title: Effect of 17beta-estradiol-bisphosphonate conjugates, potential bone-seeking estrogen pro-drugs, on 17beta-estradiol serum kinetics and bone mass in rats.
abstract: In order to target 17beta-estradiol directly at bone we synthesized three 17beta-estradiol-bisphosphonate conjugates (E2-BPs) with different esterase-sensitive linkers between both molecular moieties. The systemic administration of these compounds should result primarily in local estrogenic effects on bone with no or negligible systemic hormonal effects. Only if a considerable margin exists between the doses required for inhibition of bone loss and those for systemic hormonal effects can such a pro-drug be considered acceptable for patients refusing systemic estrogen replacement therapy for several reasons. The conjugates were tested in vitro for their 17beta-estradiol release in rat serum and in vivo for their local and systemic effects in rats: in vitro, the conjugates expressed cleavage resistance, low cleavage (4.8%), or high cleavage (33.1%) within 48 hours of incubation. The conjugate with the low-cleavage doubled 17beta-estradiol serum half-life (3.78 hours) whereas the high-cleavage conjugate resulted in approximately four times higher serum half-life (8.36 hours) when compared with free 17beta-estradiol. In ovariectomized rats, bone loss was optimally prevented by 50 nmol/kg/day of 17beta-estradiol when administered S. C. over a period of 5 weeks, and protection against uterine atrophy was achieved at doses as low as 5 nmol/kg/day. The cleavage-resistant conjugate was ineffective in preserving bone and uterus in doses ranging from 5 to 150 nmol/kg/day. The other two E2-BPs revealed a dose-dependent inhibition of bone loss which was paralleled by the respective uterus weight with a dose range of 1.5-150 nmol/kg/day being fully effective in a range similar to 17beta-estradiol alone. The higher sensitivity of the uterus versus bone to protective estrogenic effects (1:10) was abolished by the conjugates. We conclude that E2-BPs containing esterase-sensitive linkers failed to act as bone-seeking pro-drugs expressing primarily local effects on bone without systemic effects.
authors.affiliation: Department of Preclinical Research and Development, Bone Metabolism, Boehringer Mannheim GmbH, Sandhoferstrasse 116, D-68305 Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Bauss
authors.forename: A
authors.initials: A
authors.lastname: Esswein
authors.forename: K
authors.initials: K
authors.lastname: Reiff
authors.forename: G
authors.initials: G
authors.lastname: Sponer
authors.forename: B
authors.initials: B
authors.lastname: Müller-Beckmann
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001284:Atrophy / Q000517:prevention & control; D001665:Binding Sites; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000378:metabolism; D004164:Diphosphonates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D009929:Organ Size / Q000187:drug effects; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy / Q000517:prevention & control; D010052:Ovariectomy / Q000009:adverse effects; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D014599:Uterus / Q000187:drug effects / Q000473:pathology
chemical_list: D004164:Diphosphonates; D011355:Prodrugs; D004958:Estradiol