In Vivo Pharmacokinetics of Oligonucleotides Following Administration by Different Routes

This chapter summarizes data on the in vivo pharmacokinetics of deoxyribooligonucleotides introduced by traditional intravenous and intraperitoneal injection and results of the authors studies on delivery of oligonucleotides in animals by various nondamaging routes. Distribution and fate of oligonucleotides in whole organisms are affected by a few factors. To investigate molecular interactions of oligonucleotides in the bloodstream, the authors have performed affinity labeling experiments with alkylating derivatives of oligonucleotides bearing an aromatic 2-chloroethylamino group capable of crosslirtking to nucleic acids and proteins. As expected, conjugation of oligonucleotides to groups facilitating cellular uptake of the compounds considerably affects the fate of the oligonucleotides in whole organism. The chapter discusses pharmacokinetics, biodistribution, and excretion of oligodeoxynucleotides and oligodeoxynucleotide phosphorothioates in experiments with different animals. It suggests that the mechanism of oligonucleotide penetration is transcytosis through the mucosa cells. The chapter explains that the transdermal delivery of oligonucleotides can be improved considerably by using iontophoresis.