Pulmonary bioavailability of a phosphorothioate oligonucleotide (CGP 64128A): comparison with other delivery routes

Pharm Res. 1998 Apr;15(4):583-91. doi: 10.1023/a:1011934011690.


Purpose: Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents.

Methods: The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses.

Results: Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intraperitoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (< 2%). Intra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, respectively.

Conclusions: Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Intestinal Absorption
  • Lung / metabolism*
  • Lung / pathology
  • Male
  • Oligodeoxyribonucleotides, Antisense*
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / pharmacokinetics*
  • Rats
  • Rats, Wistar
  • Thionucleotides / administration & dosage
  • Thionucleotides / pharmacokinetics*
  • Tissue Distribution
  • Trachea / metabolism*
  • Trachea / pathology
  • Tritium


  • Oligodeoxyribonucleotides, Antisense
  • Oligonucleotides, Antisense
  • Thionucleotides
  • Tritium
  • ISIS 3521