Pharmacokinetic distribution of 67Cu(II)2[3,5-diisopropyl(carboxy-14C)salicylate]4 among murine tissues.
Non-toxic doses of tetrakis-mu-3,5-diisopropylsalicylatodicopper(II) [Cu(II)2(3,5-DIPS)4] have been found to have anti-inflammatory, analgesic, anti-ulcer, anti-colitis, anti-convulsant, anti-cancer, anti-mutagenic, anti-carcinogenic, and anti-diabetic activities and, in addition, facilitates recovery from lethal irradiation and ischemia-reperfusion injuries. The goal of this research was to determine the time-dependent tissue distribution and persistence of 67Cu and the 14C labeled salicylate ligand, carboxy-14C-3, 5-diisopropylsalicylate [3,5-DIP(carboxy-14C)S], following subcutaneous administration of a 50 micromole per kilogram of body mass dose of double labeled tetrakis-mu-3,5-diisopropyl[carboxy-14C]salicylatodiaquo [67Cu]dicopper(II) 67Cu(II)4[3,5-DIP(carboxy-14C)S]4. This compound was administered to nine groups of six 20 gram female C57BL/6 mice and blood, liver, kidney, intestine, lung, thymus, femur, muscle, spleen, and brain tissues removed and analyzed for 67Cu and 14C at 0.5, 1, 3, 6, 12, 24, 48, 72, and 96 hours after treatment. These data were then analyzed using a pharmacokinetic model simulation program. Both 67Cu and 14C were found in all tissues as well as urine and feces at 0.5 hour after administration. As anticipated, 67Cu entered the liver storage pool; it was conserved by the kidneys, and subsequently underwent release in maintaining 67Cu levels in all other tissues. While the presence of 67Cu correlated with the presence of the salicylate ligand, 3,5-DIP (carboxy-14C)S, early in the course of this experiment, the ligand was lost via ligand exchange and could not be measured in blood, kidney, intestine, lung, thymus, spleen, and brain after 24 hours following administration. However, 3,5-DIP(carboxy-14C)S persisted in liver, femur, and muscle throughout the 5-day period of study. It is suggested that marked lipophilicity accounts for its very rapid distribution to all tissues wherein it undergoes ligand exchange as 67Cu is incorporated into Cu-dependent enzymes and proteins and persists in tissues based upon physiological demand for Cu in meeting normal biochemical requirements.
Blincoe
Clifton
C
Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas, Medical Sciences Campus, 4301 West Markham Street, Little Rock, Arkansas 72205-7122, USA.
Chidambaram
Mani
M
Salari
Hamid
H
Bond
Kyle B
KB
Evans
Doris T
DT
Gray-Kaufman
Rhonda A
RA
Griffey
Hal Brent
HB
Tranby
Sandra Gilbreth
SG
Garner-Johnson
Buffy
B
Lee
Tina
T
Sorenson
John R J
JR
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D003301:Copper Radioisotopes; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D012459:Salicylates / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
D000893:Anti-Inflammatory Agents; D002250:Carbon Radioisotopes; D003301:Copper Radioisotopes; D012459:Salicylates; C067228:copper tetrakis(3,5-diisopropylsalicylic acid)