Plasma clearance and tissue distribution of partially thiolated polycytidylic acid and its degradation products in rodents.
Radioactive (35S-labeled) partially thiolated polycytidylic acid (MPC) was administered i.v. to male Sprague-Dawley rats. Blood samples were taken at various intervals, and the radioactivity in plasma was determined. The concentration of total radioactivity in plasma decreased rapidly postinjection, independently of the dose, and could not be readily resolved into a series of exponential terms with a high degree of confidence. Coadministration with polyinosinic acid in a 1:1 ratio significantly decreased the clearance of radioactive compounds from the plasma; moreover, the clearance of radioactivity decreased with increasing dose. Complexing with polyinosinic acid also decreased the rate of degradation of [35S]MPC as evidenced by an increase of the trichloroacetic acid-precipitable fraction (i.e., oligonucleotides larger than five to ten nucleotide units), from 0.45 to 0.92 of the total radioactivity in plasma 60 min postinjection. The plasma clearance and organ distribution of radioactivity following injection of [35S]MPC were determined in normal and leukemic RFM/Un mice. About 90% of the 35S radioactivity was removed from the plasma in 5 and 10 min, respectively, in these two groups of mice, and the residual plasma levels of radioactivity at any given time were twice as high in the leukemic group throughout an observation period of 1 hr. Organ distribution studies demonstrated significantly greater (per mg tissue) accumulation of radioactivity in the livers and spleens of the leukemic versus normal mice at all time points, while the corresponding data for the kidneys were similar for the two groups. Another study, comparing the radioactivity in suspended and washed spleen cells harvested 60 min postinjection, indicated that 4 to 10 times more MPC and/or 35S-labeled oligonucleotides were localized and bound intracellularly in the spleens of the leukemic mice. These studies of the pharmacokinetic properties and metabolic degradation of [35S]MPC suggest that this polynucleotide may be protected from degradation by complexing with polyinosinic acid and that preferential accumulation of [35S]MPC occurs in organs infiltrated by leukemic cells.
D000818:Animals; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D007942:Leukemia, Experimental / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D011066:Poly C / Q000097:blood / Q000378:metabolism*; D011131:Polyribonucleotides / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000378:metabolism; D013462:Sulfur Radioisotopes; D014018:Tissue Distribution
D011131:Polyribonucleotides; D013462:Sulfur Radioisotopes; D011066:Poly C