PHARMACOKINETICS OF OLIGONUCLEOTIDE-BASED THERAPEUTICS
Pharmacokinetic studies with different types of ONs (in particular phosphorothioate-ONs) have demon-strated that ONs are rapidly absorbed from parenteral sites. Bioavailability of ONs can be as high as 90% after intradermal injections. Oral bioavailability, how-ever, is generally very low due to their large molecular weight, multiple charges at physiological pH, andlimited stability in the gastrointestinal tract due to nuclease digestion.
ONs broadly distribute to peripheral tissues, with highest accumulation in liver, kidney, bone marrow, skeletal muscle, and skin. Passage over the blood–brain barrier has not been reported. Distribution is often fast, with reported distribution half-lives of less than an hour.
Due to the small size of oligonucleotide ther-apeutics (10–13 kDa), they are normally rapidly cleared from the circulation by renal filtration, with plasma elimination half-lives of <10 min. However, many types of ONs, especially the phosphorothioate-ONs (see below) bind extensively to plasma proteins. This high plasma protein binding protects ONs from renal filtration, so that urinary excretion of intact compound is only a minor elimination pathway for highly bound ONs and plasma elimination half-lives are much longer. Furthermore, renal filtration can be prevented by modifying the ONs with large mole-cules such as poly(ethylene glycol) as long as modification does not hamper its function. PEGylation of aptamers, for instance, results in increased blood residence times of these aptamers, without hampering the ability to bind protein targets (Watson et al., 2000). In addition to renal elimination, metabolism by exo- and endonucleases plays an important role in the elimination of ONs. Nuclease-mediated metabolism is the predominant elimination route for ONs that have been extensively distributed to peripheral tissues and/or are protected from renal elimination.