RESUMEN
PURPOSE: To analyze size changes of superabsorbent polymer (SAP) microspheres with the reduced expansion technique, and to evaluate pharmacological advantages of transarterial chemoembolization using cisplatin-loaded SAP microspheres with the reduced expansion technique. MATERIALS AND METHODS: In an in vitro study, diluted contrast materials containing different concentrations of sodium ions were examined to expand SAP microspheres and determined the reduced expansion technique. Size distributions of cisplatin-loaded SAP microspheres were analyzed. In an in vivo study, TACE was performed using cisplatin-loaded SAP microspheres with the reduced expansion and control techniques in 18 VX2 rabbits. RESULTS: The degree of expansion was reduced to the greatest extent by using a mixture of non-ionic contrast material and 10% NaCl at a 4:1 ratio. The mean diameter of the reduced expansion of cisplatin-loaded SAP microspheres was 188.4 µm, while that of the control expansion was 404.9 µm. The plasma platinum concentrations of the reduced expansion group at 5 min after TACE were significantly higher than those of the control expansion group (2.19 ± 0.77 vs. 0.75 ± 0.08 µg/mL, P = .01). The tumor platinum concentrations of the reduced expansion group at 1 h were significantly higher than those of the control expansion group (10.76 ± 2.57 vs. 1.57 ± 0.14 µg/g, P = .044). CONCLUSION: The expanding level of SAP microspheres can be reduced by using hypertonic saline. Cisplatin-loaded SAP microspheres with the reduced expansion technique have the advantages of achieving higher cisplatin tissue concentration in TACE for liver tumors.
Asunto(s)
Quimioembolización Terapéutica/métodos , Cisplatino/farmacocinética , Medios de Contraste , Neoplasias Hepáticas Experimentales/terapia , Microesferas , Solución Salina Hipertónica , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Cisplatino/administración & dosificación , Fluoroscopía , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Masculino , Polímeros , Conejos , Radiografía Intervencional/métodosRESUMEN
5-Aminosalicylic acid (5-ASA) is an orally administered therapeutic agent for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. We hypothesized that the absorption of 5-ASA is mediated by the polyspecific carnitine/organic cation transporter (OCTN1/SLC22A4), based on the similarity of chemical structure between 5-ASA and other OCTN1 substrates. Therefore, we examined the involvement of this transporter in the disposition of 5-ASA in vivo by using octn1 gene knockout (octn1(-/-)) mice. After oral administration of 5-ASA, the plasma concentrations of 5-ASA and its primary metabolite, N-acetyl-5-aminosalicylate (Ac-5-ASA), in octn1(-/-) mice were much lower than those in wild-type mice. The time required to reach maximum plasma concentration was also delayed in octn1(-/-) mice. On the other hand, the plasma concentration profiles of both 5-ASA and Ac-5-ASA after intravenous administration of 5-ASA (bolus or infusion) were similar in the two strains. Uptake of 5-ASA from the apical to the basal side of isolated small-intestinal tissues of octn1(-/-) mice, determined in an Ussing-type chamber, was lower than that in wild-type mice. Further, uptake of 5-ASA in HEK293 cells stably transfected with the OCTN1 gene, assessed as the sum of cell-associated 5-ASA and Ac-5-ASA, was higher than that in HEK293 cells transfected with the vector alone. Overall, these results indicate that OCTN1 is involved, at least in part, in the gastrointestinal absorption of 5-ASA.
Asunto(s)
Carnitina/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Absorción Intestinal , Intestino Delgado/metabolismo , Mesalamina/farmacocinética , Transportador 1 de Catión Orgánico/metabolismo , Animales , Disponibilidad Biológica , Transporte Biológico Activo , Células HEK293 , Humanos , Masculino , Proteínas de la Membrana , Mesalamina/sangre , Mesalamina/uso terapéutico , Ratones , Ratones Noqueados , Transportador 1 de Catión Orgánico/genética , Eliminación de Secuencia , TransfecciónRESUMEN
Transporter adaptor protein PDZK1 regulates several influx transporters for xenobiotics and nutrients in small intestine, and their expression on the apical membrane is diminished in pdzk1 gene knockout [pdzk1(-/-)] mice. In the present study, we initially attempted to use pdzk1(-/-) mice to functionally identify influx transporters responsible for intestinal absorption of cimetidine. Contrary to our expectation, the plasma concentration of cimetidine after oral administration to pdzk1(-/-) mice was higher than that in wild-type mice, and the double peaks of plasma concentration found in wild-type mice were not observed in pdzk1(-/-) mice. Western blot analysis of intestinal brush-border membranes revealed that expression of breast cancer resistance protein (BCRP) but not of P-glycoprotein is reduced in pdzk1(-/-) mice. This result was compatible with the reduction of apical localization of BCRP in pdzk1(-/-) mice assessed by immunohistochemical analysis. Transcellular transport of cimetidine in the basal-to-apical direction in Madin-Darby canine kidney II (MDCKII) cells stably expressing both BCRP and PDZK1 (MDCKII/BCRP/PDZK1) was higher than that in MDCKII cells stably expressing BCRP (MDCKII/BCRP) cells. Moreover, MDCKII/BCRP/PDZK1 cells are more resistant than MDCKII/BCRP cells to the cytotoxicity of the anticancer agent 7-ethyl-10-hydroxycamptothecin (SN-38), which is a substrate of BCRP. These results were consistent with the higher expression of BCRP on apical membranes in MDCKII/BCRP/PDZK1 cells. Pull-down and immunoprecipitation studies revealed a physical interaction between BCRP and PDZK1. Taken together, these findings demonstrate that PDZK1 plays a pivotal role in the apical localization of BCRP. This is the first identification of a regulatory protein that physically interacts with and regulates BCRP in small intestine in vivo.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Intestino Delgado/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Administración Oral , Animales , Transporte Biológico , Camptotecina/análogos & derivados , Camptotecina/farmacología , Línea Celular , Cimetidina/sangre , Cimetidina/farmacología , Absorción Intestinal , Irinotecán , Riñón/metabolismo , Masculino , Proteínas de la Membrana , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Dominios y Motivos de Interacción de ProteínasRESUMEN
Homeostasis in the body is at least partially maintained by mechanisms that control membrane permeability, and thereby serve to control the uptake of essential substances (e.g., nutrients) and the efflux of unwanted substances (e.g., xenobiotics and metabolites) in epithelial cells. Various transporters play fundamental roles in such bidirectional transport, but little is known about how they are organized on plasma membranes. Protein-protein interactions may play a key role: several transporters in epithelial cells interact with the so-called adaptor proteins, which are membrane anchored and interact with both transporters and other membranous proteins. Although most of the evidences for transporter-adaptor interaction has been obtained in vitro, recent studies suggest that adaptor-mediated transporter regulation does occur in vivo and could be relevant to human diseases. Thus, protein-protein interaction is not only associated with the formation of macromolecular complexes but is also involved in various cellular events, and may provide transporters with additional functionality by forming transporter networks on plasma membranes. Interactions between xenobiotic transporters and PSD95/Dlg/ZO1 (PDZ) adaptors were previously reviewed by Kato and Tsuji (2006. Eur J Pharm Sci 27:487-500); the present review focuses on the latest findings about PDZ adaptors as regulators of transporter networks and their potential role in human diseases.