Antisense Oligonucleotides and RNA Interference - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 349

7.7.1 Pharmacokinetics
AS ODNs are designed specifically and selectively to inhibit translation of target
mRNA and expression of related protein [137,138] . To elucidate the safety of AS
ODNs, their biological activity as a function of dose, rate of distribution, and mech-
anism of clearance from the body must be established. Because phosphorothioate
oligonucleotides were the first synthetically prepared antisense nucleotides, their phar-
macokinetics, and hence their efficacy and safety, has been widely studied and reported
[134-136] . Their pharmacokinetics has been found to be independent of their physical
and chemical properties. Following injection, AS ODNs bind to various proteins, dis-
tribute to various tissues, and finally get cleared from the body. The kidney, liver, and
other organs of the RES are the major organs of distribution for AS ODNs and siRNA
[135-137] , and have benefitted from their ability to target to these sites. Certain siRNA
formulations also accumulate in subcutaneous tumors through enhanced permeability
and retention due to their leaky vasculature [135] . The reported data demonstrate that
the pattern of absorption, distribution, and clearance of phosphorothioates in various
species such as mouse, rat, dog, and monkey is similar and independent of oligonucle-
otide sequence and route of administration [135-139] . With intravenous administration,
the concentration of oligonucleotides in plasma decreases rapidly, with distribution half
lives of 30-80 min, whereas with intravenous infusion, oligonucleotide concentration
[134,136] increases linearly as the dose increases [140] . Intravenous administration
of oligonucleotides also bypasses the absorption barriers to antisense drug delivery,
usually encountered with other routes of administrations. However, rapid intravenous
injection results in hemolytic effects due to high local concentrations of oligonucle-
otides. Hence, slow intravenous administration is advantageous over rapid injection.
When considering tissue distribution of phosphothiorate (PS) oligonucleotides, high-
est concentrations are found in the liver and kidney, followed by the spleen and lymph
nodes [140-142] . Tissue uptake of these oligonucleotides can be readily increased
using long-term continuous infusion, which extends the exposure of PS oligonucle-
otides to the target tissues. However, their clearance from the organs of distribution
is relatively slow, requiring a 3-times-a-week treatment regime, thereby ensuring an
enhanced biological effect.
7.7.2 Elimination
This includes both metabolism and excretion of AS ODNs. Plasma and tissue exonu-
cleases account majorly for the degradation of oligonucleotides in blood and organs of
distribution, respectively [133,143] . These exonucleases cleave oligonucleotides either
at the 3 or 5 end, liberating smaller nucleotides, each shortened by a single nucleo-
tide. The metabolism of many AS ODNs follows the same pathway as the endogenous
nucleic acids. Immediately following intravenous administration, 35% of the AS ODN
degrades within 10 min [140] . In tissue metabolism, the metabolites, being smaller,
excrete more slowly than the parent oligonucleotide [144] . These low-molecular-
weight metabolites are ultimately excreted from the body through urinary and fecal
excretion. However, excretion via bile has also been suggested for AS ODNs.