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Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and a phosphorothioate.
Mol Pharmacol. 1994 May; 45(5):932-43.MP

Abstract

Biodistribution and metabolism of oligonucleotides were determined using a 3H-labeled 20-nucleotide phosphodiester and its phosphorothioate analog. The oligonucleotides were radiolabeled by 3H-methylation of an internal deoxyctidine with HhaI methylase and S- [3H]adenosylmethionine. Biodistribution studies were conducted after intravenous injection of 6 mg/kg (5 muCi) oligonucleotide. Metabolism of the oligonucleotides was determined by paired-ion high performance liquid chromatography. After phosphodiester injections, radiolabel rapidly cleared the blood. Relative initial concentrations were as follows: kidney > blood > heart > liver > lung > spleen. Radiolabel in spleen peaked at 1 hr and remained elevated for 24 hr. At 2 hr the concentration in all organs, except spleen, was equal to that in blood. High performance liquid chromatographic analysis of the kidney, liver, and spleen extracts and urine indicated extremely rapid metabolism to monomer. Results of studies after the injection of phosphorothioate oligonucleotide differed from those using the phosphodiester. Despite its rapid clearance from blood, phosphorothioate accumulated rapidly in all tissues, especially the kidney. Kidney uptake increased over time, remaining very high for 24 hr. Ratios of organ to blood concentrations at 2 hr for all organs were 5:1 or greater. Kidney and liver ratios were 84:1 and 20:1, respectively. Analysis of the kidney and liver extracts and urine indicated that slow metabolism occurred. These data suggest that phosphodiester oligonucleotides would have limited therapeutic utility. The stability and organ distribution of the phosphorothioate oligonucleotide imply that such oligonucleotides may have therapeutic potential.

Authors+Show Affiliations

DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

8190109

Citation

Sands, H, et al. "Biodistribution and Metabolism of Internally 3H-labeled Oligonucleotides. I. Comparison of a Phosphodiester and a Phosphorothioate." Molecular Pharmacology, vol. 45, no. 5, 1994, pp. 932-43.
Sands H, Gorey-Feret LJ, Cocuzza AJ, et al. Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and a phosphorothioate. Mol Pharmacol. 1994;45(5):932-43.
Sands, H., Gorey-Feret, L. J., Cocuzza, A. J., Hobbs, F. W., Chidester, D., & Trainor, G. L. (1994). Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and a phosphorothioate. Molecular Pharmacology, 45(5), 932-43.
Sands H, et al. Biodistribution and Metabolism of Internally 3H-labeled Oligonucleotides. I. Comparison of a Phosphodiester and a Phosphorothioate. Mol Pharmacol. 1994;45(5):932-43. PubMed PMID: 8190109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and a phosphorothioate. AU - Sands,H, AU - Gorey-Feret,L J, AU - Cocuzza,A J, AU - Hobbs,F W, AU - Chidester,D, AU - Trainor,G L, PY - 1994/5/1/pubmed PY - 1994/5/1/medline PY - 1994/5/1/entrez SP - 932 EP - 43 JF - Molecular pharmacology JO - Mol Pharmacol VL - 45 IS - 5 N2 - Biodistribution and metabolism of oligonucleotides were determined using a 3H-labeled 20-nucleotide phosphodiester and its phosphorothioate analog. The oligonucleotides were radiolabeled by 3H-methylation of an internal deoxyctidine with HhaI methylase and S- [3H]adenosylmethionine. Biodistribution studies were conducted after intravenous injection of 6 mg/kg (5 muCi) oligonucleotide. Metabolism of the oligonucleotides was determined by paired-ion high performance liquid chromatography. After phosphodiester injections, radiolabel rapidly cleared the blood. Relative initial concentrations were as follows: kidney > blood > heart > liver > lung > spleen. Radiolabel in spleen peaked at 1 hr and remained elevated for 24 hr. At 2 hr the concentration in all organs, except spleen, was equal to that in blood. High performance liquid chromatographic analysis of the kidney, liver, and spleen extracts and urine indicated extremely rapid metabolism to monomer. Results of studies after the injection of phosphorothioate oligonucleotide differed from those using the phosphodiester. Despite its rapid clearance from blood, phosphorothioate accumulated rapidly in all tissues, especially the kidney. Kidney uptake increased over time, remaining very high for 24 hr. Ratios of organ to blood concentrations at 2 hr for all organs were 5:1 or greater. Kidney and liver ratios were 84:1 and 20:1, respectively. Analysis of the kidney and liver extracts and urine indicated that slow metabolism occurred. These data suggest that phosphodiester oligonucleotides would have limited therapeutic utility. The stability and organ distribution of the phosphorothioate oligonucleotide imply that such oligonucleotides may have therapeutic potential. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/8190109/Biodistribution_and_metabolism_of_internally_3H_labeled_oligonucleotides__I__Comparison_of_a_phosphodiester_and_a_phosphorothioate_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8190109 DB - PRIME DP - Unbound Medicine ER -