Alterations in the metabolism of oestrogens during treatment with aminoglutethimide in breast cancer patients. Preliminary findings.
In this small study, the effect of aminoglutethimide on the disposition of oestrogens in women with advanced breast cancer was investigated using bolus injections of 4-[14C]-oestradiol and 6,7-[3H]-oestrone sulphate, alone or in combination. No alterations in oestrogen disposition were seen after short term (6 hours) aminoglutethimide administration. During long term (3 weeks to 8 months) aminoglutethimide treatment mean 4-[14C]-oestradiol clearance was not changed. 14C-Oestrone sulphate AUC was reduced by 43% at a low dose of aminoglutethimide (125 mg twice daily) and by 65% at a high dose (250 mg 4 times daily) with hydrocortisone acetate 25 mg twice daily. The oestrone sulphate terminal elimination rate constant (lambda z) was concurrently increased (mean of 46 and 79%, respectively, with the 2 dosage regimens). A possible increase in oestrone sulphate clearance during long term treatment was tested for by injecting 6,7-[3H]-oestrone sulphate. These studies revealed a marked increase (mean 104%) in oestrone sulphate clearance in patients receiving the high dose aminoglutethimide schedule. Following injection of 4-[14C]-oestradiol plus 6,7-[3H]-oestrone sulphate, the fraction of 4-[14C]-oestradiol metabolised to oestrone sulphate was found to be reduced in all patients (mean 13%). A mean increase of 80% in the urinary excretion of 14C-oestriol was observed after 4-[14C]-oestradiol administration. Our results, although preliminary, suggest that aminoglutethimide is a potent inducer of aminoglutethimide metabolism, thereby producing a significant reduction in plasma bioavailability of oestrone sulphate. These effects may have a role in the action of aminoglutethimide, a finding which warrants further investigation.
Department of Biochemical Endocrinology, University of Bergen.
P E
PE
Lønning
S
S
Kvinnsland
T
T
Thorsen
P M
PM
Ueland
D000368:Aged; D000616:Aminoglutethimide / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000378:metabolism*; D004970:Estrone / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D013997:Time Factors
D004967:Estrogens; D000616:Aminoglutethimide; D004970:Estrone; D004958:Estradiol