In vivo studies with phosphorothioate oligonucleotides: pharmacokinetics prologue.
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.
Iversen
P
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Department of Pharmacology, University of Nebraska Medical Center, Omaha 68198-6260.
D000818:Animals; D001483:Base Sequence; D006801:Humans; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013873:Thionucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics*
D009841:Oligonucleotides; D013873:Thionucleotides