RESUMO
The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 5 acyl sarcosines and 9 sarcosinate salts as used in cosmetics; all of these ingredients are reported to function in cosmetics as hair conditioning agents and most also can function as surfactants-cleansing agents. The ingredients reviewed in this assessment are composed of an amide comprising a fatty acyl residue and sarcosine and are either free acids or simple salts thereof. The Panel relied on relevant new data, including concentration of use, and considered data from the previous Panel report, such as the reaction of sarcosine with oxidizing materials possibly resulting in nitrosation and the formation of N-nitrososarcosine. The Panel concluded that these ingredients are safe as used in cosmetics when formulated to be non-irritating, but these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed.
Assuntos
Cosméticos/toxicidade , Irritantes/toxicidade , Sarcosina/toxicidade , Tensoativos/toxicidade , Animais , Qualidade de Produtos para o Consumidor , Cosméticos/química , Cosméticos/farmacocinética , Humanos , Irritantes/química , Irritantes/farmacocinética , Compostos Nitrosos/química , Medição de Risco , Sais , Sarcosina/química , Sarcosina/farmacocinética , Tensoativos/química , Tensoativos/farmacocinéticaRESUMO
BACKGROUND & AIMS: Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) and positron emission tomography (PET). METHODS: Nine healthy participants and eight patients with varying degrees of cholestasis were examined with 11C-CSar PET and measurement of arterial and hepatic venous blood concentrations of 11C-CSar. RESULTS: Results are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20-1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13-0.91) in patients. In healthy participants, the rate constant for secretion of 11C-CSar from hepatocytes to bile was 0.36 (0.30-0.62)min-1, 20 times higher than the rate constant for backflux from hepatocytes to blood (0.02, 0.005-0.07min-1). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006-0.27)min-1, 2.3times higher than the rate constant for backflux to blood (0.05, 0.04-0.09). The increased backflux did not fully normalize exposure of the hepatocyte to bile acids as mean hepatocyte residence time of 11C-CSar was 2.5 (1.6-3.1)min in healthy participants and 6.4 (3.1-23.7)min in patients. The rate constant for transport of 11C-CSar from intrahepatic to extrahepatic bile was 0.057 (0.023-0.11)min-1 in healthy participants and only slightly reduced in patients 0.039 (0.017-0.066). CONCLUSIONS: This first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease. LAY SUMMARY: Positron emission tomography (PET) using the radiolabelled bile acid (11C-CSar) enabled quantification of the individual steps of the hepatic transport of bile acids from blood to bile in man. Cholestasis reduced uptake and secretion and increased backflux to blood. These findings improve our understanding of cholestatic liver diseases and may support therapeutic decisions. CLINICAL TRIAL REGISTRATION NUMBER: The trial is registered at ClinicalTrials.gov (NCT01879735).
Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase/metabolismo , Ácidos Cólicos/farmacocinética , Sarcosina/análogos & derivados , Idoso , Bile/metabolismo , Transporte Biológico Ativo , Radioisótopos de Carbono , Estudos de Casos e Controles , Colestase/sangue , Colestase/diagnóstico por imagem , Ácidos Cólicos/sangue , Feminino , Humanos , Cinética , Fígado/diagnóstico por imagem , Fígado/metabolismo , Circulação Hepática , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Sarcosina/sangue , Sarcosina/farmacocinética , Adulto JovemRESUMO
Photoacoustic (PA) imaging has been considered an attractive imaging modality for sensitive and in-depth imaging of biomolecules with a high resolution in vivo. PA imaging probes utilizing fluorescence dyes, including indocyanine green (ICG), have been proposed to enhance PA signal intensity. On the other hand, nanomicelles modified with polysarcosine (PSar), a biocompatible hydrophilic polymer, on their surface have previously achieved rapid tumor uptake, suggesting active transport of PSar into tumor tissues. Thus, we hypothesized that PSar-based materials might be utilized as diagnostic probes for targeting tumors and therefore evaluated the potential of PSar labeled with an ICG derivative, ICG-PSar, as a PA imaging probe for targeting cancer. In this study, ICG-PSars with differing molecular weights (10, 20, and 30 kDa) were synthesized. In vitro cellular uptake studies using ICG-PSar demonstrated rapid uptake in colon26 tumor cells partially via macropinocytosis-mediated endocytosis. In vivo fluorescence imaging and biodistribution study indicated that ICG-PSar30k exhibited high accumulation in the tumor (8.4% dose/g), with high tumor-to-blood ratios reaching 4.6 at 24 h post injection of the probe. Finally, in vivo PA imaging studies showed that PA signal increased in tumors (251%) but not in blood vessels, achieving high contrast tumor imaging at 24 h after ICG-PSar30k probe injection. These results suggest that ICG-PSar has potential as a tumor-targeting PA imaging probe.
Assuntos
Neoplasias/diagnóstico por imagem , Peptídeos/farmacocinética , Sarcosina/análogos & derivados , Animais , Linhagem Celular Tumoral , Endocitose , Humanos , Verde de Indocianina , Camundongos , Técnicas Fotoacústicas , Sarcosina/farmacocinética , Distribuição TecidualRESUMO
BACKGROUND: Nanoparticle of Lactosome, which is composed of poly(l-lactic acid)-base depsipeptide with diameter of 35nm, accumulates in solid tumors by the enhanced permeability and retention (EPR) effect. However, a pharmacokinetic alteration of Lactosome was observed when Lactosome was repeatedly administered. This phenomenon is named as the Lactosome accelerated blood clearance (ABC) phenomenon. In this study, the effect of Lactosome dose on the ABC phenomenon was examined and discussed in terms of immune tolerance. METHODS: To tumor transplanted mice, Lactosome (0-350mg/kg) was administrated. At 7days after the first administration, indocyanine green (ICG)-labeled Lactosome (ICG-Lactosome, 0-350mg/kg) was injected. Near-infrared fluorescence imaging was performed, and biodistribution of ICG-Lactosome was evaluated. Further, the produced amounts of anti-Lactosome IgM were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ICG-Lactosome accumulated in the tumor region when the first Lactosome dose exceeded over 150mg/kg. The amounts of anti-Lactosome IgM were inversely correlated with the first Lactosome doses. Even after establishment of the Lactosome ABC phenomenon with the first Lactosome dose as low as 5.0mg/kg, the Lactosome ABC phenomenon can be evaded apparently by dosing ICG-Lactosome over 50mg/kg regardless of anti-Lactosome IgM production. CONCLUSIONS: There are two different mechanisms for evasion from the Lactosome ABC phenomenon before and after its establishment. In either mechanism, however, the Lactosome ABC phenomenon can be evaded by excessive administration of Lactosome. GENERAL SIGNIFICANCE: Lactosome is a potential nanocarrier for drug and/or imaging agent delivery, which can be used for frequent administrations without significant pharmacokinetic alterations.
Assuntos
Ácido Láctico/farmacocinética , Nanopartículas , Peptídeos/farmacocinética , Polímeros/farmacocinética , Sarcosina/análogos & derivados , Animais , Portadores de Fármacos , Ensaio de Imunoadsorção Enzimática , Imunoglobulina M/sangue , Ácido Láctico/imunologia , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Peptídeos/imunologia , Poliésteres , Sarcosina/imunologia , Sarcosina/farmacocinéticaRESUMO
Nanoparticles are expected to be applicable for the theranostics as a carrier of the diagnostic and therapeutic agents. Lactosome is a polymeric micelle composed of amphiphilic polydepsipeptide, poly(sarcosine)64-block-poly(L-lactic acid)30, which was found to accumulate in solid tumors through the enhanced permeability and retention effect. However, lactosome was captured by liver on the second administration to a mouse. This phenomenon is called as the accelerated blood clearance phenomenon. On the other hand, peptide-nanosheet composed of amphiphilic polypeptide, poly(sarcosine)60-block-(L-Leu-Aib)6, where the poly(L-lactic acid) block in lactosome was replaced with the (L-Leu-Aib)6 block, abolished the accelerated blood clearance phenomenon. The ELISA and in vivo near-infrared fluorescence imaging revealed that peptide-nanosheets did not activate the immune system despite the same hydrophilic block being used. The high surface density of poly(sarcosine) chains on the peptide-nanosheet may be one of the causes of the suppressive immune response.
Assuntos
Imunossupressores/química , Nanoestruturas/química , Peptídeos/química , Sarcosina/análogos & derivados , Animais , Linhagem Celular Tumoral , Humanos , Imunoglobulina M/metabolismo , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Peptídeos/farmacocinética , Peptídeos/farmacologia , Sarcosina/química , Sarcosina/farmacocinética , Sarcosina/farmacologiaRESUMO
INTRODUCTION: [N-methyl-11C]cholylsarcosine ([11C]CSar) is a tracer for imaging and quantitative assessment of intrahepatic cholestatic liver diseases and drug-induced cholestasis by positron emission tomography (PET). The purpose of this study is to determine whole-body biodistribution and dosimetry of [11C]CSar in healthy humans. The results are compared with findings in a patient with primary sclerosing cholangitis (PSC) and a patient with primary biliary cholangitis (PBC) as well as with preclinical findings in pigs. Radiosynthesis and quality control for preparation of [11C]CSar for clinical use are also presented. METHODS: Radiosynthesis and quality control of [11C]CSar were set up in compliance with Danish/European regulations. Both healthy participants (3 females, 3 males) and patients underwent whole-body PET/CT to determine the biodistribution of [11C]CSar. The two patients were under treatment with ursodeoxycholic acid at the time of the study. Dosimetry was estimated from the PET data using the Olinda 2.0 software. RESULTS: The radiosynthesis provided [11C]CSar in a solution ready for injection. The biodistribution studies revealed that gallbladder wall, small intestine, and liver were critical organs in both healthy participants and patients with the gallbladder wall receiving the highest dose (up to 0.5â¯mGy/MBq). The gender-averaged (±SD) effective dose for the healthy participants was 6.2⯱â¯1.4⯵Sv/MBq. The effective dose for the PSC and the PBC patient was 5.2 and 7.0⯵Sv/MBq, respectively. CONCLUSION: A radiosynthesis for preparation of [11C]CSar for clinical use was developed and approved by the Danish Medicines Agency. The most critical organ was the gallbladder wall although the amount of [11C]CSar in the gallbladder was found to vary significantly between individuals. The estimated effective dose for humans was comparable to that estimated in anesthetized pigs although the absorbed dose estimates to some organs, such as the stomach, was different. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [11C]CSar PET/CT enables detailed quantitative assessment of patients with cholestatic liver disease by tracing the separate hepatobiliary transport steps of endogenous bile acids. The present work offers a radiosynthetic method and dosimetry data suitable for clinical implementation of [11C]CSar.
Assuntos
Ácidos e Sais Biliares/farmacocinética , Colestase Intra-Hepática/metabolismo , Ácidos Cólicos/farmacocinética , Fígado/metabolismo , Traçadores Radioativos , Compostos Radiofarmacêuticos/farmacocinética , Sarcosina/análogos & derivados , Adulto , Idoso , Animais , Ácidos e Sais Biliares/química , Radioisótopos de Carbono , Estudos de Casos e Controles , Colestase Intra-Hepática/patologia , Ácidos Cólicos/química , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Sarcosina/química , Sarcosina/farmacocinética , Suínos , Distribuição TecidualRESUMO
Certain mixtures of chemicals are known to synergistically enhance skin permeability to drugs. Here, we report on the transport enhancing properties of mixtures of an anionic surfactant, sodium lauroylsarcosinate (NLS) and a non-ionic surfactant, sorbitan monolaurate (S20) in 1:1 phosphate buffered saline (PBS):ethanol (EtOH) solvent. Effect of 44 different compositions of NLS:S20 on skin constituents was probed by Fourier transform-infrared (FT-IR) spectroscopy while behavior of surfactant molecules in the solvent system was probed by FT-IR and NMR spectroscopy. No aggregation of NLS or S20 alone was observed in 1:1 PBS:EtOH at all concentrations studied (0-2%, w/v). However, mixtures of NLS and S20 resulted in micelle-like aggregates at certain specific compositions. Interestingly, compositions with increased aggregation showed resemblance to those that exhibited highest skin permeabilization.
Assuntos
Adjuvantes Farmacêuticos/farmacologia , Absorção Cutânea/efeitos dos fármacos , Pele/efeitos dos fármacos , Adjuvantes Farmacêuticos/química , Adjuvantes Farmacêuticos/farmacocinética , Animais , Condutividade Elétrica , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/fisiologia , Etanol/química , Hexoses/química , Hexoses/farmacocinética , Hexoses/farmacologia , Técnicas In Vitro , Bicamadas Lipídicas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Permeabilidade/efeitos dos fármacos , Sarcosina/análogos & derivados , Sarcosina/química , Sarcosina/farmacocinética , Sarcosina/farmacologia , Pele/metabolismo , Absorção Cutânea/fisiologia , Espectroscopia de Infravermelho com Transformada de Fourier , SuínosRESUMO
Sarcosine is a known substrate of proton-coupled amino acid transporters (PATs), which are overexpressed in selected tissues and solid tumors. Sarcosine, an N-methyl derivative of the amino acid glycine and a metabolic product of choline, plays an important role for prostate cancer aggressiveness and progression. Methods:11C-radiolabeled sarcosine was tested as a new PET imaging probe in comparison with 11C-choline in 2 prostate cancer tumor xenograft models (DU-145 and PC-3). We characterized 11C-sarcosine transport in PC-3 and LNCaP tumor cells and performed 11C-sarcosine PET with CT in the first human subject with localized Gleason 4 + 3 prostate cancer. Target metabolite analyses of sarcosine and its natural precursors, glycine and choline, were performed from independent human prostate tissues. Results: In vitro assays indicated blockage of 11C-sarcosine uptake into PC-3 and LNCaP tumor cells by excess unlabeled (cold) sarcosine. 5-hydroxy-l-tryptophan, but not 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, competitively inhibited 11C-sarcosine tumor cell uptake, confirming PAT-mediated transport. In vivo tumor-to-background ratios (TBRs) obtained from 11C-sarcosine PET were significantly elevated compared with 11C-choline in DU-145 (TBR: 1.92 ± 0.11 for 11C-sarcosine vs. 1.41 ± 0.13 for 11C-choline [n = 10; P < 0.002]) and PC-3 tumors (TBR: 1.89 ± 0.2 for 11C-sarcosine vs. 1.34 ± 0.16 for 11C-choline [n = 7; P < 0.002]). 11C-sarcosine produced high-contrast images in 1 case of localized clinically significant prostate cancer. Target metabolite analyses revealed significant stepwise increases of sarcosine, glycine, and choline tissue levels from benign prostate tissue to localized prostate cancer and subsequently metastatic disease. 11C-sarcosine showed a favorable radiation dosimetry with an effective dose estimate of 0.0045 mSv/MBq, resulting in 2.68 mSv for a human subject (600-MBq dose). Conclusion:11C-sarcosine is a novel radiotracer for PATs and shows initial utility for prostate cancer imaging, with potential benefit over commonly used 11C-choline.
Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Radioisótopos de Carbono , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Prótons , Sarcosina/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radiometria , Sarcosina/farmacocinética , Distribuição TecidualRESUMO
Polysarcosine (PS), a non-ionic hydrophilic polypeptoid whose structure is similar to polypeptides, bearing repeating units of natural α-amino acid, has been used to stabilize gold nanoparticles (AuNPs) due to its excellent hydrophilicity and biocompatibility. Disulfide functionalized polysarcosines with different molecular weight were synthesized and used to cap AuNPs by traditional ligand exchange. The grafting of PS on AuNPs was evidenced by Fourier transform infrared (FTIR) spectroscopy and the alternation of surface zeta potential. The polysarcosine coated AuNPs (Au@PS) showed good stabilities in wide pH range and saline condition. They had strong resistance to ligand competition of dithiothreitol (DTT). They showed good stability in serum, with a molecular weight dependent interaction pattern with proteins. The Au@PS had very low cytotoxicity and cell uptake in vitro. Based on the results in vitro, polysarcosine with molecular weight of 5kD with the best ability to stabilize AuNPs was used for in vivo test. The Au@PS had a longer circulation time in blood after intravenous injection than that of Au@PEG, indicating a better stealth-like property of polysarcosine. The Au@PS did not cause obvious toxicity in vivo, suggesting potential applications in disease diagnosis and therapy.
Assuntos
Ouro/química , Nanopartículas Metálicas/química , Peptídeos/química , Sarcosina/análogos & derivados , Animais , Sobrevivência Celular/efeitos dos fármacos , Coloides , Dissulfetos/química , Ditiotreitol/química , Ouro/farmacocinética , Ouro/farmacologia , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Injeções Intravenosas , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Pulmão/anatomia & histologia , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/ultraestrutura , Peso Molecular , Peptídeos/farmacocinética , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Sarcosina/química , Sarcosina/farmacocinética , Sarcosina/farmacologia , Baço/anatomia & histologia , Baço/efeitos dos fármacosRESUMO
BACKGROUND: Hypofunction of NMDA receptor-mediated neurotransmission might play a critical role in schizophrenia. Sarcosine, N- methylglycine and inhibitor of the glycine transporter-1 (Gly-T1), has been suggested as a novel treatment for schizophrenia. METHODS: Open label sarcosine was added to 22 stabilized patients: 5 patients received 2 gm/d, and 17 received 4gm/d. Pharmacokinetics samples, clinical and cognitive parameters using PANSS, CGI and MCCB were collected for all patients. RESULTS: Significant improvement was observed after one week of treatment on PANSS sub-scale of 'positive symptoms' (Z= -2.68; P=0.007) and 'general psychopathology' (Z= -3.02; P=0.003), an improvement in PANSS total score and CGI-S showed a trend (Z= -2.72; P=0.06; Z=-2.69; P=0.08). Speed of processing (MCCB subscale) improved significantly (Z=-2.13; P=0.03). Sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½ hr and ~1hr, respectively. LIMITATIONS: This was a short period, open label pilot study with small sample size per dosage group. CONCLUSIONS: Sarcosine is a safe compound and might be efficacious in the treatment of schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Sarcosina/farmacologia , Sarcosina/farmacocinética , Esquizofrenia/tratamento farmacológico , Adulto , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Sarcosina/administração & dosagem , Sarcosina/efeitos adversosRESUMO
In the central nervous system, re-uptake of the neurotransmitter glycine is mediated by two different glycine transporters, GlyT1 and GlyT2. GlyT2 is found in brainstem and spinal cord, whereas GlyT1 is expressed in rat forebrain regions where it is responsible for most glycine transport activity. Initially, GlyT1 and GlyT2 were pharmacologically differentiated by sarcosine, a weak selective inhibitor of GlyT1. The recently described selective and potent GlyT1 antagonist, NFPS/ALX-5407 provided an important additional tool to further characterize GlyT1 pharmacology. In the present study, we have radiolabeled the racemic form of NFPS (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (also known as ALX-5407) to investigate its interaction with GlyT1, as well as define GlyT1 expression in the rat central nervous system. Kinetic studies indicated that [3H]NFPS binds rapidly to rat forebrain membranes and dissociates with a t(1/2) of 28 +/- 5 min. [3H]NFPS labeled a saturable population of sites in rat forebrain with a Kd of 7.1+/-1.3 nM and a B(max) of 3.14 +/- 0.26 pmol/mg protein. Bound [3H]NFPS was fully and potently displaced by unlabeled NFPS, whereas glycine and sarcosine were weak, Na+-dependent inhibitors with IC50 of 1,008 and 190 microM, respectively. Additional saturation experiments indicated that glycine and sarcosine were non-competitive antagonists of [3H]NFPS binding. Functional studies revealed that NFPS was a non-competitive inhibitor of [3H]glycine uptake and does not interact with Na+ and Cl- binding sites of GlyT1. Overall, this work shows that [3H]NFPS is a valuable tool in studying GlyT1 expression and pharmacology and that NFPS interacts with GlyT1 at a site different from the transporter translocation and ion binding sites.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Glicina/análogos & derivados , Sarcosina/análogos & derivados , Sarcosina/farmacologia , Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Sistemas de Transporte de Aminoácidos Neutros/genética , Análise de Variância , Animais , Ligação Competitiva , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sistema Nervoso Central/metabolismo , Relação Dose-Resposta a Droga , Glicina/antagonistas & inibidores , Glicina/metabolismo , Glicina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina , Humanos , Cinética , Cloreto de Lítio/farmacologia , Ensaio Radioligante/métodos , Ratos , Sarcosina/química , Sarcosina/metabolismo , Sarcosina/farmacocinética , Acetato de Sódio/farmacologia , Cloreto de Sódio/farmacologia , Fatores de Tempo , Trítio/metabolismoRESUMO
We have previously demonstrated that uptake of the amino acid amide sarcosinamide by the glioma cell line SK-MG-1 occurs via the catecholamine carrier that accommodates epinephrine (Km = 0.284 mM; Vmax = 0.154 nmol/10(6) cells/min). Sarcosinamide chloroethylnitrosourea (SarCNU), a new anticancer agent that exerts increased in vitro antitumor activity against gliomas as compared with BCNU (bis-chloroethylnitrosourea), the standard agent of choice, competitively inhibits sarcosinamide uptake by SK-MG-1 cells [inhibition constant (Ki) = 3.26 mM]. Using radiolabeled N-[3H]-sarcosinamide, we determined the transport of sarcosinamide in HT-29 colon-cancer cells, in Calu-1 lung-cancer cells, and in normal foreskin DHF fibroblasts. Sarcosinamide transport was linear for up to 1 min at 22 degrees C. In HT-29 cells and DHF fibroblasts, the uptake of sarcosinamide followed Michaelis-Menten kinetics of carrier-mediated transport. In HT-29 cells the Michaelis constant (Km) was 2.76 +/- 0.1 mM and the maximal velocity (Vmax) was 2.03 +/- 0.1 nmol/10(6) cells/min, whereas in DHF fibroblasts the respective values were 6.58 +/- 3.90 mM and 12.08 +/- 8.20 nmol/10(6) cells/min. In these two cell lines, neither epinephrine nor leucine significantly reduced sarcosinamide transport. In Calu-1 cells there was no evidence of carrier-mediated transport of either sarcosinamide or epinephrine. These nonglial cell lines lack a high-affinity catecholamine carrier. The increased cytotoxicity of SarCNU in gliomas may correlate with the presence of a high-affinity catecholamine carrier.
Assuntos
Epinefrina/farmacocinética , Sarcosina/análogos & derivados , Transporte Biológico , Neoplasias do Colo/metabolismo , Portadores de Fármacos , Fibroblastos/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Sarcosina/farmacocinética , Células Tumorais CultivadasRESUMO
Nitric oxide (NO) is well known to have a wide variety of biological and physiological functions in animals. On the basis of the fact that Fe(II)-dithiocarbamates react with NO, a Fe(II)-N-(dithiocarboxy)sarcosine complex (Fe(II)-DTCS) was proposed as a trapping agent for endogenous NO. However, quantitative pharmacokinetic investigation for NO-Fe(II)-dithiocarbamate complexes in experimental animals has been quite limited. This paper describes the results on the quantitative pharmacokinetic features of a NO-Fe(II)-N-DTCS in both the blood and bile of rats following intravenous (i.v.) administration of the complex. For this purpose, we applied two in vivo methods, i.e. (1) in vivo blood circulation monitoring-electron spin resonance (BCM-ESR) which previously developed, and (2) in vivo biliary excretion monitoring-electron spin resonance (BEM-ESR). We monitored real-time ESR signals due to nitrosyl-iron species in the circulating blood and bile flow. The ESR signal due to NO-Fe(II)-DTCS was stable in biological systems such as the fresh blood and bile. In in vivo BCM- and BEM-ESR, the pharmacokinetic parameters were calculated on the basis of the two-compartment and hepatobiliary transport models. The studies also revealed that the compound is widely distributed in the peripheral organs and partially excreted into the bile. We named a kinetic method to follow spin concentrations as spinnokinetics and this method will be useful for detecting and quantifying the endogenously generated NO in Fe(II)-DTCS administered animals.
Assuntos
Bile/metabolismo , Quelantes de Ferro/química , Óxido Nítrico/química , Sarcosina , Tiocarbamatos/química , Tiocarbamatos/farmacocinética , Animais , Sedimentação Sanguínea , Espectroscopia de Ressonância de Spin Eletrônica , Infusões Intravenosas , Cinética , Masculino , Ratos , Ratos Wistar , Sarcosina/análogos & derivados , Sarcosina/química , Sarcosina/farmacocinéticaRESUMO
The pharmacokinetics of the antitoxic and anticarcinogenic compounds diethyldithiocarbamate, prolinedithiocarbamate and sarcosinedithiocarbamate were compared in rats. The bioavailability, the distribution in the organism, the oxidation to thiuramdisulfides, the cleavage to CS2 and the excretion in urine and bile were investigated. The results showed different behaviour of the three compounds. The more toxic diethyldithiocarbamate had a short in vivo half-life, was oxidized to tetraethylthiuramdisulfide in blood, and was metabolized to high yields of CS2 in 24 h. In contrast, prolinedithiocarbamate was more stable in vivo, was found predominantly in the urinary tract and was excreted in urine. The differences could not be explained by the presence of the carboxy group in the latter dithiocarbamate, since sarcosinedithiocarbamate, which also contains a carboxy group, behaved like diethyldithiocarbamate.
Assuntos
Antineoplásicos/farmacocinética , Ditiocarb/farmacocinética , Prolina/análogos & derivados , Sarcosina/análogos & derivados , Tiocarbamatos/farmacocinética , Animais , Antineoplásicos/metabolismo , Autorradiografia , Disponibilidade Biológica , Ditiocarb/metabolismo , Meia-Vida , Oxirredução , Prolina/metabolismo , Prolina/farmacocinética , Ratos , Sarcosina/metabolismo , Sarcosina/farmacocinética , Tiocarbamatos/metabolismo , Distribuição TecidualRESUMO
The recent identification of a novel binding site for angiotensin (Ang) II as the peptidase neurolysin (E.C. 3.4.24.16) has implications for the renin-angiotensin system (RAS). This report describes the distribution of specific binding of 125I-Sarcosine1, Isoleucine8 Ang II (125I-SI Ang II) in neurolysin knockout mouse brains compared to wild-type mouse brains using quantitative receptor autoradiography. In the presence of p-chloromercuribenzoic acid (PCMB), which unmasks the novel binding site, widespread distribution of specific (3 µM Ang II displaceable) 125I-SI Ang II binding in 32 mouse brain regions was observed. Highest levels of binding >700 fmol/g initial wet weight were seen in hypothalamic, thalamic and septal regions, while the lowest level of binding <300 fmol/g initial wet weight was in the mediolateral medulla. 125I-SI Ang II binding was substantially higher by an average of 85% in wild-type mouse brains compared to neurolysin knockout brains, suggesting the presence of an additional non-AT1, non-AT2, non-neurolysin Ang II binding site in the mouse brain. Binding of 125I-SI Ang II to neurolysin in the presence of PCMB was highest in hypothalamic and ventral cortical brain regions, but broadly distributed across all regions surveyed. Non-AT1, non-AT2, non-neurolysin binding was also highest in the hypothalamus but had a different distribution than neurolysin. There was a significant reduction in AT2 receptor binding in the neurolysin knockout brain and a trend towards decreased AT1 receptor binding. In the neurolysin knockout brains, the size of the lateral ventricles was increased by 56% and the size of the mid forebrain (-2.72 to +1.48 relative to Bregma) was increased by 12%. These results confirm the identity of neurolysin as a novel Ang II binding site, suggesting that neurolysin may play a significant role in opposing the pathophysiological actions of the brain RAS and influencing brain morphology.
Assuntos
Angiotensina II , Metaloendopeptidases/metabolismo , Prosencéfalo/metabolismo , Sistema Renina-Angiotensina/fisiologia , Sarcosina , Angiotensina II/farmacocinética , Angiotensina II/farmacologia , Animais , Isótopos de Iodo/farmacocinética , Isótopos de Iodo/farmacologia , Metaloendopeptidases/genética , Camundongos , Camundongos Knockout , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Sarcosina/farmacocinética , Sarcosina/farmacologiaRESUMO
PURPOSE: GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295. PATIENTS AND METHODS: Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m(2). GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks. RESULTS: A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m(2). Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (n = 2, 5%), increased AST (n = 1, 2.5%), hypokalemia (n = 1, 2.5%), and hypoxia (n = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (n = 13; 33%). Gastrointestinal toxicities of diarrhea (n = 12, 31%), nausea (n = 8, 21%), and vomiting (n = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m(2) and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9-11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m(2) dose level. CONCLUSIONS: The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.
Assuntos
Antimitóticos/administração & dosagem , Antimitóticos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Sarcosina/análogos & derivados , Adulto , Idoso , Antimitóticos/efeitos adversos , Antimitóticos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Sarcosina/administração & dosagem , Sarcosina/efeitos adversos , Sarcosina/farmacocinética , Sarcosina/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
UNLABELLED: Excretion of conjugated bile acids into bile is an essential function of the liver, and impairment of canalicular bile acid secretion leads to cholestatic liver injury. However, hepatic excretory function cannot be quantified in vivo because of the lack of suitable methods. Cholylsarcosine is an analog of the endogenous bile acid conjugate cholylglycine and exhibits characteristics in vivo that led us to hypothesize that the (11)C-labeled form, that is, [N-methyl-(11)C]cholylsarcosine ((11)C-cholylsarcosine), would be a suitable PET tracer for quantification of hepatic excretory function. METHODS: A method for radiosynthesis of (11)C-cholylsarcosine was developed involving (11)C-methylation of glycine followed by conjugation with cholic acid. Blood-to-liver uptake and liver-to-bile excretion were investigated in vivo by dynamic (11)C-cholylsarcosine PET/CT of 2 anesthetized pigs. In pig 1, a second dynamic (11)C-cholylsarcosine PET/CT examination was preceded by a high dose of the endogenous bile acid conjugate cholyltaurine to investigate possible inhibition of the transhepatocellular transport of (11)C-cholylsarcosine. In pig 2, a second (11)C-cholylsarcosine administration was given to determine the biodistribution of the tracer by means of 5 successive whole-body PET/CT recordings. Possible formation of (11)C-metabolites was investigated by analysis of blood and bile samples from a third pig. RESULTS: The radiochemical yield was 13% ± 3% (n = 7, decay-corrected) and up to 1.1 GBq of (11)C-cholylsarcosine was produced with a radiochemical purity greater than 99%. PET/CT studies showed rapid blood-to-liver uptake and liver-to-bile excretion of (11)C-cholylsarcosine, with radioactivity concentrations being more than 90 times higher in the bile ducts than in liver tissue. Cholyltaurine inhibited the transhepatocellular transport of (11)C-cholylsarcosine, indicating that the tracer is transported by one or more of the same hepatic transporters as cholyltaurine. (11)C-cholylsarcosine underwent an enterohepatic circulation and reappeared in liver tissue and bile ducts after approximately 70 min. There were no detectable (11)C-metabolites in the plasma or bile samples, indicating that the novel conjugated bile acid (11)C-cholylsarcosine was not metabolized in the liver or in the intestines. The effective absorbed dose of (11)C-cholylsarcosine was 4.4 µSv/MBq. CONCLUSION: We have synthesized a novel conjugated bile acid analog, (11)C-cholylsarcosine, and PET/CT studies on anesthetized pigs showed that the hepatic handling of tracer uptake from blood and excretion into the bile was comparable to that for the endogenous bile acid cholyltaurine. This tracer may be valuable for future studies of normal and pathologic hepatic excretory functions in humans.
Assuntos
Ácidos e Sais Biliares/metabolismo , Ácidos Cólicos/síntese química , Testes de Função Hepática/métodos , Fígado/diagnóstico por imagem , Fígado/fisiologia , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons , Sarcosina/análogos & derivados , Tomografia Computadorizada por Raios X , Animais , Radioisótopos de Carbono , Ácidos Cólicos/metabolismo , Ácidos Cólicos/farmacocinética , Feminino , Fígado/metabolismo , Traçadores Radioativos , Radioquímica , Sarcosina/síntese química , Sarcosina/metabolismo , Sarcosina/farmacocinética , SuínosRESUMO
The success of positron emission tomography (PET) in personalised medicine and drug development requires radioisotopes that provide high quality images and flexible chemistry for a broad application. 64Cu is arguably one of the most suitable PET isotopes for imaging with the evolving target agents, but there are not many appropriate chelating agents for 64Cu and this has limited its wider application. The bi-functional chelator, SarAr is known to bind 64Cu2+ quantitatively (i.e. one metal per ligand present) and rapidly (<2 min) at 10(-6) M over a range of pH (4-9). In this paper the conjugation of SarAr to the whole and fragmented antibody is described. Conjugation of the SarAr to the protein does not impair its coordination of the 64Cu. It complexes the 64Cu2+ rapidly, quantitatively and essentially irreversibly at pH 5. Animal studies show that the 64Cu-SarAr-immunoconjugates maintain their specificity for the target and are stable in vivo. Also, SarAr is a platform technology, is easy to use in a kit formulation and is readily adaptable for the wider application in 64Cu PET imaging.
Assuntos
Radioisótopos de Cobre , Compostos Heterocíclicos , Neoplasias Experimentais/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Sarcosina/análogos & derivados , Animais , Compostos Aza , Quelantes , Compostos Heterocíclicos/farmacocinética , Humanos , Marcação por Isótopo , Taxa de Depuração Metabólica , Camundongos , Camundongos Nus , Compostos Radiofarmacêuticos , Sarcosina/farmacocinéticaRESUMO
Mouse zygotes and early cleavage-stage embryos have previously been shown to utilize glycine as an organic osmolyte, accumulating it to oppose any decrease in cell volume. Such glycine uptake in early cleavage-stage mouse embryos is via the glycine-specific Gly transporter. Mouse embryos also possess swelling-activated channels which function to release osmotically active glycine and other osmolytes when cell volume becomes too large. In this study it was found that human cleavage-stage embryos also transported glycine via a similarly saturable, sarcosine-inhibitable transporter, implying that the Gly transporter also mediates glycine transport in human embryos. Mouse zygotes have previously been shown to accumulate more intracellular glycine when cultured at increased osmolarities for 24 h. It was found in the current study that this ability was lost as preimplantation mouse embryo development proceeded, and that early cleavage-stage human embryos may also be capable of such osmosensitive accumulation of glycine. Finally, using spare human eggs which had failed to fertilize or cleave, the presence of swelling-activated currents resembling those in mouse zygotes was demonstrated. These data indicate that osmoregulation in early human embryos occurs via similar mechanisms as in the mouse.
Assuntos
Embrião de Mamíferos/metabolismo , Glicina/farmacocinética , Animais , Transporte Biológico , Fase de Clivagem do Zigoto , Meios de Cultura , Desenvolvimento Embrionário e Fetal/fisiologia , Feminino , Humanos , Camundongos , Técnicas de Patch-Clamp , Sarcosina/farmacocinética , Equilíbrio HidroeletrolíticoRESUMO
AIMS: Large oral doses of betaine have proved effective in lowering plasma homocysteine in severe hyperhomocysteinaemia. The pharmacokinetic characteristics and metabolism of betaine in humans have not been assessed and drug monitoring for betaine therapy is not available. We studied the pharmacokinetics of betaine and its metabolite dimethylglycine (DMG) in healthy subjects and in three patients with homocystinuria. METHODS: Twelve male volunteers underwent an open-label study. After one single administration of 50 mg betaine kg-1 body weight and during continuous intake of twice daily 50 mg kg-1 body weight, serial blood samples and 24 h urines were collected to determine betaine and DMG plasma concentrations and urinary excretion, respectively. Patients were evaluated after one single dose of betaine. RESULTS: We found rapid absorption (t(1/2),abs 00.28 h, s.d. 0.17) and distribution (t(1/2), lambda1 00.59 h, s.d. 0.22) of betaine. A Cmax of 0.94 mmol l-1 (s.d. 0.19) was reached after tmax 00.90 h (s.d. 0.33). The elimination half life t(1/2), z was 14.38 h (s.d. 7.17). After repeated dosage, t(1/2), lambda1 (01.77 h, s.d. 0.75) and t(1/2), z (41.17 h, s.d. 13.50) increased significantly (95% CI 0.73, 01.64 h and 19.90, 33.70 h, respectively), whereas absorption remained unchanged. DMG concentrations increased significantly after betaine administration and accumulation occurred to the same extent as with betaine. Renal clearance was low and urinary excretion of betaine was equivalent to 4% of the ingested dose. Distribution and elimination kinetics in homocystinuric patients appeared to be accelerated. CONCLUSIONS: Betaine plasma concentrations change rapidly after ingestion. Elimination half-life increased during continuous dosing over 5 days. Betaine is mainly eliminated by metabolism. More pharmacokinetic and pharmacodynamic studies in hyperhomocysteinaemic patients are needed to refine the current treatment with betaine.