title: Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients.
abstract: 4-Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effective treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of aromatase and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these plus a further 11 patients were then randomized to treatment with 250 or 500 mg i.m. every 2 weeks to determine the optimal dose for each route according to the suppression of serum estradiol levels. There was no significant difference between the 3 oral doses in their suppression of estradiol levels indicating that the maximum required p.o. dose of 4-OHA is probably 250 mg daily. Suppression by the parenteral dose of 250 mg every 2 weeks was marginally suboptimal but clinical considerations of response and tolerability indicate this as the optimal dose for i.m. injection. 4-OHA had no effect on serum levels of androstenedione, testosterone, or 5 alpha-dihydrotestosterone when given by either route but p.o. treatment with 4 doses of 250 mg daily reduced sex hormone-binding globulin levels by a mean of 34%. Serum levels of estrone as measured by gas chromatography-mass spectrometry were suppressed to approximately 40% of baseline by parenteral treatment. The half-life of 4-OHA p.o. was approximately 3 h, whereas the apparent half-life of injected drug was between 5 and 10 days after a more rapid clearance during the first 4 days after injection.
authors.affiliation: Department of Biochemical Endocrinology, Royal Marsden Hospital, London.
authors.forename: M
authors.initials: M
authors.lastname: Dowsett
authors.forename: D C
authors.initials: DC
authors.lastname: Cunningham
authors.forename: R C
authors.initials: RC
authors.lastname: Stein
authors.forename: S
authors.initials: S
authors.lastname: Evans
authors.forename: L
authors.initials: L
authors.lastname: Dehennin
authors.forename: A
authors.initials: A
authors.lastname: Hedley
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D000284:Administration, Oral; D000735:Androstenedione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood*; D004970:Estrone / Q000097:blood; D005260:Female; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D008593:Menopause; D012738:Sex Hormone-Binding Globulin / Q000032:analysis
chemical_list: D012738:Sex Hormone-Binding Globulin; D004970:Estrone; D000735:Androstenedione; D004958:Estradiol; C014594:formestane