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By J. Thomas August (Eds.)

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Urinary recovery of radioactivity was reported to be 30-60% of the total dose, with 30% of the radioactivity being intact drug. Metabolites in urine included both higher and lower molecular weight compounds. 8 ng/ml was observed a t the cessation of the infusion. 71 hr, respectively. However, degradation was extensive and intact drug pharmacokinetic models were not presented. Nearly 50% of the administered radioactivity was recovered in urine, but most of the radioactivity represented degradates.

Consequently, either uniformly 3’S-labeled or base-labeled phosphorothioates are preferable for pharmacokinetic studies. , 1993). , 1994). Finally, advances in extraction, separation, and detection methods have resulted in methods that provide excellent pharmacokinetic analyses without radiolabeling (S. T. , 1996). 1. Nuclease Stability The principal metabolic pathway for oligonucleotides is cleavage via endonucleases and exonucleases. , 1991; S . T. , 1995). Consequently, the stability of phosphorothioate oligonucleotides to nucleases is probably less than initially thought, as high concentrations (that inhibited nucleases) of oligonucleotides were employed in the early studies.

Similarly, C-2 modifications have usually resulted in destabilization. , 1991). Of the 3position-substituted bases reported to date, only the 3-deazaadenosine analog has been shown to have no negative effect on hybridization. Modifications at the C-6 and C-7 positions have likewise resulted in only a few interesting bases from the point of view of hybridization. , 1985). , 1991). , 1989). Thus, on occasion, introduction of more than one modification in a nucleobase may compensate for destabilizing effects of some modifications.

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