PLASMA-PROTEIN BINDING OF PHENYLACETATE AND PHENYLBUTYRATE, 2 NOVEL ANTINEOPLASTIC AGENTS

Phenylacetate and phenylbutyrate, two novel inducers of tumor cytostas is and differentiation, are currently in clinical trials for the treat ment of cancer in adults. The purpose of our study was to evaluate the plasma protein-binding characteristics of phenylacetate and phenylbut yrate in the plasma of normal volunteers and that of patients with can cer. Drug plasma protein-binding analysis was examined using three sep arate devices: a micropartition system and two equilibrium dialysis sy stems, all of which exhibited similar results. Phenylacetate and pheny lbutyrate concentrations were determined by high-performance liquid ch romatography. Both drugs exhibited concentration-dependent binding. Ou r results showed sodium phenylacetate to have a higher free fraction t han sodium phenylbutyrate at corresponding concentrations (>0.442 +/- 0.008 and >0.188 +/- 0.001, respectively). Plasma pH did not greatly a ffect protein binding of either drug. As albumin concentration decreas ed, an increase in free fraction of both drugs was observed, however a lpha(1)-acid glycoprotein showed no change in free fraction as its con centration increased. Patients with cancer with lower levels of albumi n showed an increase in free fraction with both phenylacetate and phen ylbutyrate. When phenylacetate and phenylbutyrate were added together in plasma, the free fraction of phenylacetate increased, whereas the p henylbutyrate free fraction slightly decreased. We conclude that pheny lacetate and phenylbutyrate have high free fractions that change with varying albumin levels and when both phenylacetate and phenylbutyrate are present together in plasma.