PHARMACOKINETICS, METABOLISM, AND ELIMINATION OF A 20-MER PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE (CGP 69846A) AFTER INTRAVENOUS AND SUBCUTANEOUS ADMINISTRATION

The pharmacokinetics, tissue distribution and metabolism of CGP 69846A , a 20-mer phosphorothioate oligodeoxynucleotide targeted against the 3'-untranslated region of human c-raf-1 kinase mRNA, were investigated in vivo in rats after intravenous and subcutaneous administration Int ravenous disposition studies with [H-3]CGP 69846A were supported with analysis by capillary gel electrophoresis and electrospray mass spectr ometry. In combination, these techniques provide a detailed account of the pharmacokinetic and metabolic profile for this compound. The elim ination of CGP 69846A after a single intravenous dose was studied over extended periods in mice using whole-body autoradiography and capilla ry gel electrophoresis. Subcutaneous administration to rats resulted i n a significant bioavailability with peak plasma levels 4.5-fold lower than after intravenous dosing. This dose route resulted in low intera nimal variability and only slightly greater metabolism of the oligonuc leotide compared to the intravenous administration. (C) 1997 Elsevier Science Inc.