Pharmacokinetics phosphorothioates

The tissue distribution of AS-ODN after a single intravenous injection has been studied extensively in many species including mouse [109], rat [110], monkey [111] and man [112].The majority of pharmacokinetic studies have been performed using phosphorothioated AS-ODNs. In general, the pharmacokinetic profiles of AS-ODNs of varying lengths (up to 20mer) and base compositions are remarkably similar in all species. 

Zhang, R., Diasio, R.B., Lu, Z., Liu, T., Jiang, Z., Galbraith, W.M. and Agrawal, S. (1995a) Pharmacokinetics and tissue disposition in rats of an oligodeoxynucleotide phosphorothioate (GEM 91) developed as a therapeutic agent for human immunodeficiency virus type-1. Biochem. Pharm., 49, 929-939. 

Zhang, R., Iyer, P., Yu, D., Zhang, X., Lu, Z., Zhao, H. and Agrawal, S. (1996) Pharmacokinetics and tissue disposition of a chimeric oligodeoxynucleotide phosphorothioate in rats following intravenous administration. J. Pharm. Exp. Ther., 278, 971-979. 

Agrawal, S., Temsamani, J. and Tang, J.Y. (1991) Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc. Natl. Acad. Sci. USA, 88, 7595-7579. 

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. 

Phillips, J.A., Craig, S.J., Bayley, D., Christian, R.A., Geary, R. and Nicklin, P.L. (1997) Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration. Biochem. Pharmacol, 54, 657-668. 

Wu, D., R. Boado, and W. Pardridge. 1996. Pharmacokinetics and blood-brain barrier transport of [3H]-biotinylated phosphorothioate oligodeoxynucleotide conjugated to a vector-mediated drug delivery system. J Pharmacol Exp Ther 276 206. 

D.K. Monteith, and A.A. Levin. 1997. Antisense oligonucleotide inhibitors for the treatment of cancer 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anti-Cancer Drug Design 12 383-393. 

A. Roskey, and S. Agrawal. 1998. Pharmacokinetics and metabolism of an oligodeoxynucleotide phosphorothioate (GEM91) in cynomolgus monkeys following intravenous infusion. Antisense Nucleic Acid Drug Dev. 8 43—52. 

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 ... 

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. 

M. Creek, and A.A. Levin. 1997. Pharmacokinetics and metabolism in mice of a phosphorothioate oligonucleotide anti-sense inhibitor of C-raf-1 kinase expression. Drug Metab. Dispos. 25 1272-1281. 

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

Geary RS, Yu RZ, Siwkowski A. Pharmacokinetic/pharmacodynamic properties of phosphorothioate 2 -0-(2-methoxyethyl) modified antisense oligonucleotides in animals and man. In Crooke ST, ed. Antisense Drug Technology. New York Dekker, 2007. 

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. 

Phillips JA, Craig SJ, Bayley D, Christian RA, Geary RS, Nicklin PL. Pharmacokinetics, metabolism and elimination of a 20-mer phosphorothioate ohgodeoxynu-cleotide (CGP 69846a) after intravenous and subcutaneous admi n istration. Iliochem Pharmacol 1997 54(6) 657-68. 

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