title: Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration.
abstract: 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. Intravenous disposition studies with [3H]CGP 69846A were supported with analysis by capillary gel electrophoresis and electrospray mass spectrometry. In combination, these techniques provide a detailed account of the pharmacokinetic and metabolic profile for this compound. The elimination of CGP 69846A after a single intravenous dose was studied over extended periods in mice using whole-body autoradiography and capillary gel electrophoresis. Subcutaneous administration to rats resulted in a significant bioavailability with peak plasma levels 4.5-fold lower than after intravenous dosing. This dose route resulted in low interanimal variability and only slightly greater metabolism of the oligonucleotide compared to the intravenous administration.
authors.affiliation: Novartis Horsham Research Centre, West Sussex, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Phillips
authors.forename: S J
authors.initials: SJ
authors.lastname: Craig
authors.forename: D
authors.initials: D
authors.lastname: Bayley
authors.forename: R A
authors.initials: RA
authors.lastname: Christian
authors.forename: R
authors.initials: R
authors.lastname: Geary
authors.forename: P L
authors.initials: PL
authors.lastname: Nicklin
mesh_terms: D000818:Animals; D019075:Electrophoresis, Capillary; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D017208:Rats, Wistar; D013873:Thionucleotides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014316:Tritium
chemical_list: D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D013873:Thionucleotides; D014316:Tritium; C099587:ISIS 5132; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf