Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m2 infused over 2 h on days 1 and 2, and G-CSF 5 micrograms/kg per day starting on day 3 until WBC was > or = 10,000/microliters. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (C(pmax)) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma disposition demonstrated biphasic clearance, with mean T1/2 alpha of 2.09 +/- 0.61 h, and T1/2 beta of 5.83 +/- 1.71 h. An AUC as high as 1768.50 micrograms.h/ml was observed at a dose of 1200 mg/m2. The total body clearance (TBC) showed an overall mean of 15.72 +/- 4.25 ml/min per m2, and mean volume of distribution (VDss) of 5.64 +/- 1.06 l/m2. The mean residual time (MRT) for etoposide was 6.24 +/- 1.61 h. In urine, etoposide but not etoposide phosphate, was identified with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etoposide with the linear dose-related C(pmax) and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic parameters of high-dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values for the clinically important C(pmax) and AUCs, clearance, terminal T1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may offer the advantage of ease of administration.