Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model

Objectives To measure the oral bioavailability of estetrol (E4) in rats relative to its subcutaneous administration and to test the bone-sparing effect of oral E4 compared to that of ethinylestradiol (EE). Methods In the bioavailability study, E4 was administered as a single dose of 0.05, 0.5 or 5.0...

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Published in:Climacteric : the journal of the International Menopause Society 2008, Vol.11 (S1), p.2-14
Main Authors: Coelingh Bennink, H. J. T., Heegaard, A.-M., Visser, M., Holinka, C. F., Christiansen, C.
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Area Under Curve
BIOAVAILABILITY
Biological Availability
BONE
Bone and Bones - drug effects
Bone and Bones - metabolism
Bone density
Bone Density - drug effects
Bone Density Conservation Agents - pharmacokinetics
Bones
Dose-Response Relationship, Drug
Drug dosages
ESTETROL
Estetrol - pharmacokinetics
Female
Hormones
Injections, Subcutaneous - veterinary
Intestinal Absorption
Osteocalcin - blood
OSTEOPOROSIS
Ovariectomy
Random Allocation
Rats
Rats, Sprague-Dawley
Rodents
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Summary:Objectives To measure the oral bioavailability of estetrol (E4) in rats relative to its subcutaneous administration and to test the bone-sparing effect of oral E4 compared to that of ethinylestradiol (EE). Methods In the bioavailability study, E4 was administered as a single dose of 0.05, 0.5 or 5.0 mg kg orally or subcutaneously to female rats. Plasma was analyzed using an LC-MS MS method. The bone study was conducted in 3-month-old female rats assigned to the following seven treatment groups of ten animals each: no treatment; sham-operated + vehicle; bilaterally ovariectomized (OVX) + vehicle; OVX + E4 0.1, 0.5, or 2.5 mg kg day and OVX + EE 0.1 mg kg day. Once-daily treatment by oral gavage was given for 4 weeks and the following measurements were performed: serum osteocalcin, bone mineral density, bone mineral content and bone mineral area of lumbar vertebrae L3-L6, peripheral quantitative computed tomography of the left tibiae and the biomechanical properties of the distal femora. Results Oral bioavailability of E4, relative to that of subcutaneous dosing, was 70% and above at the 0.05 and 0.5 mg kg doses based on the AUC0-t last. Subcutaneous dosing provided significantly higher E4 levels at the 1-h time point only, and was comparable to oral dosing after 0.5, 2, 4 and 8 h. In the bone study, E4 dose-dependently and significantly (1) inhibited the OVX-related increase in osteocalcin levels, (2) increased bone mineral density and content, and (3) increased bone strength, all attenuated by ovariectomy. In this rat model, the relative potency of the highest dose of E4 (2.5 mg kg day) was comparable to the EE dose, used as positive control. Conclusions Estetrol exhibits high oral bioavailability in the rat, a species considered relevant for pharmacological studies that are predictive for effects on human bone. Oral administration of E4 conveys dose-dependent bone-sparing effects of high-quality bone in estrogen-depleted OVX rats. Based on its bone-sparing effects, its oral bioavailability and its preclinical safety and efficacy profile, E4 may be superior to other estrogens and is a potential drug for the prevention of osteoporosis in postmenopausal women.
ISSN:1369-7137
1473-0804
DOI:10.1080/13697130701798692