Disposition of oligonucleotides in isolated perfused rat kidney: involvement of scavenger receptors in their renal uptake.
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.
Sawai
K
K
Department of Drug Delivery Research, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Mahato
R I
RI
Oka
Y
Y
Takakura
Y
Y
Hashida
M
M
D000818:Animals; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D009841:Oligonucleotides / Q000493:pharmacokinetics*; D010477:Perfusion; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
D008565:Membrane Proteins; D009841:Oligonucleotides; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B