Pharmacokinetic Aspects of Antisense Oligodeoxynucleotides and Renal Distribution

4 Pharmacokinetic Aspects of Antisense Oligodeoxynucleotides and Renal Distribution 

The tissue distribution of AS-ODN after a single intravenous injection has been studied extensively in many species including mouse [109], rat [110], monkey [111] and man [112].The majority of pharmacokinetic studies have been performed using phosphorothioated AS-ODNs. In general, the pharmacokinetic profiles of AS-ODNs of varying lengths (up to 20mer) and base compositions are remarkably similar in all species. 

In plasma, most of the phosphorothioated AS-ODNs are protein bound [113,114]. Cossum and co-workers revealed that albumin and aj-macroglobulin are responsible for this binding [114], The protein binding capacity in rat was elevated after administration of doses higher than 15-20 mg kg resulting in a dose-dependent increase in distribution volume and an increase in plasma clearance [115-117]. 

The rapid elimination from plasma following intravenous administration of phosphorothioated AS-ODN can be explained by a two compartment model in all species, i.e. an initial plasma half-life of less than 1 h [111,113,114] and a slower elimination half-life ranging between 20 and 50 h [111,113]. 

The kidneys and the liver primarily take up phosphorothioated AS-ODN after parenteral administration, accumulating more than 10% each, while the rest of the organs all accumulate less than 1% of the injected dose [110,111,114,116]. It is noteworthy that renal AS-ODN tissue levels exceed that of any other organ [110,113,114], as confirmed by the tissue to plasma ratios of approximately 85 and 20 for kidney and liver, respectively [113,118]. 

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