Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.13.97 (CYP3A4)
 6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Pharmacokinetics of ipriflavone and metabolites after oral administration of a corn-oil suspension relative to the Osteofix tablet. 1042 15

Ipriflavone, a synthetic flavonoid for the prevention and treatment of osteoporosis, has been reported to be extensively metabolized in man to seven metabolites (M1-M7). This study was performed to characterize the human liver cytochrome P450s (CYP) responsible for the metabolism of ipriflavone. Hydroxylation at the beta-ring to M3, O-dealkylation to M1 and oxidation at isopropyl group to M4 and M5 are major pathways for ipriflavone metabolism in three different human liver microsome preparations. The specific CYPs responsible for ipriflavone oxidation to the active metabolites, M1, M3, M4 and M5 were identified using a combination of correlation analysis, immuno-inhibition, chemical inhibition in human liver microsomes and metabolism by expressed recombinant CYP enzymes. The inhibitory potencies of ipriflavone and its five metabolites, M1-M5 on seven clinically important CYPs were investigated in human liver microsomes. Our results demonstrate that CYP3A4 plays the major role in O-dealkylation of ipriflavone to M1 and CYP1A2 plays a dominant role in the formation of M3, M4 and M5. Ipriflavone and/or its five metabolites were found to inhibit potently the metabolism of CYPs 1A2, 2C8, 2C9 and 2C19 substrates.
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PMID:Characterization of cytochrome P450s mediating ipriflavone metabolism in human liver microsomes. 1762 23