title: Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer.
abstract: OBJECTIVE
  Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer.
  
  
  METHODS
  PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m2. Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection.
  
  
  RESULTS
  PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55+/-18 min at the 1.8 g/m2 dose and 77+/-22 min at the 2.5 g/m2 dose. The half-life of PAG was 112+/-53 min at the 1.8 g/m2 dose and 135+/-75 min at the 2.5 g/m2 dose. The clearance of PAA was 66+/-33 ml/min per m2 at the 1.8 g/m2 dose and 60+/-24 ml/min per m2 at the 2.5 g/m2 dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (Vm and Km) were (means+/-SD) 18.4+/-13.8 mg/m2 per min and 152+/-155 microg/ml, respectively. The volumes of distribution for PAA and PAG (V(d-PAA) and V(d-PAG)) were 7.9+/-3.4 l/m2 and 34.4+/-16.1 l/m2, respectively. The first-order elimination rate constant for PAG (k(e-PAG)) was 0.0091+/-0.0039 min(-1).
  
  
  CONCLUSIONS
  The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Thompson
authors.forename: Frank
authors.initials: F
authors.lastname: Balis
authors.forename: Baruti M
authors.initials: BM
authors.lastname: Serabe
authors.forename: Stacey
authors.initials: S
authors.lastname: Berg
authors.forename: Peter
authors.initials: P
authors.lastname: Adamson
authors.forename: Renee
authors.initials: R
authors.lastname: Klenke
authors.forename: Alberta
authors.initials: A
authors.lastname: Aiken
authors.forename: Roger
authors.initials: R
authors.lastname: Packer
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Murry
authors.forename: Regina
authors.initials: R
authors.lastname: Jakacki
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D010648:Phenylacetates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000970:Antineoplastic Agents; D010648:Phenylacetates; D005973:Glutamine; C003089:phenylacetylglutamine; C025136:phenylacetic acid