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Vol. 296, Issue 2, 388-395, February 2001
Isis Pharmaceuticals, Inc., Departments of Pharmacokinetics
(R.Z.Y., R.S.G., L.M., A.A.L.), Antisense Drug Discovery (M.G., K.L.,
R.C.), and Pharmacology (H.Z., N.M.D.), Carlsbad, California
ISIS 22023 is a modified phosphorothioate antisense oligonucleotide
targeting murine Fas mRNA. Treatment of mice with ISIS 22023 reduced
Fas expression in liver in a concentration-dependent and
sequence-specific manner, which completely protected mice from
fulminant death induced by agonistic Fas antibody. In this study, we
characterized the relationships in mice between total dose
administered, dose to the target organ, and ultimately, the intracellular concentration within target cell types to the
pharmacologic activity of ISIS 22023. After subcutaneous injection,
ISIS 22023 distributed to the liver rapidly and remained in the liver
with the t1/2 ranging from 11 to 19 days,
depending on dose. There were apparent differences in patterns of
uptake and elimination in different types of liver cells.
Oligonucleotide appeared within hepatocytes rapidly, whereas the peak
concentrations in Kupffer cells were delayed until 2 days after dose
administration. Hepatocytes cleared oligonucleotide the most rapidly,
whereas Kupffer cells appeared to retain oligonucleotide longer. The
reduction of Fas mRNA levels (pharmacodynamic response)
paralleled the increase of oligonucleotide concentration in mouse liver
with maximum mRNA reduction of 90% at 2 days after a single 50 mg/kg
subcutaneous administration. Moreover, the pharmacodynamics of ISIS
22023 correlated better with the pharmacokinetics in hepatocytes,
supporting the concept that the presence of oligonucleotide in target
cells results in reductions in mRNA and, ultimately, pharmacologic
activity. These results provide a comprehensive understanding of the
kinetics of an antisense drug at the site of action and demonstrate
that the reductions in mRNA induced by this antisense oligonucleotide correlate with its concentrations in cell targets.
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