Investigation of conjugated metabolites of 4-hydroxyandrost-4-ene-3,17-dione in patient urine by liquid chromatography-atmospheric pressure ionization mass spectrometry.
Metabolism of the anticancer drug 4-hydroxyandrost-4-ene,3,17-dione (4OHA) was studied in cancer patients by HPLC-MS-MS. 40HA was administered orally to a breast cancer patient. The drug was extensively metabolized and was excreted in the urine as the 4OHA-glucuronide, 3 alpha-hydroxy-5 beta-androstan-4,17-dione (3 alpha OHA)-sulfate (or 4-hydroxytestosterone-sulfate) and 3 alpha,17-dihydroxy-5 beta-androstan-4-one (3,17-OHA)-sulfate conjugates in the 4 hr posttreatment sample. Other metabolites include 4OHA-sulfate, 3 alpha OHA-glucuronide, and 3,17-OHA-monoglucuronide. When 4OHA was given to the prostatic cancer patients intramuscularly, different metabolites were observed as compared with the female studies. The most noticeable difference is the absence of 4OHA-sulfate in both 24 and 48 hr posttreatment urine samples. The drug was eliminated mainly as 4OHA-glucuronide, 3 alpha OHA-sulfate, and 3,17-OHA-monosulfate. Other metabolites that have been detected include 3 alpha OHA-glucuronide, 3,17-OHA-glucuronide, 3,17-OHA-disulfate, and an unknown metabolite. The variation observed in metabolism could be attributed to a different route of drug administration (oral and intramuscular) and sex difference among the patients. This study describes the utilization of HPLC-MS-MS for monitoring the 4OHA conjugates and provides the first evidence of the presence of 4OHA-sulfate and its analogs in patient urinary extracts.
Poon
G K
GK
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, UK.
Chui
Y C
YC
Jarman
M
M
Rowlands
M G
MG
Kokkonen
P S
PS
Niessen
W M
WM
van der Greef
J
J
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D047072:Aromatase Inhibitors; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D009369:Neoplasms / Q000188:drug therapy / Q000652:urine; D012737:Sex Factors
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D000735:Androstenedione; C014594:formestane