TY - JOUR
T1 - Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine
AU - Piscitelli, S. C.
AU - Thibault, A.
AU - Figg, W. D.
AU - Tompkins, A.
AU - Headlee, D.
AU - Lieberman, R.
AU - Samid, D.
AU - Myers, C. E.
PY - 1995
Y1 - 1995
N2 - Phenylacetate, an inducer of tumor cytostasis and differentiation, shows promise as a relatively nontoxic antineoplastic agent. Phenylacetate, however, has an unpleasant odor that might limit patient acceptability. Phenylbutyrate, an odorless compound that also has activity in tumor models, is known to undergo rapid conversion to phenylacetate by beta-oxidation in vivo. This phase I study examined the pharmacokinetics of phenylbutyrate and characterized the disposition of the two metabolites, phenylacetate and phenylacetylglutamine. Fourteen patients with cancer (aged 51.8 ± 13.8 years) received a 30-minute infusion of phenylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m2). Serial blood samples and 24-hour urine collections were obtained. Samples were assayed by high-performance liquid chromatography. A model to simultaneously describe the pharmacokinetics of all three compounds was developed using ADAPT II. Data were modeled as molar equivalents. The model fit the data well as shown by mean (± SD) coefficients of determination (r2) for phenylbutyrate, phenylacetate, and phenylacetylglutamine, which were 0.96 ± 0.07, 0.88 ± 0.10, and 0.92 ± 0.06, respectively. The intrapatient coefficient of variation percentage (CV%) around the parameter estimates were small (range 7.233.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500-2000 μmol/L) and exhibited saturable elimination (K(m) = 34.1 ± 18.1 μg/mL and V(max) = 18.1 ± 18 mg/h/kg). Metabolism was rapid; the times to maximum concentration for phenylacetate and phenylacetylglutamine were 1 and 2 hours, respectively. The conversion of phenylbutyrate to phenylacetate was extensive (80 ± 12.6%), but serum concentrations of phenylacetate were low owing to rapid, subsequent conversion to phenylacetylglutamine. The ratio of phenylbutyrate AUC to phenylacetate AUC was 2.66. Thus, phenylbutyrate may not be a prodrug for phenylacetate and should be pursued as an independent antitumor agent.
AB - Phenylacetate, an inducer of tumor cytostasis and differentiation, shows promise as a relatively nontoxic antineoplastic agent. Phenylacetate, however, has an unpleasant odor that might limit patient acceptability. Phenylbutyrate, an odorless compound that also has activity in tumor models, is known to undergo rapid conversion to phenylacetate by beta-oxidation in vivo. This phase I study examined the pharmacokinetics of phenylbutyrate and characterized the disposition of the two metabolites, phenylacetate and phenylacetylglutamine. Fourteen patients with cancer (aged 51.8 ± 13.8 years) received a 30-minute infusion of phenylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m2). Serial blood samples and 24-hour urine collections were obtained. Samples were assayed by high-performance liquid chromatography. A model to simultaneously describe the pharmacokinetics of all three compounds was developed using ADAPT II. Data were modeled as molar equivalents. The model fit the data well as shown by mean (± SD) coefficients of determination (r2) for phenylbutyrate, phenylacetate, and phenylacetylglutamine, which were 0.96 ± 0.07, 0.88 ± 0.10, and 0.92 ± 0.06, respectively. The intrapatient coefficient of variation percentage (CV%) around the parameter estimates were small (range 7.233.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500-2000 μmol/L) and exhibited saturable elimination (K(m) = 34.1 ± 18.1 μg/mL and V(max) = 18.1 ± 18 mg/h/kg). Metabolism was rapid; the times to maximum concentration for phenylacetate and phenylacetylglutamine were 1 and 2 hours, respectively. The conversion of phenylbutyrate to phenylacetate was extensive (80 ± 12.6%), but serum concentrations of phenylacetate were low owing to rapid, subsequent conversion to phenylacetylglutamine. The ratio of phenylbutyrate AUC to phenylacetate AUC was 2.66. Thus, phenylbutyrate may not be a prodrug for phenylacetate and should be pursued as an independent antitumor agent.
UR - http://www.scopus.com/inward/record.url?scp=0028940022&partnerID=8YFLogxK
U2 - 10.1002/j.1552-4604.1995.tb04075.x
DO - 10.1002/j.1552-4604.1995.tb04075.x
M3 - Article
C2 - 7650225
AN - SCOPUS:0028940022
SN - 0091-2700
VL - 35
SP - 368
EP - 373
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
IS - 4
ER -