Distribution of ifosfamide and metabolites between plasma and erythrocytes

The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifos famide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF ) and ifosforamide mustard (IFM) between plasma and erythrocytes was examin ed in vitro and in vivo. In vitro distribution was investigated by incubati ng blood with various concentrations of IF and its metabolites. In 2 vivo d istribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiv ing9g/m(2)/72h intravenous continuous IF infusion. In vitro distribution eq uilibrium between erythrocytes and plasma was obtained quickly after drug a ddition. Mean ( sem) in vitro and in vivo erythrocyte (e)-plasma (p) partit ion coefficients (P-e/p) were 0.75 +/-0.01 and 0.81 +/-0.03, 0.62 +/-0.09 a nd 0.73 +/-0.05, 0.76 +/-0.10 and 0.93 +/-0.05 and 1.38 +/-0.04 and 0.98 +/ -0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were indepen dent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration-time curves (AUC(e/p)) were 0.96 +/-0.03, 0.87 +/-0.07,0.98 +/-0.06 and 1.34 +/-0.39, respectively. A time- and concentration-dependent distribution-equilibrium phenomenon was observe d with the relative hydrophilic IFM. It is concluded that IF and metabolite s rapidly reach distribution equilibrium between erythrocytes and plasma; t he process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wid e range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compound s. Thus, pharmacokinetic assessment using only plasma sampling yields direc t and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic-pharmacodynamic studies. Copyright (C) 2001 John Wiley & Sons, Ltd.