Uptake characteristics of oligonucleotides in the isolated rat liver perfusion system

Yoshinobu Takakura, Ram I Mahato, Mitsunobu Yoshida, Taro Kanamaru, Mitsuru Hashida

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The objective of this study was to examine the hepatic disposition characteristics of 20-mer model phosphodiester oligonucleotide (PO) and its partially phosphorothioated (PS 3 ) and fully phosphorothioated (PS) derivatives in the single-pass isolated rat liver perfusion system. [ 32 P]-labeled oligonucleotides were momentarily introduced into this system through the portal vein as a bolus input mode, and the venous outflow patterns were evaluated using statistical moment analysis. The apparent volumes of distribution of these oligonucleotides were greater than those of reference substances for vascular space (erythrocytes) and extracellular space (human serum albumin), indicating a significant interaction between oligonucleotides and the liver. Significant hepatic uptake of oligonucleotides was also observed. About 20%, 36%, and 52% of the injected dose (3 μg/rat) was taken up by the liver during a single passage after bolus injection of PO, PS 3 , and PS, respectively. In the case of PS injection, slow efflux from the liver was observed in the latter phase of perfusion. This suggests that the hepatic uptake process of these oligonucleotides greatly depended on their types. The results of collagenase perfusion experiments suggest that PS 3 oligonucleotides were taken up by both liver parenchymal and nonparenchymal cells. The amount of total recovery in the liver decreased substantially by coadministration of polyinosinic acid, dextran sulfate, polycytidic acid and 4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonic acid. This suggests that PS 3 was taken up by the liver as an anionic molecule in a nonspecific manner.

Original languageEnglish (US)
Pages (from-to)177-183
Number of pages7
JournalAntisense and Nucleic Acid Drug Development
Volume6
Issue number3
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Oligonucleotides
Liver
Rats
Perfusion
Poly I
Stilbenes
Dextran Sulfate
Acids
Collagenases
Injections
Serum Albumin
Extracellular Space
Portal Vein
Blood Vessels
Derivatives
Recovery
Erythrocytes
Molecules

ASJC Scopus subject areas

  • Genetics
  • Pharmacology

Cite this

Uptake characteristics of oligonucleotides in the isolated rat liver perfusion system. / Takakura, Yoshinobu; Mahato, Ram I; Yoshida, Mitsunobu; Kanamaru, Taro; Hashida, Mitsuru.

In: Antisense and Nucleic Acid Drug Development, Vol. 6, No. 3, 01.01.1996, p. 177-183.

Research output: Contribution to journalArticle

Takakura, Yoshinobu ; Mahato, Ram I ; Yoshida, Mitsunobu ; Kanamaru, Taro ; Hashida, Mitsuru. / Uptake characteristics of oligonucleotides in the isolated rat liver perfusion system. In: Antisense and Nucleic Acid Drug Development. 1996 ; Vol. 6, No. 3. pp. 177-183.
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