Clinical pharmacokinetics and metabolism of paclitaxel after polychemotherapy with the cytoprotective agent amifostine

Background: Cytoprotection of healthy cells represents a new approach in ca ncer chemotherapy, but a pharmacokinetic drug interaction between the cytos tatic and the cytoprotectant is undesired. Methods: The purpose was to eval uate the clinical pharmacokinetics (PHK) of paclitaxel (PACLI) and its meta bolites under cytoprotection in patients suffering from breast cancer. PACL I was administered alone and in a second cycle in combination with amifosti ne (AMI) as a paired cross over. Results: In both treatment schedules the s teady state of PACLI occurred after 3 hours, the t(max) of metabolites betw een 3 and 4 hours. The mean steady-state concentration was c(max) = 5432 +/ - 1238 ng/ml in the control group and c(max) = 5140 +/- 2407 ng/ml in the A MI group. For the serum metabolites, the findings were very similar: 6-OH-P ACLI: c(max) 413 +/- 153 ng/ml versus 432 +/- 304 ng/ml, 3"-OH-PACLI: c(max ) 99 +/- 103 ng/ml versus 123 +/- 98 ng/ml, 3",6-DiOH-PACLI: c(max) 43 +/- 55 ng/ml versus 75 +/- 85 ng/ml. AUC values of metabolites were slightly hi gher in the AMI group, but PHK seemed equal. Conclusion: The results gave e vidence, that cytoprotection with AMI has no clinical consequences on PACLI pharmacokinetics and biotransformation.