Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Franke
Ryan M
RM
St Jude Children's Research Hospital, Memphis, TN, USA.
Carducci
Michael A
MA
Rudek
Michelle A
MA
Baker
Sharyn D
SD
Sparreboom
Alex
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015142:Baltimore; D001692:Biological Transport; D001711:Biotransformation; D001944:Breath Tests; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D000077143:Docetaxel; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D009503:Neutropenia / Q000139:chemically induced; D009919:Orchiectomy; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014162:Transfection; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D029362:Organic Anion Transporters, Sodium-Independent; C490280:SLC22A7 protein, human; C088800:Slc22a7 protein, rat; D043823:Taxoids; D000077143:Docetaxel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human