RT Journal Article
SR Electronic
T1 Disposition of oligonucleotides in isolated perfused rat kidney: involvement of scavenger receptors in their renal uptake.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 284
OP 290
VO 279
IS 1
A1 K Sawai
A1 R I Mahato
A1 Y Oka
A1 Y Takakura
A1 M Hashida
YR 1996
UL http://jpet.aspetjournals.org/content/279/1/284.abstract
AB The objective of this study was to clarify the renal disposition characteristics of a 20-mer model phosphodiester oligonucleotide and its partially (PS3) and fully (PS) phosphorothioated derivatives, in isolated rat perfused kidney. Venous outflow and urinary excretion pattern, as well as tissue accumulation of radioactivity after bolus injection of 32P-labeled oligonucleotides, were evaluated under both filtering and nonfiltering conditions. The binding affinity of oligonucleotides to bovine serum albumin in the perfusate increased as the number of sulfur atoms present in the oligonucleotide molecules increased, resulting in 21, 60 and 86% binding to bovine serum albumin for phosphodiester oligonucleotide, PS3 and PS, respectively. The apparent steady-state distribution volumes of the oligonucleotides, as calculated from the venous outflow patterns, were larger than that of inulin, which corresponds to the extracellular volume of the kidney, suggesting their interaction with tissue from the vascular space. PS showed the largest distribution volume. Urinary excretion of oligonucleotides was greatly restricted, compared with that of inulin, which was used as a marker of glomerular filtration rate. The accumulation of these oligonucleotides was ascribed to both tubular reabsorption and uptake from the capillary side. The uptake of oligonucleotides from the capillary side increased as the number of sulfur atoms present in the molecules increased, suggesting sulfur atom-dependent interactions between oligonucleotides and renal tissue. In addition, the uptake of PS3 was a saturable process. Furthermore, coadministration of dextran sulfate and polyinosinic acid inhibited the renal uptake of PS3, whereas polycytidic acid and 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulfonic acid did not, suggesting that oligonucleotides were taken up via the scavenger receptor-mediated process for polyanions. These findings provide valuable information for the development of delivery systems for antisense oligonucleotides.