Pharmacokinetics of antisense analogues in the central nervous system.
A thorough evaluation of the pharmacokinetical properties of oligodeoxyribonucleotides (ODN) is a first step towards their rational application as gene expression blockers in the central nervous system (CNS). In this paper we present our own data, as well as those of other authors, on tissue distribution, stability, retention and cellular uptake of phosphodiester, phosphorothioate, and end-capped analogues of ODN introduced into the CNS. ODN are easily distributed within nervous tissue, and their tissue penetration depends on anatomical conditions. Retention of radioactivity delivered with ODN within nervous tissue is higher for phosphodiesters than for phosphorothioates. On the other hand, the tissue stability of phosphorothioates is substantially greater than the tissue stability of phosphodiesters as well as that of end-capped ODN. If the elimination process of ODN is also due to their degradation, it is apparently accomplished by endonucleases, because the recovery of end-capped ODN (resistant to exonucleases) was similar to unprotected phosphodiesters. The uptake of ODN by nerve cells is rather poor, although we have shown that phosphorothioates at least can be internalized by nerve cells in vivo. ODN are metabolized by nerve cells, which results in the formation of unidentified molecules of higher molecular weight than ODN themselves.
Szklarczyk
A
A
Nencki Institute of Experimental Biology, Warsaw, Poland.
Kaczmarek
L
L
D000818:Animals; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics*; D013873:Thionucleotides / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides