In vivo studies with phosphorothioate oligonucleotides: pharmacokinetics prologue.

Abstract

Phosphorothioate oligonucleotides which contain 35S at each internucleoside linkage have been prepared and employed to evaluate the in vivo pharmacokinetics in mice, rats and rabbits. A single administration of a 27-mer complementary to the rev gene of HIV into adult male rats by either the intravenous or intraperitoneal route reveals a biphasic plasma elimination. An initial half-life of 15-25 min represents distribution out of the plasma compartment and a second half-life of 20-40 h represents elimination from the body. The second half-life is significantly longer than a variety of nucleic acids such as poly-IC and Ampligen and suggests therapy with phosphorothioate oligonucleotides should be possible and practical. Repeated daily injections of the 27-mer provides steady-state concentrations in 6-9 days, confirming the estimated long half-life from single injection studies. Finally, chronic treatment studies indicate that the phosphorothioate oligonucleotides are relatively non-toxic. Hence, pharmacokinetic considerations are not likely to be limiting factors in anti-cancer drug design with phosphorothioate oligonucleotides.

• Authors: P Iversen
• Journal: Anti-cancer drug design (Anticancer Drug Des) Vol. 6 Issue 6 Pg. 531-8 (Dec 1991) ISSN: 0266-9536 [Print] United States
• PMID: 1772568 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Oligonucleotides
• Thionucleotides

Topics

• Animals
• Base Sequence
• Humans
• Molecular Sequence Data
• Oligonucleotides (administration & dosage, pharmacokinetics)
• Thionucleotides (administration & dosage, pharmacokinetics)