Apigenin Luteolin Quercetin Genistein and Daidzein

Oral Clearance Values

A limited number of studies have investigated the oral clearance of apigenin, luteolin, quercetin, genistein, and daidzein in humans, although more studies have been conducted in rodents. Because of their complex metabolism and the analytical difficulty of measuring the vari-

ous metabolites, many questions remain. Some details on the available human studies are listed in Table J.5.

TABLE J.6 ESTIMATED ORAL CLEARANCE VALUES OF FLAVONOIDS

FLAVONOID

ESTIMATED TOTAL ORAL CLEARANCE OF FLAVONOID (L/Hr)

Apigenin

4.8

Genistein

3.7

Daidzein

4.9

Luteolin

14

Quercetin

24

Data from Table J.5.

TABLE J.7 REQUIRED DOSE FOR FLAVONOIDS BASED ON PHARMACOKINETIC DATA

FLAVONOID

ORAL CLEARANCE* (L/Hr)

REQUIRED DOSE (grams/day)

Genistein

3.7

0.72

Daidzein

4.9

0.90

Apigenin

4.8

0.93

Luteolin

14

2.9

Quercetin

24

5.2

From Table J.6.

Some discrepancy exists in the literature regarding the relative bioavailabilities of genistein and daidzein. The data in Table J.5 suggest that genistein is slightly more bioavailable than daidzein (the average oral clearance of genistein is lower). This trend is supported by a number of human studies that measured peak plasma concentrations.41'89'90 However, two human studies and one rat study that measured urinary output suggested daidzein is more bioavailable than gen-istein.90'91'92 The human urinary studies indicated that daidzein is 1.4- to 2.3-fold more bioavailable than genistein. Interestingly, the FOC model produced a somewhat similar result; it predicted free daidzein was 3.1-fold more bioavailable than free genistein (see Table I.1). Nonetheless, since the studies using human plasma suggest that genistein is slightly more bioavailable than daidzein' we use the values in Table J.5 for further dose calculations.

Unfortunately, the pharmacokinetic parameters of apigenin and luteolin have not been studied in humans, and only one study on luteolin in rats is available. In that one, the oral clearance for total luteolin was approximately 0.23 L/hr. The human equivalent is about 14 L/hr.

We can estimate the total oral clearance values for apigenin and luteolin by using the TOC model from Appendix I. As listed in Tables I.2 and I.3, the total oral clearance values predicted for apigenin and luteolin are 4.8 and 15 L/hr, respectively.3 The value of 15 L/hr for luteolin is nearly identical with the 14-L/hr value scaled above from a rat study, so we use the 14-L/hr value. For apigenin, we use the value predicted by the TOC model. Based on the above, the total oral clearance values for daidzein, genistein, and quercetin are shown in Table J.6.

Dose Calculations

The aglycones for all flavonoids listed in Table J.6 are active in vitro at a concentration of roughly 15 mM. Therefore, we use a target in-vivo concentration of 30 mM, after adjustment for conjugates. For genistein and daidzein, 30 mM is larger than the normal total (free plus a In using Equation I.2, the percent of free apigenin in the plasma chosen was 3 percent, the same for luteolin.

conjugate) plasma concentrations of about 0.28 mM that occurs in subjects consuming a high-soy diet.40 The same is true for quercetin, where average fasting total plasma concentrations are about 0.07 mM.49,93 We can confidently assume that 30 mM is also much larger than normal apigenin and luteolin plasma concentrations. We see then that therapeutic concentrations are well above normal concentrations, as would be expected. Table J.7 shows the resulting dose estimates based on a 30-mM target.

The dose estimates calculated above are similar to doses scaled from animal antitumor studies mentioned in Chapter 19. The 720-milligram dose of genistein is within the range of 250 milligrams to 9.9 grams scaled from animal antitumor experiments. The 930-milligram dose for apigenin is just below the range of 1.2 to 2.5 grams scaled from an animal antitumor experiment. The 2.9-gram dose for luteolin is within the range of 1.1 to 3.4 grams scaled from an animal antitumor experiment. The 5.2-gram dose for quercetin is just above the range of 1.2 to 4.9 grams scaled from animal antitumor experiments.

In addition, the calculated doses for apigenin, luteolin, and quercetin are similar to those scaled from animal anti-inflammatory experiments. Intraperitoneal administration of apigenin and luteolin (at 8 to 50 mg/kg) produced anti-inflammatory effects in rats; the equivalent

TABLE J.8 ESTIMATED THERAPEUTIC AND LOAEL DOSES FOR ISOFLAVONES, FLAVONES,

AND FLAVONOLS

DESCRIPTION

GENISTEIN DOSE (g/day)

APIGENIN DOSE (g/day)

LUTEOLIN DOSE (g/day)

QUERCETIN DOSE (g/day)

Required dose as scaled from animal antitumor studies

0.25 to 9.9 (average 2.3)

1.2 to 2.5

1.1 to 3.4

1.2 to 4.9

Required dose as scaled from animal antiinflammatory studies

none

0.66 to 4.1

0.66 to 4.1

1 to 4

Required dose as estimated from pharmacokinetic calculations

0.72

0.93

2.9

5.2

Target dose based on an average from animal antitumor studies and pharmacokinetic calculations

1.5

1.5

2.5

3.8

Minimum required antitumor dose assuming 15-fold synergistic benefits

0.1

0.1

0.17

0.25

Commonly prescribed human dose in noncancerous conditions

0.05

0.01

uncertain

1

Estimated LOAEL dose

1.6

3.2

4.4

6.5

Tentative dose recommendation for further research

0.1 to 1.1

0.1 to 1.5

0.17 to 1.8*

0.25 to 1.8*

Minimum degree of synergism required

1.4-fold potency increase

none

1.4-fold potency increase

2.1-fold potency increase

Upper value based on daidzein LOAEL. ^ Upper value based on the general linear bioavailability limit of 1.8 grams per day.

human oral dose is about 0.66 to 4.1 grams.94 95 Quercetin produced anti-inflammatory effects within the range of 1 to 4 grams, as scaled to humans, after oral administration in mice, rats, and guinea pigs. Anti-inflammatory effects were also produced at a dose of 2.6 grams, scaled to humans (oral equivalent), after intra-peritoneal administration in rats.96,97

To obtain target doses for these flavonoids, we can use an average of the doses calculated from pharmacokinetic and in-vitro data and those scaled from animal antitumor experiments. The results are in Table J.8.

Also in this table are the minimum required doses based on a full 15-fold increase in potency due to syner-gism. These minimum daily doses are 100 milligrams for genistein, 100 milligrams for apigenin, 170 milligrams for luteolin, and 250 milligrams for quercetin. Although these doses are above normal dietary intake, they are likely to be safe. One study reported that the dietary intake of genistein in Japanese subjects averaged about 20 milligrams per day (daidzein intake was 12 milligrams daily).98 The average dietary intake of api-genin, luteolin, and quercetin in subjects from the Netherlands was smaller, at about 0.69, 0.92, and 16 milligrams per day, respectively.99

The minimum dose of 100 milligrams for genistein is larger than the commonly prescribed dose for noncan-

cerous conditions. The recommended genistein dose based on the label of some products is about 50 milligrams. The commonly prescribed doses of apigenin and luteolin are more difficult to determine. Chamomile products that are standardized for 1 percent apigenin are commercially available. When used according to the manufacturer's recommendations, the daily dose would provide about 10 milligrams of apigenin. No products standardized for luteolin are commercially available, although other herbs besides chamomile contain api-genin and/or luteolin. The commonly prescribed dose for quercetin supplements, as provided on the label of some products, is about 1 gram per day.

The exact LOAEL doses for these flavonoids are uncertain. Animal and human studies suggest that the human LOAEL dose for genistein is greater than 1.1 grams per day:

• In rat studies, the NOAEL dose for genistein was about 1.6 grams per day, as scaled to humans.100 The LOAEL dose can be expected to be equal to or somewhat higher than the NOAEL dose.

• In a study on dogs, no adverse acute effects were seen after oral administration of 63 mg/kg of gen-istein.101 The human equivalent is about 2.7 grams.

• Preliminary results of a phase I human clinical trial on genistein (as given in a soy isoflavone mixture)

TABLE J.9 AVERAGE AMOUNTS OF CATECHINS IN GREEN TEA EXTRACT

SAMPLE

UNITS

EGCG

EGC

EC

ECG

REFERENCES

One gram tea extract (GTE) containing 35% (350 mg) catechins

mg

120

92

34

32

5, 51, 106-109

% of total catechins

34

26

9.7

9.1

% of total tea solids

12

9.2

3.4

3.2

Dried tea leaf

% of total

2

1.5

0.57

0.53

This assumes that 20% of total catechins are from catechin compounds not listed. EGC = epigallocatechin, EC = epicatechin, ECG = epicatechin gallate

indicate that subjects can safely receive doses of at least 1.1 grams (16 mg/kg).102

The LOAEL dose for genistein predicted by the TOPKAT model is similar to the above doses. The TOPKAT model predicted

LOAEL doses for genistein, apigenin, luteo-lin, and quercetin in rats of 97, 200, 270, and 400 mg/kg. These correspond to human doses of about 1.6, 3.2, 4.4, and 6.5 grams per day. Because this model appears to accurately predict the LOAEL dose for genistein, we base our LOAEL dose estimates for all these flavonoids on the TOPKAT results.

Since genistein occurs naturally with daidzein in soy (in about a 1 to 1 ratio), the toxicity of daidzein is also of interest. The TOPKAT model predicted a LOAEL dose of daidzein in rats of 69 mg/kg. The corresponding human dose is about 1.1 grams. This suggests that administration of a mixed soy isoflavone product should not exceed about 1.1 grams for daidzein, or subsequently, 1.1 grams for genistein.

The estimates presented in Table J.8 are not likely to be in error due to dose-dependent bioavailability issues. The human pharmacokinetic studies for genistein and quercetin used doses of 8 to 71 milligrams, which is below the linear bioavailability limit of 600 milligrams per administration (1.8 grams per day). The same is true for the rat pharmacokinetic study for luteolin, which used a dose of 230 milligrams, as scaled to humans.

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