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

Authors :
Geary, Richard S.
Leeds, Janet M.
Fitchett, Jon
Burckin, Todd
Truong, Loanne
Spainhour, Charles
Creek, Moire
Levin, Arthur A.
Source :
Drug Metabolism and Disposition; November 1997, Vol. 25 Issue: 11 p1272-1281, 10p
Publication Year :
1997

Abstract

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

Details

Language :
English
ISSN :
00909556 and 1521009X
Volume :
25
Issue :
11
Database :
Supplemental Index
Journal :
Drug Metabolism and Disposition
Publication Type :
Periodical
Accession number :
ejs68335629
Full Text :
https://doi.org/10.1124/dmd.25.11.1272