Pharmacokinetics and Metabolism in Mice of a Phosphorothioate Oligonucleotide Antisense Inhibitor of C-raf-1 Kinase Expression

摘要: The plasma and tissue disposition of CGP 69846A (ISIS 5132) was characterized in male CD-1 mice following iv bolus injections administered every other day for 28 days (total 15 doses). doses ranged from 0.8 mg/kg to 100 mg/kg. Urinary excretion oligonucleotide also monitored over a 24-hr period single dose administration the same range. Pharmacokinetic profiles were determined (dose 1) after multiple 15) at 4 20 Concentrations kidney, liver, spleen, heart, lung, lymph nodes 1, 8, all doses. Capillary gel electrophoresis used quantitate intact (full-length) its metabolites (down toN − 11 base deletions) both time points. by rapid distribution into tissues analyzed. Rapid clearance parent (9.3–14.3 ml/min/kg) predominantly result and, lesser extent, metabolism. Appearance pattern chain-shortened seen consistent with exonuclease-mediated deletion. No measurable accumulation observed multiple-dose administration, but liver kidney exhibited 2–3-fold accumulations. In general, half-lives elimination 16–60 hr compared 30–45 min. After repeated administrations, significant decreases volume steady state (Vss) not Changes evidence saturation high may explain changes absence alteration metabolism or accumulation. minor pathway immediately administration. However, amount excreted urine increased as function less than 1% approximately 13% range