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 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 6 hr ) 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.