This study investigates the impact of dose escalation and of doxorubicin and cyclophosphamide coadministration on the pharmacokinetics of etoposide (ETO). Pharmacokinetics of ETO were analyzed in seven patients with breast cancer receiving 3-4 cycles of conventional-dose (CD) and one final course of high-dose (HD) chemotherapy including ETO (450 mg/m(2) and 2100 mg/m(2), respectively, fractionated over 3 consecutive days). ETO was given as monoinfusion apart from day 1 of CD, where cyclophosphamide and doxorubicin were coadministered. Plasma samples obtained on day 1 and day 2 of CD- and HD-therapy, respectively, were analyzed for ETO by HPLC. Data from a total of 25 cycles of CD- and 7 cycles of HD-therapy are given as means +/- SD for CD-day 1, CD-day 2, HD-day 1 and HD-day 2, respectively. Following administration of 210+/-29, 278+/-41, 1143+/-79 and 1143+/-79 mg ETO, the AUC (0-24 h, normalized to 150 mg/m(2)) was 123+/-23, 113+/-22, 92+/-11 and 100+/-22 microgxh/ml. The AUC and CL of single-agent ETO were not significantly different between CD (day 2) and both days of HD ETO. However, we observed a modest but significant difference for AUC and CL between day 1 of CD (coadministration of doxorubicin and cyclophosphamide) and day 2 of CD (ETO monoinfusion), the AUC and CL being 9% higher (see above) and 10% lower (21.1 vs. 23.3 ml/minxm(2)) ( P<0.05), respectively, on day 1. The fraction of unbound ETO was similar on all occasions (range: 5.5%-6.6%). Interpatient variability for AUC and CL during CD-therapy was moderate with coefficients of variation (CV) of 17%-20%, while intraindividual variability was comparatively high and almost in the same range (CV of 13%-16%). Pharmacokinetics of etoposide were not significantly altered following fivefold dose escalation in the same patients. A 10% decrease in systemic clearance of etoposide was observed during doxorubicin and cyclophosphamide coadministration, which could result from drug interactions affecting renal and/or metabolic elimination of etoposide. The magnitude of the decrease, however, is unlikely to be of clinical significance.