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Evaluation of CYP450 inhibitory effects and steady-state pharmacokinetics of genistein in combination with cholecalciferol and citrated zinc bisglycinate in postmenopausal women.

Burnett BP, Pillai L, Bitto A, Squadrito F, Levy RM - Int J Womens Health (2011)

Bottom Line: The product showed minimal inhibition of 1A2, 2C19, 2D6, and 3A4, exhibiting IC(50) > 10 μM, but 2C8 and 2C9 yielded IC(50) of 2.5 μM and 2.8 μM, respectively, concentrations which are theroretically achievable when dosing the product twice daily.After seven days of administration in a steady-state pharmacokinetic study, significant differences were found for unconjugated genistein (including free and protein-bound), regarding time to peak concentration (1.88 ± 1.36 hours), maximum concentration reached (0.052 ± 0.055 μM), elimination half-life (2.3 ± 1.6 hours), and area under the concentration-time curve (53.75 ± 17.59 ng · hour/mL) compared with results for total genistein (including glucuronidated and sulfonated conjugates) time to peak concentration (2.22 ± 1.09 hours), maximum concentration reached (2.95 ± 1.64 μM), elimination half-life (10.4 ± 4.1 hours), and area under the concentration-time curve (10424 ± 6290 ng · hour/mL) in fasting subjects.Coadministration of food tended to extend the time and extent of absorption as well as slow elimination of genistein, but not in a statistically significant manner.

View Article: PubMed Central - PubMed

Affiliation: Primus Pharmaceuticals Inc, Scottsdale, AZ, USA.

ABSTRACT

Background: The combination of genistein 27 mg, cholecalciferol 200 IU, citrated zinc bisglycinate (4 mg elemental zinc) 20 mg per capsule in Fosteum(®), a prescription medical food regulated by the FDA and indicated for the dietary management of osteopenia and osteoporosis, was tested for drug interactions and to determine the pharmacokinetic profile for genistein, the principal bone-modulating ingredient in the product.

Methods: In vitro human liver microsome cytochrome P450 (CYP450) assays were used to test the product for potential drug interactions with the isoforms 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Due to specific 2C8 and 2C9 inhibition, a steady-state pharmacokinetic study was performed to assess serum genistein concentrations by high-pressure liquid chromatography-coupled mass spectroscopy in healthy fasting (n = 10) and fed (n = 10) postmenopausal women.

Results: The product showed minimal inhibition of 1A2, 2C19, 2D6, and 3A4, exhibiting IC(50) > 10 μM, but 2C8 and 2C9 yielded IC(50) of 2.5 μM and 2.8 μM, respectively, concentrations which are theroretically achievable when dosing the product twice daily. After seven days of administration in a steady-state pharmacokinetic study, significant differences were found for unconjugated genistein (including free and protein-bound), regarding time to peak concentration (1.88 ± 1.36 hours), maximum concentration reached (0.052 ± 0.055 μM), elimination half-life (2.3 ± 1.6 hours), and area under the concentration-time curve (53.75 ± 17.59 ng · hour/mL) compared with results for total genistein (including glucuronidated and sulfonated conjugates) time to peak concentration (2.22 ± 1.09 hours), maximum concentration reached (2.95 ± 1.64 μM), elimination half-life (10.4 ± 4.1 hours), and area under the concentration-time curve (10424 ± 6290 ng · hour/mL) in fasting subjects. Coadministration of food tended to extend the time and extent of absorption as well as slow elimination of genistein, but not in a statistically significant manner.

Conclusion: Because the serum genistein concentrations achieved during pharmacokinetic testing at therapeutic doses were well below those required for enzyme inhibition in the in vitro liver microsome assays, these results indicate a low potential for drug interactions.

No MeSH data available.


Related in: MedlinePlus

Genistein aglycone.
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getmorefigures.php?uid=PMC3140810&req=5

f1-ijwh-3-139: Genistein aglycone.

Mentions: Genistein is an isoflavone found in small quantities in certain legumes throughout the plant kingdom (Figure 1). Unfermented soybeans are a particularly rich source of genistin, the glucoside precursor of genistein, although the concentration varies with the strain, location, and environmental conditions of cultivation of the plant. Another widely utilized source of genistin is Sophora japonica L.2 Asian populations, for whom fermented soy food and other isoflavone containing plants are dietary staples, are estimated to consume 25–100 mg of isoflavone daily.3 The majority of isoflavone consumption is in the form of aglycone rather than as glucosides. In contrast, intake of isoflavones in the US is estimated at only 0.15–3 mg per day, with much of it being in glucoside forms.4,5 Therefore, non-Asian populations may not reap the benefits of high intake of isoflavone, in particular, genistein aglycone.


Evaluation of CYP450 inhibitory effects and steady-state pharmacokinetics of genistein in combination with cholecalciferol and citrated zinc bisglycinate in postmenopausal women.

Burnett BP, Pillai L, Bitto A, Squadrito F, Levy RM - Int J Womens Health (2011)

Genistein aglycone.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140810&req=5

f1-ijwh-3-139: Genistein aglycone.
Mentions: Genistein is an isoflavone found in small quantities in certain legumes throughout the plant kingdom (Figure 1). Unfermented soybeans are a particularly rich source of genistin, the glucoside precursor of genistein, although the concentration varies with the strain, location, and environmental conditions of cultivation of the plant. Another widely utilized source of genistin is Sophora japonica L.2 Asian populations, for whom fermented soy food and other isoflavone containing plants are dietary staples, are estimated to consume 25–100 mg of isoflavone daily.3 The majority of isoflavone consumption is in the form of aglycone rather than as glucosides. In contrast, intake of isoflavones in the US is estimated at only 0.15–3 mg per day, with much of it being in glucoside forms.4,5 Therefore, non-Asian populations may not reap the benefits of high intake of isoflavone, in particular, genistein aglycone.

Bottom Line: The product showed minimal inhibition of 1A2, 2C19, 2D6, and 3A4, exhibiting IC(50) > 10 μM, but 2C8 and 2C9 yielded IC(50) of 2.5 μM and 2.8 μM, respectively, concentrations which are theroretically achievable when dosing the product twice daily.After seven days of administration in a steady-state pharmacokinetic study, significant differences were found for unconjugated genistein (including free and protein-bound), regarding time to peak concentration (1.88 ± 1.36 hours), maximum concentration reached (0.052 ± 0.055 μM), elimination half-life (2.3 ± 1.6 hours), and area under the concentration-time curve (53.75 ± 17.59 ng · hour/mL) compared with results for total genistein (including glucuronidated and sulfonated conjugates) time to peak concentration (2.22 ± 1.09 hours), maximum concentration reached (2.95 ± 1.64 μM), elimination half-life (10.4 ± 4.1 hours), and area under the concentration-time curve (10424 ± 6290 ng · hour/mL) in fasting subjects.Coadministration of food tended to extend the time and extent of absorption as well as slow elimination of genistein, but not in a statistically significant manner.

View Article: PubMed Central - PubMed

Affiliation: Primus Pharmaceuticals Inc, Scottsdale, AZ, USA.

ABSTRACT

Background: The combination of genistein 27 mg, cholecalciferol 200 IU, citrated zinc bisglycinate (4 mg elemental zinc) 20 mg per capsule in Fosteum(®), a prescription medical food regulated by the FDA and indicated for the dietary management of osteopenia and osteoporosis, was tested for drug interactions and to determine the pharmacokinetic profile for genistein, the principal bone-modulating ingredient in the product.

Methods: In vitro human liver microsome cytochrome P450 (CYP450) assays were used to test the product for potential drug interactions with the isoforms 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Due to specific 2C8 and 2C9 inhibition, a steady-state pharmacokinetic study was performed to assess serum genistein concentrations by high-pressure liquid chromatography-coupled mass spectroscopy in healthy fasting (n = 10) and fed (n = 10) postmenopausal women.

Results: The product showed minimal inhibition of 1A2, 2C19, 2D6, and 3A4, exhibiting IC(50) > 10 μM, but 2C8 and 2C9 yielded IC(50) of 2.5 μM and 2.8 μM, respectively, concentrations which are theroretically achievable when dosing the product twice daily. After seven days of administration in a steady-state pharmacokinetic study, significant differences were found for unconjugated genistein (including free and protein-bound), regarding time to peak concentration (1.88 ± 1.36 hours), maximum concentration reached (0.052 ± 0.055 μM), elimination half-life (2.3 ± 1.6 hours), and area under the concentration-time curve (53.75 ± 17.59 ng · hour/mL) compared with results for total genistein (including glucuronidated and sulfonated conjugates) time to peak concentration (2.22 ± 1.09 hours), maximum concentration reached (2.95 ± 1.64 μM), elimination half-life (10.4 ± 4.1 hours), and area under the concentration-time curve (10424 ± 6290 ng · hour/mL) in fasting subjects. Coadministration of food tended to extend the time and extent of absorption as well as slow elimination of genistein, but not in a statistically significant manner.

Conclusion: Because the serum genistein concentrations achieved during pharmacokinetic testing at therapeutic doses were well below those required for enzyme inhibition in the in vitro liver microsome assays, these results indicate a low potential for drug interactions.

No MeSH data available.


Related in: MedlinePlus