Glufosfamide metabolism in patients using phosphorus-31 NMR

1141 Phosphorus-31 NMR ( 31 P NMR) was used to determine the urinary excretion of glufosfamide (GLUIF) and its phosphorylated metabolites (isophosphoramide mustard (IPM), phosphorylethanolamine (PEA) and glycerophosphorylethanolamine (GPE)) in 10 patients treated with a short infusion (0.5 or 1 h) of the drug at doses of 2.5, 4.5, 6 or 8 g/m 2 . The concentrations of PEA and GPE resulting from GLUIF metabolism were obtained by subtracting (if necessary) their endogenous concentrations in the predose urine of each patient from their total concentration measured in each sample. The total 24h-urinary excretion of GLUIF and its phosphorylated metabolites represents between 30 and 60% of the dose, the percentage increasing with the dose. Unchanged GLUIF was by far the major compound excreted, representing between 83 and 89% of the phosphorus containing compounds (PCC) detected. IPM, its degradation compound PEA, and GPE resulting from PEA metabolism are minor compounds accounting for 2-3% (IPM and PEA) and 0.5-2% (GPE) of the total excreted. 86% of GLUIF and 84% of the total PCC were excreted in the first 8h after the start of the infusion. 31 P NMR spectra of the plasma samples from the same patients (except one treated at 2.5 g/m 2 ) were performed. In all the samples taken after drug administration, GLUIF was the sole compound detected in addition to endogenous phosphate ion and phospholipids. Pharmacokinetic analysis showed (i) no significative variation for t 1/2 and plasmatic clearance (CLp) between 4.5 and 6 g/m 2 doses, (ii) a slight increase of t 1/2 and a slight decrease of CLp between 6 and 8 g/m 2 doses. Dose-dependent pharmacokinetics of GLUIF was likely due to a capacity-limited metabolism.