Pharmacokinetic evaluation of oral 17β-oestradiol and two different fat soluble analogues in ovariectomized women

Abstract

A randomised, single-blind comparative study was carried out in 9 ovariectomized women to evaluate the kinetics of single doses of three different steroid combinations: 0.150 mg desogestrel + 2.0 mg micronized 17 beta-oestradiol, 0.150 mg desogestrel + 0.500 mg 17 beta-oestradiol cyclo-octyl acetate and 0.150 mg desogestrel + 1.0 mg 17 beta-oestradiol decanoate. Serum levels of 17 beta-oestradiol and oestrone were measured, as well as the excretion of 17 beta-oestradiol and its metabolites (oestrone and oestriol) in urine. In relation to the doses given, higher peak serum concentrations of 17 beta-oestradiol were obtained after the two fat soluble analogues, while the AUCs were similar to that after micronised 17 beta-oestradiol. However, there was more extensive conversion of the micronised 17 beta-oestradiol preparation into oestrone compared to 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate. The oestrone/17 beta-oestradiol serum concentration ratio was approximately 2.6 before tablet intake and remained essentially unchanged after intake of 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate. After micronized 17 beta-oestradiol however, there was a 2-3-fold increase in the ratio at Cmax and slower elimination of 17 beta-oestradiol from plasma, which may be due to the fact that high serum oestrone levels may serve as a reservoir, since both a metabolite and also a precursor of 17 beta-oestradiol. The urinary excretion of 17 beta-oestradiol, oestrone and oestriol was highest after oral administration of micronized 17 beta-oestradiol compared to 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens

“…y, young women; p, postmenopausal women; m, male subjects; ep, early menopausal; lp, late menopausal estradiol did not substantially improve oral bioavailability. Other approaches to improve the bioavailability were either to administer prodrugs of estradiol, such as long-chain fatty esters (SCHUBERT et al 1993) or sulfamates (ELGER et al 1995); to choose alternative routes of administration, such as sublingual (PRICE et al 1997), vaginal (KALUND-JENSEN andMYREN 1984;NASH et al1997;SCHMIDT et al 1994) or intramuscular administration (DOSTERBERG and NISHINO 1982); or to use subcutaneous pellets (SUHONEN et al 1993). The transdermal route of estradiol administration has attracted increasing attention during the last few years, not only because the first-pass effect could be avoided, but also because, in contrast to the oral route, a more physiological ratio of estradiol to estrone concentrations was achieved in the plasma.…”

Newly discovered orally active pure antiestrogens

“…These data led to the concern that oral administration of 17-hydroxy derivatives 11a and 11b to humans may also give a large amount of corresponding 17-keto derivatives 12a and 12b. Conversion from the 17-hydroxy to the 17-keto derivative is well documented in the metabolism of estradiol (E 2 ) in monkeys and humans, [18][19][20][21][22][23][24][25][26][27] in which orally administered 17-hydroxy derivative E 2 is easily converted to 17-keto derivative estrone (E 1 ), whereas orally administered E 1 is not easily converted to E 2 . These data provoked us to investigate the pharmacokinetic profiles and biological activities of 17-keto derivatives 12a and 12b.…”