RESUMEN
Clinical failure of novel drugs is often related to their rapid metabolism and excretion. This highlights the importance of elucidation of their pharmacokinetic profile already at the preclinical stage of drug development. Triapine, the most prominent representative of α-N-heterocyclic thiosemicarbazones, was investigated in more than 30 clinical phase I/II trials, but the results against solid tumors were disappointing. Recent investigations from our group suggested that this is, at least partially, based on the fast metabolism and excretion. In order to establish more detailed structure/activity/metabolism relationships, herein a panel of 10 different Triapine derivatives was investigated for their metabolic pathways. From the biological point of view, the panel consists of terminally dimethylated thiosemicarbazones with nanomolar IC50 values, derivatives with micromolar cytotoxicities comparable to Triapine and a completely inactive representative. To study the oxidative metabolism, a purely instrumental approach based on electrochemistry/mass spectrometry was applied and the results were compared to the data obtained from microsomal incubations. Overall, the investigated thiosemicarbazones underwent the phase I metabolic reactions dehydrogenation, hydroxylation, oxidative desulfuration (to semicarbazone and amidrazone) and demethylation. Notably, dehydrogenation resulted in a ring-closure reaction with formation of thiadiazoles. Although strong differences between the metabolic pathways of the different thiosemicarbazones were observed, they could not be directly correlated to their cytotoxicities. Finally, the metabolic pathways for the most cytotoxic compound were elucidated also in tissues collected from drug-treated mice, confirming the data obtained by electrochemical oxidation and microsomes. In addition, the in vivo experiments revealed a very fast metabolism and excretion of the compound. Graphical abstract Structure/activity/metabolisation relationships for 10 anticancer thiosemicarbazones were established using electrochemical oxidation coupled to mass spectrometry (EC-MS) and human liver microsomes analyzed by LC-MS.
Asunto(s)
Redes y Vías Metabólicas , Piridinas/metabolismo , Tiosemicarbazonas/metabolismo , Animales , Humanos , Hidroxilación , Riñón/metabolismo , Hígado/metabolismo , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Oxidación-Reducción , Piridinas/análisis , Piridinas/sangre , Piridinas/orina , Tiosemicarbazonas/análisis , Tiosemicarbazonas/sangre , Tiosemicarbazonas/orinaRESUMEN
The ribonucleotide reductase inhibitor and radiosensitizer triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), NSC 663249) is clinically being evaluated via the intravenous (IV) route for the treatment of cervical and vulvar cancer in combination with primary cisplatin chemoradiation. The need for a 2-h infusion and frequent administration of triapine is logistically challenging, prompting us to pursue oral (PO) administration. In support of the clinical trial investigating oral triapine in combination with chemoradiation, we developed and validated a novel LC-MS/MS assay for the quantification of triapine in 50µL human plasma. After protein precipitation, chromatographic separation of the supernatant was achieved with a Shodex ODP2 column and an isocratic acetonitrile-water mobile phase with 10% ammonium acetate. Detection with an ABI 4000 mass spectrometer utilized electrospray positive mode ionization. The assay was linear from 3 to 3,000ng/mL and proved to be accurate (97.1-103.1%) and precise (<7.4% CV), and met the U.S. FDA guidance for bioanalytical method validation. This LC-MS/MS assay will be an essential tool to further define the pharmacokinetics and oral bioavailability of triapine.
Asunto(s)
Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/química , Plasma/química , Piridinas/sangre , Piridinas/química , Ribonucleótido Reductasas/antagonistas & inhibidores , Tiosemicarbazonas/sangre , Tiosemicarbazonas/química , Bioensayo/métodos , Cromatografía Liquida/métodos , Humanos , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
Triapine has been investigated as anticancer drug in multiple clinical phase I/II trials. Although promising anti-leukemic activity was observed, Triapine was ineffective against solid tumors. The reasons are currently widely unknown. The biological activity of Triapine is strongly connected to its iron complex (Fe-Triapine) which is pharmacologically not investigated. Here, novel analytical tools for Triapine and Fe-Triapine were developed and applied for cell extracts and body fluids of treated mice. Triapine and its iron complex showed a completely different behavior: for Triapine, low protein binding was observed in contrast to fast protein adduct formation of Fe-Triapine. Notably, both drugs were rapidly cleared from the body (serum half-life time <1h). Remarkably, in contrast to Triapine, where (in accordance to clinical data) basically no renal excretion was found, the iron complex was effectively excreted via urine. Moreover, no Fe-Triapine was detected in serum or cytosolic extracts after Triapine treatment. Taken together, our study will help to further understand the biological behavior of Triapine and its Fe-complex and allow the development of novel thiosemicarbazones with pronounced activity against solid tumor types.
Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias del Colon/tratamiento farmacológico , Complejos de Coordinación/farmacocinética , Hierro/farmacocinética , Piridinas/farmacocinética , Tiosemicarbazonas/farmacocinética , Animales , Antineoplásicos/sangre , Antineoplásicos/orina , Proteínas Sanguíneas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Neoplasias del Colon/patología , Complejos de Coordinación/sangre , Complejos de Coordinación/orina , Femenino , Semivida , Hierro/sangre , Hierro/orina , Masculino , Ratones , Ratones Endogámicos BALB C , Unión Proteica , Piridinas/sangre , Piridinas/orina , Tiosemicarbazonas/sangre , Tiosemicarbazonas/orina , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Copper(II)bis(thiosemicarbazonato) complexes such as [(64)Cu]Cu-ATSM continue to be investigated for positron emission tomography (PET) imaging of tumour hypoxia. However, the currently proposed mechanisms for the mode of action of these complexes are unable to account fully for their observed biological behaviour. In order to examine the roles of the copper metal and the ligand, we designed a pair of (123)I/(64)Cu-copper bis(thiosemicarbazonates), radiolabelled at either the metal or at the ligand. In vitro cellular retention studies of the orthogonal pair demonstrate for the first time that retention under hypoxia involves dissociation of the copper bis(thiosemicarbazone) complex, consistent with the previously suggested mechanism of reductive trapping of copper. In contrast, in vivo biodistribution and dynamic PET/SPECT imaging of the orthogonally labelled complexes underline our previous findings for [(64)Cu]Cu-ATSM and [(64)Cu]Cu-acetate, providing further support for the important contribution of copper metabolism in the in vivo hypoxia selectivity of Cu-ATSM. This dual radiolabelling approach may find applications for determining the speciation of other metal complexes in vitro and in vivo.
Asunto(s)
Radioisótopos de Cobre/farmacocinética , Hipoxia/diagnóstico , Neoplasias/diagnóstico , Compuestos Organometálicos/farmacocinética , Tomografía de Emisión de Positrones , Tiosemicarbazonas/farmacocinética , Tomografía Computarizada de Emisión de Fotón Único , Animales , Línea Celular , Complejos de Coordinación , Radioisótopos de Cobre/sangre , Radioisótopos de Cobre/química , Femenino , Humanos , Hipoxia/complicaciones , Hipoxia/metabolismo , Ratones , Neoplasias/complicaciones , Neoplasias/metabolismo , Compuestos Organometálicos/sangre , Compuestos Organometálicos/química , Tiosemicarbazonas/sangre , Tiosemicarbazonas/química , Distribución TisularRESUMEN
Triapine is an inhibitor of ribonucleotide reductase (RNR). Studies have shown that triapine significantly decreases the activity of RNR and enhanced the radiation-mediated cytotoxicity in cervical and colon cancer. In this work, we have developed and validated a selective and sensitive LC-MS/MS method for the determination of triapine in human plasma. In this method, 2-[(3-fluoro-2-pyridinyl)methylene] hydrazinecarbothioamide (NSC 266749) was used as the internal standard (IS); plasma samples were prepared by deproteinization with acetonitrile; tripaine and the IS were separated on a Waters Xbridge Shield RP18 column (3.5 µm; 2.1 × 50 mm) using a mobile phase containing 25.0% methanol and 75.0% ammonium bicarbonate buffer (10.0 mM, pH 8.50; v/v); column eluate was monitored by positive turbo-ionspray tandem mass spectrometry; and quantitation of triapine was carried out in multiple-reaction-monitoring mode. The method developed had a linear calibration range of 0.250-50.0 ng/mL with correlation coefficient of 0.999 for triapine in human plasma. The IS-normalized recovery and the IS-normalized matrix factor of triapine were 101-104% and 0.89-1.05, respectively. The accuracy expressed as percentage error and precision expressed as coefficient of variation were ≤±6 and ≤8%, respectively. The validated LC-MS/MS method was applied to the measurement of triapine in patient samples from a phase I clinical trial.
Asunto(s)
Cromatografía Liquida/métodos , Inhibidores Enzimáticos/sangre , Piridinas/sangre , Espectrometría de Masas en Tándem/métodos , Tiosemicarbazonas/sangre , Humanos , Ribonucleótido Reductasas/antagonistas & inhibidoresRESUMEN
Novel thiosemicarbazone metal chelators are extensively studied anti-cancer agents with marked and selective activity against a wide variety of cancer cells, as well as human tumor xenografts in mice. This study describes the first validated LC-MS/MS method for the simultaneous quantification of 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT) and its main metabolites (E/Z isomers of the semicarbazone structure, M1-E and M1-Z, and the amidrazone metabolite, M2) in plasma. Separation was achieved using a C18 column with ammonium formate/acetonitrile mixture as the mobile phase. Plasma samples were treated using solid-phase extraction on 96-well plates. This method was validated over the concentration range of 0.18-2.80 µM for Bp4eT, 0.02-0.37 µM for both M1-E and M1-Z, and 0.10-1.60 µM for M2. This methodology was applied to the analysis of samples from in vivo experiments, allowing for the concentration-time profile to be simultaneously assessed for the parent drug and its metabolites. The current study addresses the lack of knowledge regarding the quantitative analysis of thiosemicarbazone anti-cancer drugs and their metabolites in plasma and provides the first pharmacokinetic data on a lead compound of this class.
Asunto(s)
Antineoplásicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Tiosemicarbazonas/sangre , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Masculino , Proyectos Piloto , Ratas , Ratas Wistar , Tiosemicarbazonas/metabolismo , Tiosemicarbazonas/farmacocinéticaRESUMEN
PURPOSE: The purpose of this study was to develop a population pharmacokinetic (PK) model for 3-AP, to evaluate the effect of ABCB1 polymorphisms on the pharmacokinetic profile of 3-AP, and to assess the relationship between 3AP disposition and patient covariates. METHODS: A total of 40 patients with advanced cancer from two phase 1 studies were included in the population PK model building. Patients received 3-AP 25-105 mg/m(2) IV on day 1. 3-AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-h period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed-effects modeling approach using the NONMEM system. RESULTS: 3-AP pharmacokinetics were described as a 3-compartment model with first-order elimination, with one compartment representing the plasma and another representing erythrocyte concentrations. Gender was associated with volume of distribution, in which women had a lower V2. The number of cycles administered was associated with clearance; those with decreased clearance were more likely to receive less than 2 cycles before going off study. CONCLUSION: This study suggests that monitoring 3-AP plasma concentrations in the first cycle and dose adjustment in those with decreased clearance may be helpful in decreasing toxicity associated with the 3-AP.
Asunto(s)
Modelos Biológicos , Neoplasias/metabolismo , Piridinas/farmacocinética , Tiosemicarbazonas/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Sangre/metabolismo , Superficie Corporal , Ensayos Clínicos Fase I como Asunto , Simulación por Computador , Eritrocitos/metabolismo , Femenino , Genotipo , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Estadísticos , Neoplasias/tratamiento farmacológico , Piridinas/administración & dosificación , Piridinas/sangre , Piridinas/metabolismo , Caracteres Sexuales , Tiosemicarbazonas/administración & dosificación , Tiosemicarbazonas/sangre , Tiosemicarbazonas/metabolismoRESUMEN
The aim of this study was to develop and validate HPLC methods for the determination in plasma of two novel thiosemicarbazone anti-tumour drugs developed in our laboratories (Dp44mT and N4mT). The appropriate separations were achieved using a HS F5 HPLC column with the mobile phase composed of a mixture of either acetate buffer/EDTA or EDTA and acetonitrile (62:38 and 50:50, v/v, respectively). The plasma samples were pretreated with SPE (phenyl and C18, respectively). Furthermore, these methods were successfully applied to in vitro plasma stability experiments. The investigation has clearly shown that both thiosemicarbazones are markedly more stable in plasma than their aroylhydrazone forerunners.
Asunto(s)
Antineoplásicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Naftalenos/sangre , Tiosemicarbazonas/sangre , Análisis de Varianza , Animales , Interpretación Estadística de Datos , Estabilidad de Medicamentos , Humanos , Isoniazida/análogos & derivados , Isoniazida/análisis , Isoniazida/metabolismo , Piridoxal/análogos & derivados , Piridoxal/análisis , Piridoxal/metabolismo , Conejos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , PorcinosRESUMEN
UNLABELLED: A water-soluble glucose conjugate of the hypoxia tracer 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) was synthesized and radiolabeled (64Cu-ATSE/A-G). Here we report our initial biological experiments with 64Cu-ATSE/A-G and compare the results with those obtained for 64Cu-ATSM and 18F-FDG. METHODS: The uptake of 64Cu-ATSE/A-G and 64Cu-ATSM into HeLa cells in vitro was investigated at a range of dissolved oxygen concentrations representing normoxia, hypoxia, and anoxia. Small-animal PET with 64Cu-ATSE/A-G was performed in male BDIX rats implanted with P22 syngeneic carcinosarcomas. Images of 64Cu-ATSM and 18F-FDG were obtained in the same model for comparison. RESULTS: 64CuATSE/A-G showed oxygen concentration-dependent uptake in vitro and, under anoxic conditions, showed slightly lower levels of cellular uptake than 64Cu-ATSM; uptake levels under hypoxic conditions were also lower. Whereas the normoxic uptake of 64Cu-ATSM increased linearly over time, 64Cu-ATSE/A-G uptake remained at low levels over the entire time course. In the PET study, 64CuATSE/A-G showed good tumor uptake and a biodistribution pattern substantially different from that of each of the controls. In marked contrast to the findings for 64Cu-ATSM, renal clearance and accumulation in the bladder were observed. 64Cu-ATSE/A-G did not display the characteristic brain and heart uptake of 18F-FDG. CONCLUSION: The in vitro cell uptake studies demonstrated that 64Cu-ATSE/A-G retained hypoxia selectivity and had improved characteristics when compared with 64Cu-ATSM. The in vivo PET results indicated a difference in the excretion pathways, with a shift from primarily hepatointestinal for 64Cu-ATSM to partially renal with 64Cu-ATSE/A-G. This finding is consistent with the hydrophilic nature of the glucose conjugate. A comparison with 18F-FDG PET results revealed that 64Cu-ATSE/A-G was not a surrogate for glucose metabolism. We have demonstrated that our method for the modification of Cu-bis(thiosemicarbazonato) complexes allows their biodistribution to be modified without negating their hypoxia selectivity or tumor uptake properties.
Asunto(s)
Radioisótopos de Cobre/química , Glucosa/química , Hipoxia/diagnóstico por imagen , Tiosemicarbazonas/química , Tiosemicarbazonas/metabolismo , Animales , Carcinosarcoma/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Células HeLa , Humanos , Hipoxia/metabolismo , Masculino , Oxígeno/metabolismo , Tomografía de Emisión de Positrones , Ratas , Tiosemicarbazonas/sangreRESUMEN
PURPOSE: A Phase I study in patients with advanced cancer was conducted to determine the safety, pharmacokinetics, and maximum tolerated dose of Triapine, a new, potent small-molecule inhibitor of ribonucleotide reductase. EXPERIMENTAL DESIGN: Triapine was administered by 2-h i.v. infusion daily for 5 days. Courses were repeated every 4 weeks. The starting dose was 5 mg/m(2)/day, but was reduced to 2 mg/m(2)/day after the first patient developed a hepatic adverse event. The dose was subsequently escalated using a modified Fibonacci scheme in cohorts of 3-6 patients. After the 12 mg/m(2)/day dose level, the study design was amended to permit 100% dose escalation in single-patient cohorts until the first episode of a drug-related grade 2 adverse event or dose-limiting toxicity (DLT). On reaching a dose of 96 mg/m(2)/day, the study was amended to determine the safety and tolerability of the 96-mg/m(2) dose administered daily for 5 days every 2 weeks in an expanded cohort of patients. RESULTS: A total of 32 patients received treatment. During the dose escalation phase of the study, grade 2-4 drug-related adverse events were first observed at a dose of 96 mg/m(2)/day. Grade 3-4 leukopenia was the primary toxicity observed among four patients treated at this dose, which occurred in the week after treatment and resolved to grade 1 or lower by day 15. Fifteen patients were subsequently treated at the 96-mg/m(2) dose, daily for 5 days, with courses repeated every 2 weeks. The most common nonhematological toxicities for the latter schedule were asthenia, fever, nausea and vomiting, mucositis, decreased serum bicarbonate, and hyperbilirubinemia, and were predominantly grade 1-2 in severity and rapidly reversible. Hematological toxicity on the every-other-week schedule consisted of leukopenia (grade 4 in 93% in at least one course) and anemia (grade 2 in 71%, grade 3 in 22%). Thrombocytopenia was less common and was grade 3-4 in severity in only 22%. Triapine showed linear pharmacokinetic behavior although interpatient variability was relatively high. Peak concentrations at the 96-mg/m(2)/day dose averaged 8 microM, and the mean elimination T(1/2) ranged from 35 min to 3 h, with a median value of approximately 1 h. Cumulative urinary recovery averaged 1-3% of the administered dose, suggesting that the elimination of Triapine was primarily through metabolism. No partial or complete responses were observed. CONCLUSIONS: Triapine administered at a dose of 96 mg/m(2) by 2-h i.v. infusion daily for 5 days on an every-other-week schedule demonstrates an acceptable safety profile. Serum concentrations that surpass in vitro tumor growth-inhibitory concentrations are achieved for brief periods of time each day and are sufficient to produce myelosuppression, the expected consequence of ribonucleotide reductase inhibition. Phase II trials are indicated but will proceed with a daily-for-4-days schedule to reduce the incidence of grade 4 leukopenia. The safety profile also supports the initiation of Phase I combination trials with other anticancer agents.
Asunto(s)
Neoplasias/tratamiento farmacológico , Piridinas/sangre , Piridinas/toxicidad , Tiosemicarbazonas/sangre , Tiosemicarbazonas/toxicidad , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/toxicidad , Astenia/inducido químicamente , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/toxicidad , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/patología , Piridinas/administración & dosificación , Ribonucleótido Reductasas/antagonistas & inhibidores , Tiosemicarbazonas/administración & dosificaciónRESUMEN
62Cu(T1/2 = 9.8 min) is a generator-produced positron-emitting radionuclide with a half-life amenable to blood-pool imaging with PET. Three bifunctional chelates [cyclic anhydride of diethylenetriaminepentaacetic acid (cDTPAA), 6-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane-N,N ',N", N"'-tetraacetic acid (BAT), and p-carboxyethylphenylglyoxal-bis-(4N-methyl-thiosemicarbazone (CE-DTS)] were conjugated to HSA and labeled with 67Cu. The labeling efficiency of 67Cu-DTS-HSA was > 90%, whereas the labeling yields of 67Cu-DTPA-HSA and 67Cu-benzyl-TETA-HSA were less than 70%. Blood clearance and biodistribution of these three 67Cu-labeled conjugates were determined in rats. Of the three 67Cu-labeled bifunctional chelate-HSA conjugates, 67Cu-benzyl-TETA-HSA remained in the blood pool the longest, achieving stable blood levels at times longer than 24 h post-injection. The 67Cu radioactivity cleared the blood within 60 min post-injection of 67Cu-DTS-HSA, and within 10 min after administration of 67Cu-DTPA-HSA, indicating the dissociation of Cu2+ from these conjugates. Copper-labeled DTS-HSA achieved stable blood concentrations for at least 30 min post-injection and was therefore evaluated as a vascular imaging agent. DTS-HSA and benzyl-TETA-HSA were labeled with 62Cu and administered to a dog for blood-pool imaging using PET. Images were nearly identical to an image taken after administration of C15O. Because of the high labeling efficiency, DTS-HSA can be labeled with 62Cu without purification, making it more practical than 62Cu-benzyl-TETA-HSA as a blood-pool imaging agent.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Radioisótopos de Cobre , Corazón/diagnóstico por imagen , Compuestos Organometálicos/sangre , Albúmina Sérica , Animales , Quelantes/química , Quelantes/farmacocinética , Cobre/sangre , Cobre/química , Cobre/farmacocinética , Vasos Coronarios/diagnóstico por imagen , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/farmacocinética , Diagnóstico por Imagen/métodos , Perros , Estabilidad de Medicamentos , Femenino , Compuestos Heterocíclicos/sangre , Compuestos Heterocíclicos/farmacocinética , Masculino , Compuestos Organometálicos/farmacocinética , Ácido Pentético/análisis , Ácido Pentético/química , Ácido Pentético/farmacocinética , Ratas , Ratas Sprague-Dawley , Albúmina Sérica/análisis , Albúmina Sérica/química , Albúmina Sérica/farmacocinética , Albúmina Sérica Humana , Tiosemicarbazonas/sangre , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Distribución Tisular , Tomografía Computarizada de EmisiónRESUMEN
The partitioning of [67Cu]Cu-PTSM between plasma and red blood cells (RBC) was investigated in vitro with human, rat, pig and dog blood. Significant inter-species variability is observed in the plasma/RBC partitioning of tracer, ranging from c. 75% association with plasma in human blood to only c. 35% association with plasma in dog blood. This inter-species difference results from selective association of the [67Cu]Cu-PTSM tracer with human albumin. When [67Cu]Cu-PTSM is mixed with human blood in vitro at 37 degrees C the fraction of 67Cu-radioactivity that remains plasma-associated decreases with time, apparently due to the expected intracellular decomposition of the Cu-PTSM complex by RBC; however, this process is sufficiently slow that it should have limited influence on [62Cu]CU-PTSM biodistribution following intravenous injection. Octanol extraction of blood was found to be an effective technique for quantitating the amount of intact [67Cu]Cu-PTSM complex in blood samples. When imaging with [62Cu]Cu-PTSM, octanol extraction may be useful for determining the [62Cu]Cu-PTSM content of arterial blood samples to establish a true radiotracer input function.
Asunto(s)
Compuestos Organometálicos/sangre , Tiosemicarbazonas/sangre , Animales , Radioisótopos de Cobre , Perros , Eritrocitos/metabolismo , Humanos , Masculino , Compuestos Organometálicos/farmacocinética , Ratas , Ratas Sprague-Dawley , Solventes , Porcinos , Tiosemicarbazonas/farmacocinética , Distribución TisularRESUMEN
62Cu-Labeling of human serum albumin-dithiosemicarbazone (HSA-DTS) conjugate was performed using a newly developed 62Zn/62Cu generator system. HSA-DTS was easily labeled with 62Cu, by simple mixing with 62Cu-generator eluate. In vivo blood clearance of 62Cu-HSA-DTS was similar to 131I-HSA, indicating the high applicability of 62Cu-HSA-DTS as a method for plasma volume measurement. In a positron emission tomography study of a dog, a clear plasma pool image of the head region was obtained.