The plasma clearance, tissue distribution, metabolism, and excretion of free Adriamycin (Adr) and liposome-entrapped Adr (Adr/L) was examined after iv and ip administration to rats. When given iv, free Adr was cleared more rapidly from plasma than was Adr/L. In contrast, Adr and Adr/L were cleared from plasma at similar rates when given by the ip route and peak plasma concentrations were significantly lower than observed after iv treatment. Irrespective of the route of administration, tissue distribution of Adr was altered after liposome entrapment, with increased uptake of Adr equivalents into liver and spleen and decreased uptake into kidney, heart, and lung. However, tissue concentrations of Adr were generally lower in rats treated ip with Adr or Adr/L than in animals dosed iv. Furthermore, an enhanced uptake of Adr/L relative to free Adr in lymph nodes draining the peritoneal cavity was observed only in animals treated by the ip route. The rates of both biliary and urinary excretion of Adr were 1/3-1/2 of control after liposome entrapment regardless of the route of administration, although excretion rates in rats dosed ip were half of those observed in animals treated by the iv route. Similarly, liposome entrapment of bromosulfophthalein was found to decrease its biliary excretion rate to 1/3-1/2 of control. Bile and urine of rats given Adr/L iv contained a higher proportion of Adr metabolites and less unchanged Adr than was found in animals receiving the free drug. This finding suggests that liposome entrapment of Adr leads to a modification in the metabolism of this drug in rats.