure blood radioactivity concentrations. All 4 patients with SIH demonstrated leakage, 2 of 4 within one hour after injection. Bladder visualization was observed falsely in 4 of 5 patients with NPH, considered to be the result of a lumbar puncture complication. In this false bladder visualization, blood radioactivity showed a more rapid raise and fall than in CSF leakage of SIH. The combination of radionuclide cisternography, including early time points and blood sampling, may enable accurate diagnosis of SIH.

Reliability of one-point blood sampling method for calculating input function in Na18F PET

Conventional methods of quantitative Na18F positron emission tomography require multiple arterial blood sampling in order to obtain the input function, and the procedures are invasive and complicated. This study aims to establish a simplified and reliable technique for obtaining the input function. Multiple arterial blood sampling was performed on 12 persons. The time point for one-point sampling was determined as the time when (1) the plasma radioactivity obtained showed the highest correlation to the real integrated value, which was calculated from the input function, and (2) the coefficient of variation of the real integrated value divided by plasma radioactivity obtained at each time point became the minimum. Scaling factors were obtained in order to estimate the plasma radioactivity at each time point, and a reference table was produced in order to estimate the input function. The optimal timing for one-point sampling was 12 min after intravenous injection of Na18F. The estimated integrated value obtained from arterial blood sampling at 12 min and the reference table was highly correlated with the real integrated value (P<0.001). Levels of plasma radioactivity of arterial blood and venous blood were almost the same at 12 and 40 min after Na18F injection. Percentage errors in the estimation of the integrated value were 2.63% (n=12) for the arterial blood collected at 12 min and 4.14% (n=12) for the venous blood collected at 30 min. This simplified method is clinically applicable and would replace traditional methods that require multiple blood sampling.

Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography

Numerous knockout mouse studies have revealed that P-glycoprotein (P-gp) significantly limits drug distribution across the mouse blood-brain barrier (BBB). To determine the importance of P-gp at the human BBB, we developed a state-of-the-art, noninvasive, quantitative imaging technique to measure P-gp activity by use of carbon 11-labeled verapamil as the P-gp substrate and cyclosporine (INN, ciclosporin) as the P-gp inhibitor. In brief, 11C-verapamil (approximately 0.2 mCi/kg) was administered to healthy volunteers (n = 12 [6 women and 6 men]) as an intravenous infusion over a period of approximately 1 minute before and after at least a 1-hour infusion of cyclosporine (2.5 mg x kg(-1) x h(-1)). Arterial blood samples and brain positron emission tomography images were obtained at frequent intervals for 45 minutes. Both blood and plasma radioactivity contents were determined in each verapamil sample. The content of verapamil and its metabolites in the 20- and 45-minute plasma samples was determined by a rapid solid-phase extraction method. The brain uptake of 11C-radioactivity (brain area under the curve [AUCbrain ]/blood area under the curve [AUCblood]) was determined in the presence and absence of cyclosporine. The AUCbrain/AUCblood ratio of 11C-radioactivity was increased by 88% +/- 20% (1.02 +/- 0.18 versus 0.55 +/- 0.10, P < .001) in the presence of cyclosporine (mean blood concentration, 2.8 +/- 0.4 micromol/L) without affecting 11C-verapamil metabolism or plasma protein binding. The corresponding increases for the brain white and gray matter were 84% +/- 13% and 84% +/- 18%, respectively. This is the first time that P-gp activity at the human BBB has been measured. The modest inhibition of human BBB P-gp by cyclosporine has implications for P-gp-based drug interactions at the human BBB. Our method for imaging P-gp activity can be used to identify multidrug-resistant tumors or to determine the contribution of P-gp polymorphism, inhibition, or induction to interindividual variability in drug response.

Biodistribution and excretion of radioactivity after the administration of 166Ho-chitosan complex (DW-166HC) into the prostate of rat

The objective of this study was to determine the fate of the 166Ho-chitosan complex (DW-166HC) in rats by examining its absorption, distribution and excretion after administration into the prostate. About 100 microCi of DW-166HC [containing 0.1875 mg of Ho(NO3)3.5H2O and 0.25 mg of chitosan] was administered intraprostatically. The level of radioactivity in blood, urinary and faecal excretion, and radioactivity distribution were examined. To determine the effect of chitosan in DW-166HC, 166Ho nitrate alone [0.1875 mg of Ho(NO3)3.5H2O] was administered into the prostate of male rats, and radioactivity distribution was examined using whole-body autoradiography. After administration of DW-166HC into the prostate, cumulative urinary and faecal excretion over the period 0-72 h was 0.35% and 0.11%, respectively. The radioactivity at the administration site was extremely high at all time points up to 144 h (>98% of injected dose). The small amount of radioactivity which did transfer from the administration site distributed mainly to the liver, spleen, kidney cortex and bone. Compared with the DW-166HC group, the group that received 166Ho nitrate alone displayed three- to fourfold higher levels of radioactivity in the main tissues, including liver, spleen, kidney cortex and bone, at 24 h after administration (P < 0.05). The results of this study show clearly that most of the administered DW-166HC remained at the administration site. It is concluded that the chitosan complex may be used to retain 166Ho within a limited area in cancer of the prostate.

Sodium pertechnetate (Na99mTcO4) biodistribution in mice exposed to cigarette smoke

BackgroundThe biological effects of cigarette smoke are not fully known. To improve our understanding of the action of various chemical agents, we investigated the biodistribution of sodium pertechnetate (Na99mTcO4) in mice exposed to cigarette smoke.MethodsFifteen BALB/c male mice were exposed to the smoke of nine whole commercial cigarettes per day, 3 times/day, for up to 10 days to whole body exposure in a chamber. A control group of 5 BALB/c male mice was sham-smoked. One day later, the exposed and control groups of mice received (7.4 MBq/0.3 ml) of Na99mTcO4 before being killed at 30 min. Bones, brain, heart, intestine, kidney, liver, lungs, muscle, pancreas, spleen, stomach, testis and thyroid were weighed and these organs and blood radioactivity recorded with a gamma counter. The percentage per gram of tissue of injected dose (%ID/g) was determined for each organ.ResultsCigarette smoke significantly decreased (p < 0.05) the %ID/g in red blood cells, bone, kidney, lung, spleen, stomach, testis and thyroid of the exposed mice.ConclusionThe toxic effects of cigarette smoke reduced the Na99mTcO4 biodistribution.