Circulatory kinetics of intravenously injected 238Pu(IV) citrate and 14C-CaNa3-DTPA in mice: comparison with rat, dog, and reference man.
New ligands for in vivo chelation of Pu(IV) are being synthesized and evaluated in mice for efficacy and toxicity. Biokinetic studies of the new ligands, CaNa3-DTPA, and Pu(IV) are major components of those investigations. Young adult female mice were injected intravenously (iv) with 3H-inulin, 14C-CaNa3-DTPA, or 238Pu(IV) citrate to provide baseline data for plasma clearance, tissue uptake, and excretion rates and to determine the dilution volume (VOD) and renal clearance rate (RC) of filterable substances. Published plasma clearance data for iv-injected 14C-CaNa3-DTPA and Pu(IV) citrate in Reference Man, dog, and rat were collected. Based on combined data for 3H-inulin and 14C-CaNa3-DTPA, VOD = 17% of body weight and RC = 18 mL kg(-1) min(-1) for mice. Retention of 14C-CaNa3-DTPA in the four species is proportional to body weight and inversely proportional to RC: Integrals of the retention of 14C-CaNa3-DTPA from R(t) = 1.0 to R(t) = 0.05 are 108, 43, 28, and 10 DF min, respectively, for Reference Man, dog, rat, and mouse. Clearances of iv-injected Pu(IV) citrate from plasma are in the same order: The plasma curve integrals from injection to 1440 min are 840, 640, 280, and 67 DF min, respectively, for Reference Man, dog, rat, and mouse. In mice, a large fraction of newly injected Pu(IV) is rapidly transferred to the interstitial water of bulk soft tissue (excluding liver and kidneys), from which it is cleared at the same rate as from the plasma. Rapid plasma clearance, escape into interstitial water (22%ID at 20 min), significant early urinary excretion (8%ID in 12 h), and prompt deposition in liver and skeleton (complete in 12 h) are evidence of inefficient binding to plasma protein (mainly transferrin) of newly injected Pu(IV) in mice. Conversely, slow plasma clearance, little early urinary excretion, and delayed deposition in liver and skeleton reflect more efficient binding by transferrin of newly injected Pu(IV) in Reference Man and dog. Pharmacokinetic parameters (effective dosage, effective concentration) of CaNa3-DTPA, alone or combined with plasma Pu(IV) integrals, yielded only qualitative predictions of the relative efficacies of CaNa3-DTPA therapy in four species. The need for improved models of Pu(IV) and ligand biokinetics and the suitability of the three animals for predicting chelation therapy outcomes in humans are discussed.
Durbin
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Chemical Sciences Division Ernest Orlando Lawrence Berkeley National Laboratory University of California, Berkeley 94720, USA.
Kullgren
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B
Schmidt
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D000818:Animals; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D019343:Citric Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D004369:Pentetic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011005:Plutonium / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D019343:Citric Acid; D011005:Plutonium; C086408:plutonium citrate; D004369:Pentetic Acid