The flavonol monohydroxyethylrutoside (monoHER) has demonstrated protection against doxorubicin-induced cardiotoxicity in in vitro and in vivo studies without affecting the antitumor effect. In the present phase I study, the possible side effects and the pharmacokinetics of monoHER were evaluated in healthy volunteers with the aim to develop a safe and feasible dose to be evaluated in cancer patients treated with doxorubicin. The study was performed as a single blind, randomized trial in healthy volunteers (age between 19 and 56 years). At each dose level, six subjects received monoHER and three placebo. MonoHER was solubilized in 100 ml dextrose 5% and administered as an i.v. infusion in 10 min. The placebo consisted of 100 ml dextrose 5%. The starting dose of monoHER was 100 mg/m(2). Dose escalation by 100% of the preceding dose took place after finishing each dose level until the protecting pharmacokinetic values for C (max) and AUC(infinity) (as observed in mice after 500 mg/kg monoHER i.p.) were reached and/or serious side effects were observed. The dose was escalated up to 1,500 mg/m(2). The mean values of C (max) and AUC(infinity) were 360+/-69.3 microM and 6.8+/-2.1 micromol min/ml, respectively. These values were comparable to the C (max) and AUC(infinity) observed under the protecting conditions in mice. No serious side effects occurred during the entire study. Thus, 1,500 mg/m(2) is a feasible and safe dose to be evaluated in a phase II study to investigate the protective properties of monoHER against doxorubicin-induced cardiotoxicity in cancer patients.