Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat

The aim of this study was to develop a whole body physiologically based mod el of the pharmacokinetics (PBPK) of the phosphorothioate oligonucleotide ( PS-ODN) ISIS 1082 in vivo. Rats were administered an intravenous (i.v.) bol us dose of ISIS 1082 (10 mg/kg plus H-3 tracer), and arterial blood and tis sues were taken at specific times up to 72 hours. Radioactivity was measure d in all samples. The parent compound was determined specifically in blood and tissues at 90 minutes and in liver and kidney also at 24 hours, using c apillary gel electrophoresis (CGE), A whole body PBPK model was fitted to t he combined blood and tissue radioactivity data using nonlinear regression analysis. CGE analysis indicated that the predominant species in plasma and all tissues is ISIS 1082, together with some n-1 and n-2 metabolites. Tota l radioactivity primarily reflects these species. The whole body model succ essfully described temporal events in all tissues. However, to adequately m odel the experimental data, all tissues had to be partitioned into vascular and extravascular spaces to accommodate the relatively slow distribution o f ISIS 1082 out of blood because of a permeability rate limitation, ISIS 10 82 distributes extensively into tissues, but the relative affinity varies e normously, being highest for kidney and liver and lowest for muscle and bra in, A whole body PBPK model with a permeability rate limited tissue distrib ution was developed that adequately described events in both blood and tiss ue for an oligonucleotide. This model has the potential not only to charact erize the events in individual tissues throughout the body for such compoun ds but also to scale across animal species, including human.