Ipriflavone (Osteofix)

Ipriflavone is a synthetic isoflavone derivative used to suppress bone resorption.

In Vitro:Ipriflavone inhibits the proliferation and DNA synthesis of MDA-231 cells and blocks the ligand-induced phosphorylation of Tyr(845) of the EGFR. Ipriflavone does not promote apoptosis of MDA-231 cells[1]. Ipriflavone also promotes the deposition of calcium and the formation of mineralized nodules by newborn rat calvarial osteoblast-like cells as well as the activity of alkaline phosphatase[2].

In Vivo:Daily oral administration of ipriflavone at 12 mg/mouse significantly inhibits the development of new osteolytic bone metastases and the progression of established osteolytic lesions, prolonging the life of tumor-bearing mice. Ipriflavone reduces the number of osteoclasts at the bone-cancer interface with no severe adverse effects on the host[1]. 1-month treatment with ipriflavone increases bone density and improves the biomechanical properties of adult rat male bones without altering mineral composition[3]

References:
[1]. Iisaki T, et al. Ipriflavone inhibits osteolytic bone metastasis of human breast cancer cells in a nude mouse model. Int J Cancer. 2002 Aug 1;100(4):381-7. [2]. Hagiwara H, et al. Ipriflavone down-regulates endothelin receptor levels during differentiation of rat calvarial osteoblast-like cells. J Biochem. 1999 Jul;126(1):168-73. [3]. Civitelli R, et al. Ipriflavone improves bone density and biomechanical properties of adult male rat bones. Calcif Tissue Int. 1995 Mar;56(3):215-9.

Pharmacokinetics of ipriflavone and metabolites after oral administration of a corn-oil suspension relative to the Osteofix tablet.[Pubmed:10423615]

Am J Ther. 1997 Jul-Aug;4(7-8):229-38.

Ipriflavone (IP) is a derivative of naturally occurring isoflavones and is marketed as Osteofix for the treatment of osteoporosis in Europe. IP has poor aqueous solubility, and the Osteofix compressed tablet has poor and variable bioavailability (F ). IP is incompletely absorbed after oral administration and is converted to five major metabolites (M1, M2, M3, M4, and M5). It is also further converted to metabolites M6 and M7 to a very small extent. The metabolites, especially M2 and M5, also have activity. A pilot study was conducted in healthy male volunteers that showed an 8- to 20-fold increase in the IP bioavailability after administration of Osteofix tablets in the fed state relative to the fasting state. A four-way crossover study was conducted in 16 healthy male volunteers, receiving Osteofix in fed state and 50, 100, and 200 mg of IP corn-oil suspension in fasted state. All IP administrations were safe and well tolerated. There was a reduction in the IP plasma level variability after 100-mg corn-oil administration as compared with that for the tablet. There was an increased relative F after the suspension, which was such that the 50-mg IP corn-oil suspension yielded similar levels as the 200-mg tablet. M5 was the major metabolite, consistent with earlier reports. The area under the curve to the last measured time point (AUC ( t ) ) levels were lower for M5, M3, and M2; higher for M1 and M2; and similar for IP after 50-mg corn-oil administration, as compared with the values for the tablet. This result may partially be explained by differences in the half-lives. Absorption/formation of M2 was delayed. The metabolite formation, except for M1 and M5, decreased with increased doses, which was accompanied by the prolonged half-life of IP and nonproportional increase in the IP AUC ( t ). This result may be due to autoinhibition of IP metabolism, because IP is an inhibitor of CYP3A4, and the metabolism of IP may be partly CYP3A4 mediated. Osteofix F may be improved by formulations that increase solubility, such as the corn-oil suspension. Although equivalent IP exposure from the tablet may be achieved at much lower overall doses because of the improved F by the corn-oil suspension, higher doses may require reconfirmation of safety and efficacy, given the differences in metabolic profiles obtained at higher doses.