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).


CONCLUSIONS
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.
Engels
Frederike K
FK
Department of Medical Oncology, Erasmus MC - Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. frederike.engels@yahoo.fr
Loos
Walter J
WJ
Mathot
Ron A A
RA
van Schaik
Ron H N
RH
Verweij
Jaap
J
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D000077143:Docetaxel; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000378:metabolism* / Q000652:urine; D014316:Tritium
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065607:Cytochrome P-450 Enzyme Inhibitors; D043823:Taxoids; D014316:Tritium; D000077143:Docetaxel; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole