Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice.
We describe preliminary studies of the pharmacokinetics, biodistribution, and excretion of an oligodeoxy-nucleotide phosphorothioate ([S]oligonucleotide) in mice. After either intravenous or intraperitoneal administration of a single dose (30 mg/kg of body weight), [S]oligonucleotide (35S-labeled at each internucleotide linkage) was found in most of the tissues for up to 48 hr. About 30% of the dose was excreted in urine within 24 hr, irrespective of the mode of administration; the excreted [S]oligonucleotide was found to be extensively degraded. In plasma, stomach, heart, and intestine, the [S]oligonucleotide was degraded by only 15%, whereas in the kidney and liver degradation was about 50% in 48 hr. The surprising observation was made that chain length extension of administered [S]oligonucleotide occurred in kidney, liver, and intestine. These results provide an initial definition of parameters for the pharmaceutical development of antisense oligonucleotides.
Agrawal
S
S
Worcester Foundation for Experimental Biology, Shrewsbury, MA 01545.
Temsamani
J
J
Tang
J Y
JY
D000818:Animals; D001483:Base Sequence; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013462:Sulfur Radioisotopes; D013873:Thionucleotides / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D013462:Sulfur Radioisotopes; D013873:Thionucleotides