Patients and Methods: Pharmacokinetics was performed in 80 cycles and 36 women with previously untreated metastatic breast cancer. PTX, DOX, and their metabolites 6 alpha-hydroxyl-PTX (6 alpha OH-PTX) and doxorubicinol (DOL) were measured by high-pressure liquid chromatography (HPLC). Human breast cancer MCF-7 wild-type (WT) and resistant (TH) cell lines were cultured in whole human plasma to study anthracycline retention after treatment with different combinations of PIX, Cremophor EL (GEL) (PEG35 castor oil; BASF, Parsippany, NJ), and DOX.

Results: Pharmacokinetic interference between PTX and DOX wets responsible for nonlinearity of DOX plasma disposition and increased concentrations of DOX and DOL. These effects were PTX dose-dependent, DOX concentration-dependent, and likely a result of interference at the level of liver elimination, In view of the physiologic role of P-glycoproteins (P-gp) in xenobiotic biliary excretion, retention of DOX was assessed in MCF-7 WT and MCF-7 TH cells. Intracellular was significantly higher in MCF-7 WT than MCF-7 TH (P <.05). However, concomitant exposure to DOX, PTX, and CEL caused similar DOX retention in both MCF-7 WT and TH cells.

Conclusion: PTX, as clinically formulated in GEL, is responsible a nonlinear disposition of DOX and DOL, Nonlinearity is PTX- and DOX-dependent, and possibly caused by competition for biliary excretion of taxanes and anthracyclines mediated by P-gp, Nonlinearity indicates that even minor modifications of dose and infusion duration of DOX and PTX may lead to unpredictable pharmacodynamic consequences. The postulated role of p-gp suggests that CEL is clinically active, and advises caution in designing combinations of PTX with other drugs that ore substrate for P gp. (C) 1997 by American Society of Clinical Oncology.