Toxicology

Advances in Pharmacology by J. Thomas August (Eds.)

By J. Thomas August (Eds.)

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D. Pharmacokinetic Properties To study the pharmacokinetics of phosphorothioate oligonucleotides, a variety of labeling techniques have been used. In some cases, 3’- or 5’-32P end-labeled or fluorescently labeled oligonucleotides have been used in in vitro or in vivo studies. These are probably less satisfactory than internally labeled compounds because terminal phosphates are rapidly removed by phosphatases, and fluorescently labeled oligonucleotides have physicochemical properties that differ from those of the unmodified oligonucleotides.

D. In Vivo Efeas To date, relatively few in vivo studies have been reported. The properties of 5’-cholesterol and S’-C-18 amine conjugates of a 20-mer phosphorothioate oligodeoxynucleotide have been determined in mice. v. bolus dose found in the liver. The cholesterol conjugate, in fact, resulted in more than 8 0 % of the dose accumulating in the liver. Neither conjugate enhanced stability in plasma, liver, or kidney (S. T. , 1996). , 1997f). , 1995). 4.

It also seems likely that the effects of various conjugates on cellular uptake may be affected by the cell type and target studied. For example, we have studied cholic acid conjugates of phosphorothioate deoxyoligonucleotides or phosphorothioate 2’methoxyoligonucleotides and observed enhanced activity against HIV and no effect on the activity of ICAM-directed oligonucleotides. Pharmacology of Antisense Oligonucleotides 35 In addition, polycationic substitutions and various groups designed to bind to cellular carrier systems have been synthesized.

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