Influence of ketoconazole on the fecal and urinary disposition of docetaxel
Objective: The anticancer drug docetaxel is extensively metabolized by cytochrome P450 (CYP) 3A isozymes. Furthermore, docetaxel is also a substrate for the transmembrane ATP-binding cassette efflux transporter protein ABCB1. CYP3A-inhibition significantly reduces docetaxel total systemic clearance, on average by 50%. However, data on the effect of CYP3A-inhibition on the fecal and urinary excretion of docetaxel are lacking. To further elucidate the role of CYP3A- and ABCB1-mediated elimination pathways for docetaxel we investigated the effect of the potent CYP3A-inhibitor, and also ABCB1-inhibitor, ketoconazole on the fecal and urinary disposition of docetaxel in cancer patients. Methods: Fifteen patients were treated with docetaxel (100 mg/m2), followed 3 weeks later by a reduced dose in combination with orally administered ketoconazole, or vice versa. Six patients were also administered [3H]-radiolabeled docetaxel. Fecal and urinary specimens, collected up to 72-h post-infusion, were analyzed for cumulative parent drug and radioactivity excretion. Results: Ketoconazole coadministration increased fecal parent drug excretion twofold from 2.6 ± 2.8 to 5.2 ± 5.4% (mean ± SD, P = 0.03) but did not affect urinary parent drug excretion (P = 0.69). The sum of fecal and urinary parent drug excretion was 5.3 ± 3.0% for docetaxel alone and 7.8 ± 5.6% in the presence of ketoconazole, respectively (P = 0.04). Total recovered radioactivity values were 45.8 ± 19.1 and 32.4 ± 19.7%, respectively (P = 0.23). Conclusion: CYP3A-inhibition by ketoconazole increases fecal parent drug excretion twofold in cancer patients. A more pronounced increase was not achieved, most likely due to concomitant intestinal ABCB1-inhibition.
|Keywords||3, Clinical trial, Docetaxel, Drug-interaction, Fecal disposition, H]-radiolabeled docetaxel, Ketoconazole, Mass balance, Urinary disposition, [|
|Persistent URL||dx.doi.org/10.1007/s00280-006-0412-5, hdl.handle.net/1765/36038|
Engels, F.K., Loos, W.J., Mathot, R.A., van Schaik, R.H.N., & Verweij, J.. (2007). Influence of ketoconazole on the fecal and urinary disposition of docetaxel. Cancer Chemotherapy and Pharmacology, 60(4), 569–579. doi:10.1007/s00280-006-0412-5