PHARMACOKINETICS OF ANTISENSE ANALOGS IN THE CENTRAL-NERVOUS-SYSTEM

A thorough evaluation of the pharmacokinetical properties of oligodeox yribonucleotides (ODN) is a first step towards their rational applicat ion as gene expression blockers in the central nervous system (CNS). I n this paper we present our own data, as well as those of other author s, on tissue distribution, stability, retention and cellular uptake of phosphodiester, phosphorothioate, and end-capped analogues of ODN int roduced into the CNS. ODN are easily distributed within nervous tissue , and their tissue penetration depends on anatomical conditions. Reten tion of radioactivity delivered with ODN within nervous tissue is high er for phosphodiesters than for phosphorothioates. On the other hand, the tissue stability of phosphorothioates is substantially greater tha n the tissue stability of phosphodiesters as well as that of end-cappe d ODN. If the elimination process of ODN is also due to their degradat ion, it is apparently accomplished by endonucleases, because the recov ery of endcapped ODN (resistant to exonucleases) was similar to unprot ected phosphodiesters. The uptake of ODN by nerve cells is rather poor , although we have shown that phosphorothioates at least can be intern alized by nerve cells in vivo. ODN are metabolized by nerve cells, whi ch results in the formation of unidentified molecules of higher molecu lar weight than ODN themselves. (C) 1997 Elsevier Science Ltd.