Chemical and enzymatic stability of a cyclic depsipeptide, the novel, marine-derived, anti-cancer agent kahalalide F

Kahalallde F is a cyclic depsipeptide Isolated from the Hawaiian mollusk Elysia rutescens. This compound is under present phase I clinical investigations as an anti-tumor drug. The role of possible metabolic reactions of this drug in (pre-)clinical investigations has not yet been explored. The first results for kahalalide IF In this field of research are given in this paper. The chemical degradation of kahalailde F was Investigated under acid, neutral and alkaline conditions using high-performance liquid chromatography with ultraviolet detection. The half-lives at 80 degreesC were 1.1, 20 and 8.6 h at pH 0, 1 and 7, respectively. At 26 degreesC and pH 11, the half-life was 1.65 h. At pH 7 and 11, only one reaction product of kahalalide F was observed, kahalalide G, the hydrolyzed lactone product of kahalailde F. At pH 0 and 1, additional reaction products emerged. Metabolic conversion of kahalalide IF was tested in vitro using three different enzyme systems based on pooled human microsomes, pooled human plasma and uridine 5'-diphosphoglucuronyl transferase, respectively. The incubated samples were analyzed using the same chromatographic technique as for the degradation samples. Biotransformations were not observed under these conditions and, therefore, it is concluded that kahalailde F is a metabolically stable drug. [(C) 2001 Lippincott Williams & Wilkins.].