title: Enhanced biliary iron excretion with amphiphilic diethylenetriaminepentaacetic acid.
abstract: The elimination of toxic metal ions metabolically accumulated by patients remains a difficult clinical problem and a target of drug development. DTPA (diethylenetriaminepentaacetic acid) is a hydrophilic chelating agent with high affinity for divalent and trivalent metal ions including iron but with a limited ability to cross cell membranes for access to iron stores. In this study we have synthesized an amphiphilic form of this chelator-DTPA covalently linked to the phospholipid phosphatidylethanolamine (PE)--to produce a chelator that incorporates completely and stably into liposome membranes for efficient delivery to the liver and reticuloendothelial system. Biliary and urinary excretion of iron were studied in iron-loaded rats (n = 15) in association with a 2-hr intravenous infusion of sonicated liposomes of 1:1 amphiphilic phosphatidylethanolamine-DTPA/egg phosphatidylcholine (L-PE-DTPA) and compared with excretion obtained using equivalent amounts of water-soluble DTPA (alone or mixed with egg phosphatidylcholine liposomes [L-DTPA] as controls). For a 6-hr period, the administration of L-PE-DTPA resulted in approximately a 20-fold increase in biliary iron excretion (480 +/- 160 micrograms/6 hr, mean +/- S.D.) compared with that seen with DTPA (21.2 +/- 4.0 micrograms/6 hr) and L-DTPA (23.1 +/- 5.0 micrograms/6 hr) (p less than 0.05, analysis of variance). Urinary iron excretion was significantly decreased with L-PE-DTPA (41.5 +/- 38 micrograms/6 hr) compared with DTPA (154 +/- 110 micrograms/6 hr) and L-DTPA (86 +/- 17 micrograms/6 hr) (p less than 0.05). Combined biliary and urinary excretion of iron was three to four times greater with L-PE-DTPA.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, University of Western Ontario, London, Canada.
authors.forename: P C
authors.initials: PC
authors.lastname: Adams
authors.forename: E
authors.initials: E
authors.lastname: Lin
authors.forename: K R
authors.initials: KR
authors.lastname: Barber
authors.forename: C W
authors.initials: CW
authors.lastname: Grant
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D007501:Iron / Q000378:metabolism*; D008081:Liposomes; D008297:Male; D009994:Osmolar Concentration; D004369:Pentetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D002614:Chelating Agents; D008081:Liposomes; D004369:Pentetic Acid; D007501:Iron