Hepatic distribution of a phosphorothioate oligodeoxynucleotide within rodents following intravenous administration

Citation
Mj. Graham et al., Hepatic distribution of a phosphorothioate oligodeoxynucleotide within rodents following intravenous administration, BIOCH PHARM, 62(3), 2001, pp. 297-306
Citations number
36
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
3
Year of publication
2001
Pages
297 - 306
Database
ISI
SICI code
0006-2952(20010801)62:3<297:HDOAPO>2.0.ZU;2-D
Abstract
The pharmacokinetics of ISIS 1082, a 21-base heterosequence phosphorothioat e oligodeoxynucleotide, were characterized within rodent whole liver, and c ellular and subcellular compartments. Cross-species comparisons were perfor med using Sprague-Dawley rat and CD-1 mouse strains. Although whole liver o ligonucleotide deposition and the proportion of drug found within parenchym al and nonparenchymal cells were similar between the two rodent species as a function of both time and dose, dramatic differences in subcellular pharm acokinetics were observed. Specifically, within murine hepatocyte nuclei, d rug was observed at the 10 mg/kg dose, whereas in the rat nuclear-associate d levels required the administration of 25 mg/kg. Under all experimental re gimens, murine hepatic nuclear-associated drug concentrations were at least 2-fold higher than those round in rat liver cells, More detailed metabolic analysis was also performed using high performance liquid chromatography/e leotrospray-mass spectrometry (HPLC/ES-MS) and demonstrated that although t he extent of metabolism was similar for rat and mouse, the pattern of n-1 m etabolites Varied as a function of both species and cell type. While rat an d mouse hepatocytes and rat nonparenchymal cellular metabolites were predom inantly products of 3'-exonuclease degradation, mouse nonparenchymal cells contained a majority of n-1 metabolites produced by 5'-exonucleolytic activ ity. Based upon these data, it would appear that subcellular oligonucleotid e disposition and metabolism among rodent species are more divergent than w hole organ pharmacokinetics might predict. (C) 2001 Elsevier Science Inc. A ll rights reserved.