Hepatic distribution of a phosphorothioate oligodeoxynucleotide within rodents following intravenous administration

• Published in: Biochemical pharmacology 2001-08, Vol.62 (3), p.297-306
• Main Authors: Graham, Mark J., Crooke, Stanley T., Lemonidis, Kristina M., Gaus, Hans J., Templin, Michael V., Crooke, Rosanne M.
• Format: Article
• Language: English
• Subjects: Animals; Antisense; Antiviral Agents - metabolism; Antiviral Agents - pharmacokinetics; Biological and medical sciences; Capillary gel electrophoresis; Dose-Response Relationship, Drug; General pharmacology; Hepatic; Injections, Intravenous; Kinetics; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Oligodeoxyribonucleotides, Antisense - metabolism; Oligodeoxyribonucleotides, Antisense - pharmacokinetics; Oligonucleotide; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Rodent; Subcellular Fractions - metabolism; Thionucleotides - metabolism; Thionucleotides - pharmacokinetics; Time Factors; Tissue Distribution
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(01)00669-4

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.