Murine metabolism and disposition of iron:adriamycin complexes

Previous studies have reported antitumor activity and reduced cardiotoxicity for a putative 3:1 complex of iron:Adriamycin (ADR). We have studied the tissue distribution and metabolism of a wide variety of freshly prepared and lyophilized iron:ADR preparations after administration to BALB/c mice (ADR, 16 mg/kg i.v.). Tissue concentrations of ADR given without iron were initially highest in kidney and liver, and ADR fluorescence was lost from all tissues except the spleen with a t1/2 of 15 to 18 hr. ADR remained the major fluorescent species in liver and kidney from 0.5 to 72 hr after treatment. Freshly prepared iron:ADR (1:1) behaved similarly to ADR except for a slightly longer tissue t1/2 in heart, liver, and kidney. The tissue distribution of freshly prepared 2:1 and 3:1 iron:ADR was very different from that of ADR without iron; lung containing the highest concentrations of ADR fluorescence. Administration of freshly prepared 1:1, 2:1, and 3:1 iron:ADR resulted in some increase in adriamycinol in the liver, but ADR was always the major fluorescent species present. The tissue distribution of 1:1 iron:ADR that had been aged for 48 or 96 hr was similar to that of fresh 2:1 and 3:1 iron:ADR rather than ADR or fresh 1:1 iron:ADR. When lyophilized iron:ADR preparations were reconstituted and administered, the 0.5-hr tissue distribution of 0.1:1, 0.2:1, 0.25:1, and 0.33:1 iron:ADR was the same as ADR alone, but 0.5:1, 1:1, 2:1, and 3:1 iron:ADR were all accumulated primarily in the lung. Physicochemical studies confirm the production of microaggregated iron:ADR complexes and light microscopy allows visualization and sizing of these aggregates. We feel that trapping of these iron:ADR aggregates in the pulmonary vascular bed accounts for the observed dramatic alteration in tissue distribution. Light and electron microscopic studies confirm the intravascular sequestration of iron in pulmonary capillaries.