Liposome encapsulation circumvents the hepatic clearance mechanisms of all- trans-retinoic acid

Abstract

All- trans-retinoic acid (ATRA) has been proven active against a range of malignancies in isolated tissue culture systems and in human clinical trials, but the duration of its effects has been transient. Recent evidence indicates that the basis for the limited duration of ATRA's activity, at least in one form of leukemia, is a pharmacological adaptation that results in reduced serum concentration after prolonged treatment. This finding suggests that an i.v. formulation of ATRA may significantly improve the potency and duration of ATRA's activity in leukemia and, potentially, other malignancies as well. Liposomal ATRA (L-ATRA) was developed to provide a formulation of this retinoic acid isomer that can be administered intravenously to provide potential pharmacological advantages over the oral formulation. When L-ATRA was administered to rats over a prolonged period, the blood levels of the drug did not change over time. In vitro studies of isolated liver microsomes revealed that catabolism of the drug was not altered in rats that were repeatedly administered the L-ATRA formulation. Whereas microsomes isolated from animals that were orally administered free ATRA the same number of times with the same doses showed a significant increase in metabolism of the drug. These results suggest that an i.v. formulation of ATRA such as L-ATRA could be extremely useful in inducing long-term remissions in patients with APL.