RESUMEN
The effects of renal injury on the urinary excretion and tissue distribution of a 20-mer phosphorothioate oligonucleotide were investigated in male Sprague-Dawley rats. Renal injury was produced by treating the rats with either 5.0 mg/kg cisplatin or 2.5 mg/kg of a monoclonal antibody (mAb) directed toward Thy1.1. Controls received saline. Three days after cisplatin treatment or 2 days after anti- Thy1.1 treatment, the rats received 10 mg/kg ISIS 3521. Blood was collected at various times to assess the plasma concentrations of ISIS 3521, and rats were killed at various times from 6 to 48 hours after intravenous (i.v.) infusion of oligonucleotide to assess tissue concentrations by capillary gel electrophoresis (CGE). Cisplatin and anti-Thy1.1 antibody produced histologic and biochemical changes consistent with proximal tubular damage and glomerular damage, respectively. Urinary excretion of oligonucleotides was increased 2- to 4-fold of control; however, this amount accounted for only 1% to 2% of dose compared to 0.5% in controls. Proximal tubular damage reduced renal accumulations of ISIS 3521 and other oligonucleotide metabolites, but there were no obvious compensatory increases in concentrations in other organs except for a slight increase in spleen levels of total oligonucleotide. Glomerular damage was not associated with any change in oligonucleotide disposition. Immunohistochemical studies showed no evidence of alterations in the pattern of distribution within the injured kidney. The data suggest that acute renal dysfunction, either renal tubular or glomerular, does not markedly alter the urinary elimination and tissue deposition of a phosphorothioate oligonucleotide.
Asunto(s)
Glomérulos Renales/efectos de los fármacos , Túbulos Renales/efectos de los fármacos , Oligodesoxirribonucleótidos Antisentido/farmacocinética , Tionucleótidos/farmacocinética , Animales , Inmunohistoquímica , Glomérulos Renales/lesiones , Glomérulos Renales/patología , Túbulos Renales/lesiones , Túbulos Renales/patología , Masculino , Oligodesoxirribonucleótidos Antisentido/sangre , Oligodesoxirribonucleótidos Antisentido/farmacología , Oligodesoxirribonucleótidos Antisentido/orina , Especificidad de Órganos , Ratas , Ratas Sprague-Dawley , Tionucleótidos/sangre , Tionucleótidos/farmacología , Tionucleótidos/orina , Factores de TiempoRESUMEN
Biodistribution and metabolism of a mixed backbone oligonucleotide (MBO), GEM 231, targeted to the RIalpha subunit of protein kinase A has been studied in normal and tumor xenografted mice. The study has been carried out using [35S]-labeled MBO following single and multiple administrations of doses varying from 2 to 50 mg/kg. MBO showed wide tissue distribution following intravenous and subcutaneous administration. The highest concentration of MBO was in the kidney and liver. The general disposition of MBO was followed by digitized autoradiographic pictures of tumored mice and further confirmed wide tissue disposition and also showed defined intratumor uptake of MBO. Multiple dose administration showed increased disposition in the majority of the tissues/organs, with the exception of the kidneys. Analysis of the extracted MBO by polyacrylamide gel electrophoresis (PAGE) showed the presence of primarily intact MBO along with its degraded forms. Based on our radioactivity levels, the primary route of excretion was in urine, analysis of which showed mainly degraded forms of MBO.
Asunto(s)
Oligodesoxirribonucleótidos Antisentido/administración & dosificación , Oligodesoxirribonucleótidos Antisentido/metabolismo , Animales , Autorradiografía , Proteínas Quinasas Dependientes de AMP Cíclico/biosíntesis , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Electroforesis en Gel de Poliacrilamida , Inyecciones Intravenosas , Inyecciones Subcutáneas , Riñón/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos , Trasplante de Neoplasias , Oligodesoxirribonucleótidos Antisentido/sangre , Oligodesoxirribonucleótidos Antisentido/orina , Radioisótopos de AzufreRESUMEN
BACKGROUND: Phosphorothioate oligonucleotides, in general, possess properties that could be utilized in the development of therapeutic heavy metal chelators. METHODS: Iron excretion was measured in 16 patients participating in studies to test the safety of OL(1)p53, a 20-mer phosphorothioate oligonucleotide complementary to p53 mRNA. Patients were given OL(1)p53 at doses of 0.05 to 0.25 mg/kg/h for 10 days by continuous intravenous infusion. Urine was collected during the study and analyzed for iron, copper, cadmium, and zinc. RESULTS: We found that phosphorothioate oligonucleotides have a high affinity for iron as well as several other clinically relevant toxic metals. Analysis of patient urine following administration of OL(1)p53 reveals a 7.5-fold increase in iron excretion at low doses (0.05 mg/kg/h). CONCLUSIONS: Phosphorothioate oligonucleotides may have therapeutic potential as heavy metal chelators. Low doses of phosphorothioate oligonucleotide facilitated the excretion of iron. Renal clearance of iron-phosphorothioate oligonucleotide complexes most likely involves secretion into proximal tubules.