Pharmacokinetics phosphorothioate oligonucleotides

Peng, B., Andrews, J., Nestorov, I., Brennan, B., Nicklin, P. and Rowland, M. (2001) Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat. Antisense Nucleic Acid Drug Develop., 11, 15-27. 

T. Burckin, L. Truong, and A.A. Levin. 1997. Pharmacokinetic properties of phosphorothioate oligonucleotides. Nucleosides Nucleotides 16 1689-1693. 

Pharmacokinetics of a 14C-labeled phosphorothioate oligonucleotide, ISIS 2105, after intradermal administration to rats./. Pharmacol. Exp. Ther. 269 ... 

Yu, R.Z., R.S. Geary, J.M. Leeds,T. Ushiro-Watanabe, M. Moore, J. Fitchett, J. Matson, T. Burckin, M.V. Templin, and A.A. Levin. 2001. Comparison of pharmacokinetics and tissue disposition of an antisense phosphorothioate oligonucleotide target-... 

P.J. Schechter. 1999. Pharmacokinetics and tolerability of intravenous trecovirsen (GEM 91), an antisense phosphorothioate oligonucleotide, in HIV-positive subjects. /. Clin. Pharmacol. 39 47-54. 

Leeds, J.M., and R.S. Geary. 1998. Pharmacokinetic properties of phosphorothioate oligonucleotides in humans. In ... 

A. Zutsi, A.A. Levin, and D.J. Kornbmst. 1997. Pharmacokinetics of a potential human cytomegalovirus therapeutic, a phosphorothioate oligonucleotide, after intravitreal injections in the rabbit. Drug Metab. Dispos. 25 921-926. 

Levin AA, Geary RS, Leeds JM, Monteith DK, Yu RZ,Templin MV, Henry SPThe pharmacokinetics and toxicity of phosphorothioate oligonucleotides. In Thomas JA, ed. Biotechnology and Safety Assessment. Philadelphia Taylor and Francis, 1998 151—75. 

In conclusion, phosphorothioate oligonucleotides may interact with a wide range of proteins through several types of mechanisms. These interactions may influence the pharmacokinetic, pharmacologic, and toxicologic properties of these molecules. They may also complicate studies on the mechanism of action of these drugs, and may obscure an antisense activity. For example, phosphorothio-... 

Phosphorothioate oligonucleotides have perhaps outperformed many expectations. They display attractive parenteral pharmacokinetic properties. They have produced potent systemic effects in a number of animal models and, in many experiments, the antisense mechanism has been directly demonstrated as the hoped-for selectivity. Further, these compounds appear to display satisfactory therapeutic indices for many indications. 

Perhaps more important, 2 -0-(2-metho3 -ethyl) chimeras are substantially more stable than phosphorothioate oligonucleotides. In mice, rats, and monkeys, the elimination half-life is nearly 30 days in plasma and several tissues (314, 366-368). Furthermore, in the liver, elegant correlations between pharmacokinetic and pharmacodynamic effects have been reported to show a duration of pharmacological action of nearly 20 days in the mouse (369). 

Templin M V, Levin A A, et al. (2000). Pharmacokinetic and toxicity profile of a phosphorothioate oligonucleotide following inhalation delivery to lung in mice. Anti-sense Nucleic Acid Drug Dev. 10 359-368. 

Henry SP, Templin MV, Gillett N, et al. Correlation of toxicity and pharmacokinetic properties of a phosphorothioate oligonucleotide designed to inhibit ICAM-1. Toxicol Pathol 1999 27 95-100. 

Srinivasan SK, Iversen P (1995) Review of in vivo pharmacokinetics and toxicology of phosphorothioate oligonucleotides. J Clin Lab Anal 9(2) 129-137... 

Agrawal S, Tan W, Cai Q et al (1997) In vivo pharmacokinetics of phosphorothioate oligonucleotides containing contiguous guanosines. Antisense Nucleic Acid Drug Dev 7 245-249... 

J. Matson, H. Sasmor, L. Cummins, and A.A. Levin. 2003. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2 -0-(2-methoxyethyl) modified antisense oligonucleotide comparison across species. Drug Metah. Dispos. 31 1419-1428. 

Levin, A.A. 1999. A review of issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim. Biophys. Acta 1489 69-84. 

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