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.
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