Metabolism and Elimination of Antisense Oligodeoxynucleotides

A prerequisite to acquire an antisense effect is the maintenance of AS-ODN within the target cells. Several studies have reported that the majority of phosphorothioated AS-ODNs taken up by the kidney remains intact for several hours [110,113]. In fact, 4 days after administration, 3% of the infused dose was still present in the kidney intactly [110]. Although several studies have confirmed the presence of intact AS-ODN in the kidney, concomitant metabolism in the kidney of 20% after 6 h [113], 50% after 48 h [118,126] and 50% after 4 days [114] has also been reported. 

In spite of the improved stability to nucleases, achieved through chemical modification, AS-ODN degradation in plasma still occurs, predominantly from the 3 -terminus. In the liver and kidney, the major sites of metabolism, AS-ODNs are degraded from the 5 -terminus as well [127,128]. 

5 Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell 

Elimination of phosphorothioated AS-ODN takes place primarily via the urine. Approximately 30% of the injected dose is found in the urine within 24 h [110,113], Althought in most cases only metabolites of AS-ODN could be demonstrated in the urine [110,118], Agrawal and co-workers described the excretion of intact AS-ODN in the urine after a dose of 30 mg kg [126], The saturation of plasma protein binding and proximal tubular uptake could explain this observation [114,116], 

Excretion via faeces is a minor route of elimination, accounting for less than 10% of the administered dose [113,126], 

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