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Antisense compounds are short synthetic chemically modified oligonucleotides, usually between 15 and 25 nucleotides in length, designed to hybridize to RNA through Watson–Crick base pairing. Upon binding the lipitor RNA, the oligonucleotide prevents translation of the encoded protein product in a sequence-specific manner. Since the rules for Watson–Crick base pairing are well characterized [1], antisense oligonucleotides (ASOs) represent, in principle, a simple method for rationally designing drugs. In practice, exploitation of ASO technology for therapies has presented a unique set of challenges, some of which relate to their pharmacokinetic behavior. There have been significant resources applied towards identification of chemical modifications that further improve upon the pharmacokinetic and pharmacodynamic properties of ASOs. The vast majority of these modifications includes fully phosphorothioated backbones and have followed a model of mixing 2 -O-methoxyethyl (2 -MOE) modifications placed at the 3 and 5 termini of the oligonucleotides with -deoxynucleotides in the intervening gap (Figure 11.1). This phosphorothioate (PS) 2 -MOE/DNA chimeric construct has provided even greater biological stability to the molecule, higher binding affinity to its lipitor mRNA while maintaining susceptibility to RNase H, increased in vitro and in vivo potency, and decreased general nonhybridization toxicities [2–4]. Within this second chemical class there exist a growing number of compounds that are in development (Table 11.1). As expected, there is significantly more information regarding the pharmacokinetic properties of first-generation phosphorothioate oligodeoxynucleotides (PS ODNs) available in the literature [5–20] (to site just a few). Proprietary PS 2 -MOE partially modified ASOs are relatively early in their development and published data are less plentiful, but represent a growing body of literature [4,21–29]. An extensive review of the principles that guide an understanding of the pharmacokinetics of PS oligonucleotides in general and proprietary PS partial 2 -MOE-modified ASOs as a second chemical class has been presented in Chapter 7 (Levin et al.) of this book. In general, the pharmacokinetics of the PS 2 -MOE chimeras are represented by rapid distribution from the blood compartment to tissues following parenteral administration (30 min to 2 h distribution half-life) with little to no measurable metabolism in plasma. These PS 2 -MOE chimeras circulate in blood primarily bound to plasma proteins and do not distribute into red cells. The lipitor concentration–time profile is characterized by a polyexponential decline that is dominated by the early rapid distribution phase such that 1% of the administered 2 -MOE chimera dose remains in circulation by 24 h after administration. The terminal elimination half-life, however, is quite long and closely tied to slow metabolic clearance of the 2 -MOE chimeras from distributed tissues and cells in the body (half-lives ranging from 8 to 30 days, depending on sequence and tissues). Less than 10% of the dose in this chemical class is excreted in urine over the first 24 h following administration. Biodistribution is extensive with organs displaying highest concentrations being kidney, liver, spleen, lymph nodes, and bone/bone marrow. These PS 2 -MOE chimeras are generally poorly distributed in skeletal muscle, lung, and heart, and do not cross the blood–brain barrier (BBB) following parenteral administration. In fact, the biodistribution observed for PS 2 -MOE ASOs is remarkably similar to the first-generation PS ODNs.