Differential metabolism of 3FDT and docetaxel in RLMs, rats, and HLMs

• The C–F for C–H replacement at the C3′ group of docetaxel blocks its metabolism.
• The major metabolism site shifted from the C3′ group of docetaxel to the baccatin moiety of 3FDT.
• The main P450 switched from CYP3A for docetaxel to CYP3A and CYP2E1 for 3FDT.

3FDT, an analog of docetaxel with a blocked metabolism at its 3′-N-tert-butyloxyl group with three fluorine atoms, exhibits more potent cytotoxicity than docetaxel both with human cancer cell line SK-OV-3 in vitro and with human non-small cell lung cancer A549 xenografts in vivo. To further develop pharmacodynamically and pharmacokinetically favorable fluorinated docetaxel analogs as anticancer agents, we chose 3FDT as the model compound to identify the metabolites of 3FDT in RLMs, rats, and HLMs and the cytochrome P450 enzymes responsible for the metabolism of 3FDT. Our findings indicated that the major metabolic site switched from the C3′ appendage for docetaxel to the taxane ring for 3FDT, and the main metabolizing P450 enzymes switched from CYP3A to CYP3A4 and CYP2E1.

Compared with docetaxel, the major oxidation site of 3FDT shifted from the C3′-N-tert-butyloxyl group to the baccatin moiety and the main metabolizing P450 shifted from CYP3A to CYP3A and CYP2E1.Figure optionsDownload as PowerPoint slide