Castration-Dependent Pharmacokinetics of Docetaxel in Patients With Prostate Cancer
- 20 October 2010
- journal article
- clinical trial
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 28 (30), 4562-4567
- https://doi.org/10.1200/jco.2010.30.7025
Abstract
To assess whether the low incidence of severe neutropenia in castrated men with prostate cancer treated with docetaxel is the result of changes in systemic clearance. A total of 10 noncastrated and 20 castrated men with prostate cancer were studied to achieve 80% power (α = .05) to detect at least a 25% change in the clearance of docetaxel. The erythromycin breath test was evaluated to determine hepatic activity of cytochrome P450 3A4 (CYP3A4), the main docetaxel-metabolizing enzyme. Additional studies were performed in rats and transfected cells overexpressing human or rodent transporters. Docetaxel clearance was increased by approximately 100% in castrated men and was associated with a two-fold reduction in area under the curve (P = .0001), although hepatic activity of CYP3A4 was unchanged (P = .26). In rats, castration was associated with higher uptake of docetaxel in the liver and a concurrent increase in the expression of rOat2 (Slc22a7), an organic anion transporter that regulates, in part, the transfer of docetaxel from the circulation into hepatocytes. It is recommended that castration- and/or hormone-related changes in the clearance of oncology drugs should be considered as a possible risk factor for treatment failure.Keywords
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