Octadentate hydroxypyridinonate (HOPO) ligands for plutonium (i.v.): pharmacokinetics and oral efficacy.
Linear octadentate spermine based 3,4,3-LI(1,2-HOPO) and the mixed ligand, 3,4,3-LI(1,2-Me-3,2-HOPO), are the most effective agents for decorporation of Pu prepared so far; they are effective at low dosage, orally active, and of low toxicity at effective injected dosage. Their pharmacological properties are favourable for in vivo Pu chelation--penetration of extracellular water, useful residence in the circulation, substantial hepato-biliary excretion, low but useful GI absorption, and transitory residence in the kidneys. Reductions of body Pu were significant, compared with controls, when oral administration to normally fed mice (30 or 100 micromol kg(-1)) was delayed as long as 24 h after i.v. Pu injection. The HOPO ligands (10-100 micromol kg(-1)) or CaNa3-DTPA (100 or 300 micromol kg(-1)) were given orally to normally fed mice starting at 4 h after an i.v. Pu injection and continued 5 d per week for 3 weeks. 3,4,3-LI(1,2-HOPO) (100 micromol kg(-1)) reduced Pu in skeleton, liver, and body, to 44 +/- 9, 18 +/- 8, and 38 +/- 7% of controls, respectively, reductions significantly greater than with the mixed HOPO ligand or with three times more CaNa3-DTPA.
Durbin
P W
PW
Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. PWDurbin-Heavey@LBL.gov
Kullgren
B
B
Xu
J
J
Raymond
K N
KN
Hengé-Napoli
M H
MH
Bailly
T
T
Burgada
R
R
D000284:Administration, Oral; D000818:Animals; D001822:Body Burden; D001842:Bone and Bones / Q000378:metabolism*; D002614:Chelating Agents / Q000008:administration & dosage; D015913:Chelation Therapy / Q000379:methods*; D004064:Digestive System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D007275:Injections, Intravenous; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D011005:Plutonium / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics* / Q000652:urine*; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology*; D014915:Whole-Body Counting / Q000379:methods*
D002614:Chelating Agents; D008024:Ligands; D011725:Pyridines; D011005:Plutonium