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Friday 26 January 2007

Influence of ketoconazole on the fecal and urinary disposition of docetaxel.

By: Engels FK, Loos WJ, Mathot RA, van Schaik RH, Verweij J.

Cancer Chemother Pharmacol 2007 Jan 26; [Epub ahead of print]

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/m(2)), followed 3 weeks later by a reduced dose in combination with orally administered ketoconazole, or vice versa. Six patients were also administered [(3)H]-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.

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