Mj. Graham et al., Hepatic distribution of a phosphorothioate oligodeoxynucleotide within rodents following intravenous administration, BIOCH PHARM, 62(3), 2001, pp. 297-306
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.