DISPOSITION OF PHENYLBUTYRATE AND ITS METABOLITES, PHENYLACETATE AND PHENYLACETYLGLUTAMINE

Phenylacetate, an inducer of tumor cytostasis and differentiation, sho ws promise as a relatively nontoxic antineoplastic agent, Phenylacetat e, however, has an unpleasant odor that might limit patient acceptabil ity. Phenylbutyrate, an odorless compound that also has activity in tu mor models, is known to undergo rapid conversion to phenylacetate by b eta-oxidation in vivo. This phase I study examined the pharmacokinetic s of phenylbutyrate and characterized the disposition of the two metab olites, phenylacetate and phenylacetylglutamine, Fourteen patients wit h cancer (aged 51.8 +/- 13.8 years) received a 30-minute infusion of p henylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m(2)), Serial b lood samples and 24-hour urine collections were obtained. Samples were assayed by high-performance liquid chromatography. A model to simulta neously describe the pharmacokinetics of all three compounds was devel oped using ADAPT II. Data were modeled as molar equivalents. The model Ft the data well os shown by mean (+/-SD) coefficients of determinati on (r(2)) for phenylbutyrate, phenylacetate, and phenylacetylglutamine , which were 0.96 +/- 0.07, 0.88 +/- 0.10, and 0.92 +/- 0.06, respecti vely. The intrapatient coefficient of variation percentage (CV%) aroun d the parameter estimates were small (range 7.2-33.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500-2000 mu mol/L) and exhibited saturable elimination (K-m = 34.1 +/ - 18.1 mu g/mL and V-max = 18.1 +/- 18 mg/h/kg). Metabolism was rapid; the rimes to maximum concentration for phenylacetate and phenylacetyl glutamine were 1 and 2 hours, respectively. The conversion of phenylbu tyrate to phenylacetate was extensive (80 +/- 12.6%), but serum concen trations of phenylacetate were low owing to rapid, subsequent conversi on to phenylacetylglutamine. The ratio of phenylbutyrate AUC to phenyl acetate AUC was 2.66. Thus, phenylbutyrate may not be a prodrug for ph enylacetate and should be pursued as an independent antitumor agent.