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 watersoluble 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 μg/6 hr, mean ± S.D.) compared with that seen with DTPA (21.2 ± 4.0μg/6 hr) and L-DTPA (23.1 ± 5.0 μg/6 hr) (p < 0.05, analysis of variance). Urinary iron excretion was significantly decreased with L-PE-DTPA (41.5 ± 38 μg/6hr) compared with DTPA (154 ± 110 μg/6 hr) and L-DTPA (86 ± 17 μg/6 hr) (p < 0.05). Combined biliary and urinary excretion of iron was three to four times greater with L-PE-DTPA. This study suggests that the use of a highly water-insoluble amphiphilic form of DTPA as sonicated liposomes altered the route and extent of delivery of the chelator to the iron stores, resulting in a significant increase in biliary iron excretion. (HEPATOLOGY 1991;14:1230–1234.)