Pharmacokinetics of oligonucleotides.

The effectiveness of antisense oligonucleotides as therapeutic agents depends on their pharmacokinetics, tissue disposition, stability, elimination and safety profile. Pharmacokinetic data allow one to determine the frequency of administration and any potential toxicity associated with chronic administration. Phosphorothioate oligonucleotides degrade from the 3' end, the 5' end, and both the 3' and 5' ends in a time- and tissue-dependent manner. After intravenous administration in mice, rats and monkeys, phosphorothioate oligonucleotides are detected in plasma; they distribute rapidly and are retained in the majority of tissues. The major route of elimination is the urine. The pharmacokinetic profile is similar following subcutaneous, intradermal or intraperitoneal administration, but with lower maximum plasma concentrations. Phosphorothioate oligonucleotides have a short plasma half-life in humans. End-modified, mixed-backbone oligonucleotides (MBOs) contain nuclease-resistant 2'-O-alkylribonucleotides or methylphosphonate internucleotide linkages at both the 3' and 5' ends of phosphorothioate oligonucleotides. These end-modified MBOs have pharmacokinetic profiles similar to those of the parent phosphorothioate oligonucleotides, but they are significantly more stable in vivo and they can be administered orally. Centrally modified MBOs contain modified RNA or DNA in the centre of a phosphorothioate oligonucleotide. They show controlled degradation and elimination following administration in rats. The pharmacokinetics of antisense oligonucleotides depends on the sequence, the nature of the oligonucleotide linkages and the secondary structure.