RENAL DISPOSITION CHARACTERISTICS OF OLIGONUCLEOTIDES MODIFIED AT TERMINAL LINKAGES IN THE PERFUSED RAT-KIDNEY

Citation
K. Sawai et al., RENAL DISPOSITION CHARACTERISTICS OF OLIGONUCLEOTIDES MODIFIED AT TERMINAL LINKAGES IN THE PERFUSED RAT-KIDNEY, Antisense research and development, 5(4), 1995, pp. 279-287
Citations number
56
Categorie Soggetti
Medicine, Research & Experimental","Biothechnology & Applied Migrobiology
ISSN journal
10505261
Volume
5
Issue
4
Year of publication
1995
Pages
279 - 287
Database
ISI
SICI code
1050-5261(1995)5:4<279:RDCOOM>2.0.ZU;2-0
Abstract
To clarify the renal disposition characteristics of oligonucleotides a t the organ level, the renal handling of model end-capped oligonucleot ides, 3'-methoxyethylamine 5'-biotin-decathymidylic acid containing ph osphoramidate modifications at 3'- and 5'-terminal internucleoside lin kages (T-10) and its phosphorothioate (Ts(10)), were studied in the pe rfused rat kidney. In a single-pass indicator dilution experiment, ven ous outflow and urinary excretion patterns and tissue accumulation of radiolabeled oligonucleotides were evaluated under filtering or nonfil tering conditions. No significant binding to bovine serum albumin (BSA ) in the perfusate was observed for T-10, whereas more than 90% of Ts( 10) bound to BSA. The steady-state distribution volume of T-10 calcula ted from the venous outflow pattern was larger than that of inulin, wh ich corresponds to the extracellular volume of the kidney, whereas the distribution volume of Ts(10) was larger than that of BSA (the intrav ascular volume). These results suggested their interaction with the va scular wall, Rapid urinary excretion was observed for T-10, similar to inulin used as a marker of golmerular filtration rate. On the other h and, urinary excretion of Ts(10) was greatly restricted due to its hig h binding ability (>90%) to BSA in the perfusate. A significant amount of T-10 and Ts(10) was accumulated in the kidney (T-10, 1.8% of injec ted dose; Ts(10), 1.3%) compared with inulin (0.2%) and BSA (<0.1%). T he accumulation of these oligonucleotides was ascribed to both tubular reabsorption and uptake from the capillary side. In addition, the upt ake of T-10 from the capillary side was significantly inhibited by sim ultaneous injection of dextran sulfate, suggesting that the oligonucle otide was taken up as an anionic molecule. These findings will be usef ul information for the development of delivery systems for antisense o ligonucleotides.