PHARMACOKINETICS AND TISSUE DISPOSITION OF A CHIMERIC OLIGODEOXYNUCLEOSIDE PHOSPHOROTHIOATE IN RATS AFTER INTRAVENOUS ADMINISTRATION

Antisense oligonucleotides represent a novel therapeutic principle for designing drugs against various diseases. Oligonucleotides can be che mically modified to improve their pharmacokinetics and in vivo stabili ty, and it is important to understand the effect of these modification s. In the present study, the pharmacokinetics of a 25-mer phosphorothi oate oligonucleotide containing four contiguous, internucleotide, meth ylphosphonate linkages at the 3'- and 5'-ends (chimeric oligonucleotid e) were determined in rats after i.v. administration of the S-35-label ed oligonucleotide at a dose of 30 mg/kg. Plasma disappearance of the oligonucleotide could be described by a two-compartment model, with ha lf-lives of 0.38 and 52.9 hr. The intact chimeric oligonucleotide was detected in plasma up to 6 hr after dosing. Urinary excretion represen ted the major elimination pathway, with approximately 21% of the admin istered dose being excreted within 24 hr and 35% being excreted over a 240-hr period after dosing. The majority of the radioactivity in urin e was associated with the intact oligonucleotide within 6 hr after dos ing and with increasing degradation products thereafter. Fecal excreti on was a minor elimination path way. The oligonucleotide was widely di stributed in tissues, with the majority of the radioactivity in most t issues being intact up to 48 hr after dosing. Compared with oligodeoxy nucleotide phosphorothioates, the chimeric oligonucleotide was signifi cantly more stable in vivo. The presence of intact oligonucleotide in plasma and tissues even 12 hr after dosing is a significant advantage over an ''all''-phosphorothioate analog. Thus, the chimeric oligonucle otide could provide a longer duration of action as an antisense agent after its administration.