Effect of medical castration on CYP3A4 enzyme activity using the erythromycin breath test.
OBJECTIVE
Testosterone administration can lead to increased antipyrine clearance in humans. Medical or surgical castration is a standard treatment of progressive prostate carcinoma, but the effect of the subsequent fall of testosterone concentrations upon drug metabolism has not been reported.


METHODS
Eleven men with a biopsy-proven diagnosis of progressive prostate cancer were enrolled after providing informed consent. CYP3A4 activity was determined using the erythromycin breath test (EBT) in each patient prior to their beginning with an LHRH-agonist (leuprolide or goserelin). No patients had elected to undergo orchiectomy during the period of subject accrual. Each subject underwent a second EBT 2 months after beginning LHRH suppression. Blood samples were collected at these time points to determine changes in testosterone and leutinizing hormone.


RESULTS
All subjects had a predictable drop in serum testosterone concentrations over the 8-week course of the study, but concentrations in three did not fall below castrate levels (<50 ng/dl). There was no statistically significant change in CYP3A4 activity using the EBT method (p = 0.88). The extent and direction of changes in CYP3A4 activity was highly variable, with three subjects experiencing an increase in activity, and five demonstrating a decrease in activity.


CONCLUSIONS
There is no clinically significant change in CYP3A4 activity after medical castration. No changes in the clearance of docetaxel or other CYP3A4 substrates are likely during and after medical castration. Although similar findings are expected after orchiectomy, we were not able to test this presumption because of patient preference for medical castration.
Hutson
Paul R
PR
School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA. prhutson@pharmacy.wisc.edu
Oettel
Kurt
K
Douglas
Jeff
J
Ritter
Mark
M
Messing
Ed
E
Staab
Mary Jane
MJ
Alberti
Dona
D
Horvath
Dorthea
D
Wilding
George
G
D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004917:Erythromycin; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D017273:Goserelin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D016729:Leuprolide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000201:enzymology / Q000628:therapy*; D013739:Testosterone / Q000097:blood*
D018931:Antineoplastic Agents, Hormonal; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016729:Leuprolide