Clinical pharmacokinetics and metabolism of paclitaxel after polychemotherapy with the cytoprotective agent amifostine.
BACKGROUND
Cytoprotection of healthy cells represents a new approach in cancer chemotherapy, but a pharmacokinetic drug interaction between the cytostatic and the cytoprotectant is undesired.


METHODS
The purpose was to evaluate the clinical pharmacokinetics (PHK) of paclitaxel (PACLI) and its metabolites under cytoprotection in patients suffering from breast cancer. PACLI was administered alone and in a second cycle in combination with amifostine (AMI) as a paired cross over.


RESULTS
In both treatment schedules the steady state of PACLI occurred after 3 hours, the tmax of metabolites between 3 and 4 hours. The mean steady-state concentration was cmax = 5432 +/- 1238 ng/ml in the control group and cmax = 5140 +/- 2407 ng/ml in the AMI group. For the serum metabolites, the findings were very similar: 6-OH-PACLI: cmax 413 +/- 153 ng/ml versus 432 +/- 304 ng/ml, 3"-OH-PACLI: cmax 99 +/- 103 ng/ml versus 123 +/- 98 ng/ml, 3",6-DiOH-PACLI: cmax 43 +/- 55 ng/ml versus 75 +/- 85 ng/ml. AUC values of metabolites were slightly higher in the AMI group, but PHK seemed equal.


CONCLUSIONS
The results gave evidence, that cytoprotection with AMI has no clinical consequences on PACLI pharmacokinetics and biotransformation.
Czejka
M
M
Pharmacokinetics and Drug Metabolism Unit, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. czejka@speedy.pch.univie.ac.at
Schueller
J
J
Eder
I
I
Reznicek
G
G
Kraule
C
C
Zeleni
U
U
Freitag
R
R
D000368:Aged; D004999:Amifostine / Q000008:administration & dosage / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001711:Biotransformation; D001943:Breast Neoplasms / Q000473:pathology / Q000601:surgery*; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D011837:Radiation-Protective Agents; D004999:Amifostine; D017239:Paclitaxel