Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer
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. 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. 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 μg/ml, respectively. The volumes of distribution for PAA and PAG (Vd-PAA and Vd-PAG) were 7.9±3.4 l/m2 and 34.4±16.1 l/m2, respectively. The first-order elimination rate constant for PAG (ke-PAG) was 0.0091±0.0039 min−1. 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.