Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols.

The plasma pharmacokinetics of Adriamycin and adriamycinol following a 15-min infusion of 75 mg/sq m of Adriamycin were studied in ten patients previously untreated with Adriamycin. The disappearance kinetics of Adriamycin could adequately be described by a biexponential equation with an initial half-life of 8-min and a terminal half-life of 30 hr. The major drug exposure (area under the concentration-time curve) occurs during the terminal phase where drug concentrations are generally less than 10(-7) M (0.05 micrograms/ml). An improvement in the high-performance liquid chromatography sensitivity facilitated the determination of the terminal phase. The plasma kinetics of adriamycinol, the major and only known active metabolite of Adriamycin, show a rapid initial increase in plasma concentration followed by a slow decline which parallels that of Adriamycin during the terminal phase. The relative drug exposure of adriamycinol to Adriamycin was approximately 50%. The relationship between the measured plasma drug levels and free drug available for distribution into tissues was studied by comparing the plasma binding characteristics of Adriamycin and adriamycinol. A constant 20 to 25% of the total plasma concentrations of both Adriamycin and adriamycinol was freely diffusible over the whole range of observed concentrations, 20 nM to 2 microM. Thus, the free drug exposure (area under the concentration-time curve) of tumor and host tissues in vivo can be determined from these plasma measurements, since the free drug exposures in plasma and in extracellular fluid are equivalent. These results can also serve as a guide for the design of clinically relevant in vitro studies of Adriamycin and adriamycinol. The pharmacokinetic parameters determined in this study have been used to simulate plasma concentration-time courses for a variety of Adriamycin treatment schedules. Alternatives are suggested which reduce peak plasma Adriamycin concentration while antitumor area under the concentration-time curve is maintained.