Hepatic distribution of a phosphorothioate oligodeoxynucleotide within rodents following intravenous administration.
The pharmacokinetics of ISIS 1082, a 21-base heterosequence phosphorothioate oligodeoxynucleotide, were characterized within rodent whole liver, and cellular and subcellular compartments. Cross-species comparisons were performed using Sprague-Dawley rat and CD-1 mouse strains. Although whole liver oligonucleotide deposition and the proportion of drug found within parenchymal and nonparenchymal cells were similar between the two rodent species as a function of both time and dose, dramatic differences in subcellular pharmacokinetics were observed. Specifically, within murine hepatocyte nuclei, drug was observed at the 10 mg/kg dose, whereas in the rat nuclear-associated levels required the administration of 25 mg/kg. Under all experimental regimens, murine hepatic nuclear-associated drug concentrations were at least 2-fold higher than those found in rat liver cells. More detailed metabolic analysis was also performed using high performance liquid chromatography/electrospray-mass spectrometry (HPLC/ES-MS) and demonstrated that although the extent of metabolism was similar for rat and mouse, the pattern of n-1 metabolites varied as a function of both species and cell type. While rat and mouse hepatocytes and rat nonparenchymal cellular metabolites were predominantly products of 3'-exonuclease degradation, mouse nonparenchymal cells contained a majority of n-1 metabolites produced by 5'-exonucleolytic activity. Based upon these data, it would appear that subcellular oligonucleotide disposition and metabolism among rodent species are more divergent than whole organ pharmacokinetics might predict.
Graham
M J
MJ
ISIS Pharmaceuticals, Inc., Carlsbad Research Center, 1896 Rutherford Rd., Carlsbad, CA 92008, USA. mgraham@isisph.com
Crooke
S T
ST
Lemonidis
K M
KM
Gaus
H J
HJ
Templin
M V
MV
Crooke
R M
RM
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
D000998:Antiviral Agents; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides; C075374:ISIS 1082