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 model of the pharmacokinetics (PBPK) of the phosphorothioate oligonucleotide (PS-ODN) ISIS 1082 in vivo. Rats were administered an intravenous (i.v.) bolus dose of ISIS 1082 (10 mg/kg plus 3H tracer), and arterial blood and tissues were taken at specific times up to 72 hours. Radioactivity was measured 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 capillary gel electrophoresis (CGE). A whole body PBPK model was fitted to the 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. Total radioactivity primarily reflects these species. The whole body model successfully described temporal events in all tissues. However, to adequately model the experimental data, all tissues had to be partitioned into vascular and extravascular spaces to accommodate the relatively slow distribution of ISIS 1082 out of blood because of a permeability rate limitation. ISIS 1082 distributes extensively into tissues, but the relative affinity varies enormously, being highest for kidney and liver and lowest for muscle and brain. A whole body PBPK model with a permeability rate limited tissue distribution was developed that adequately described events in both blood and tissue for an oligonucleotide. This model has the potential not only to characterize the events in individual tissues throughout the body for such compounds but also to scale across animal species, including human.
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
B
B
Peng
J
J
Andrews
I
I
Nestorov
B
B
Brennan
P
P
Nicklin
M
M
Rowland
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000235:genetics / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014316:Tritium
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D014316:Tritium