Consideraciones finales
SISTEMAS ELECTORALES PARLAMENTARIOS
IV. Los efectos de los sistemas electorales según el enfoque histórico-empírico
The metabolism, bioavailability and pharmacokinetics of many nutra- ceuticals have been reported, particularly over the previous 10 years. Results have been presented for both physiological and dietary com- pounds after supplementation, which may cause problems in interpret- ing the data.
Metabolism data
Metabolites have now been identified for the majority of nutraceuticals, and a number of these may be responsible for the activity of particular nutraceuticals. The evidence is discussed in later chapters. Table 4.1 lists the physiological and dietary levels of some major nutraceuticals and their metabolites. Rarely do available dietary levels impact on physio- logical levels. Except for excessive intake of foods containing coenzyme Q10 (Co Q10), carnitine, soy and tea phenolics, and creatine, there is little chance of normal dietary supplementation substantially increasing physiological levels. With some nutraceuticals there are no physiological levels, and no realistic dietary sources. With others any physiological levels are caused by consumption of specific foods, for example those containing lycopene, tea catechins or soy isoflavones. Although metabo- lites have been identified for many entities, detailed lists have still not been collated for others.
Bioavailability data
Studies on the bioavailability of a number of nutraceuticals have been carried out, revealing wide differences. These data give an insight into the possible effectiveness of the different entities following consumption. Table 4.2 lists reported levels from a variety of studies, from which a rough comparison can be made. Nevertheless, as in the case of serum levels, a number of variable circumstances were involved in deriving these figures and any conclusions should be treated with caution. The
Nutraceutical Physiological level Dietary level Metabolites Glucosamine1 No data N/A Glucosaminic acid
Chondroitin2 N/A – Lower molecular weight polysaccharide
Chondroitin3 N/A – Chondroitin-4-sulfate
Methylsulfonylmethane4 4 mg/person Minimal DMS
Methylsulfonylmethane5 4 mg/person Minimal Methionine?
Coenzyme Q106 0.5g/mL 3–5 mg/day Coenzyme Q9
Coenzyme Q107 0.5g/mL 3–5 mg/day 6-(5⬘ and 6⬘) Carboxylated derivatives
Melatonin8 10–50 pg/mL Minimal 6-Hydroxymelatonin
plasma (day–night)
Carnitine9 9 mg/L 3–97 mg/100 g meats Acetylcarnitine, C-4/C-8 acetyl carnitines,
propionylcarnitine
Carnitine10 9 mg/L 3–97 mg/100 g meats ␥-Butyrobetaine, acetylcarnitine
Acetyl-L-carnitine11 No data, present No data, present Carnitine
Octacosanol/ policosanol12 Present in central N/A Fatty acids
nervous system
Octacosanol/policosanol13 See above N/A Myristic, palmitic, stearic, oleic, and
palmitoleic acids Octacosanol/policosanol14 See above N/A See above
S-Adenosyl methionine15 30–40 ng/mL – Methylthioadenosine, S-adenosylhomocysteine,
adenosine, putrescine, polyamines S-Adenosyl methionine16 30–40 ng/mL 0.1–10 mg/kg food Taurine
n-3-Fatty acids17 1–3% total body fat ⱕ10% total fat ALA씮EPA/DHA
n-3-Fatty acids18 1–3% total body fat ⱕ10% total fat ALA씮EPA/DHA
␥-Linolenic acid19 4–6 g/mL Minimal
71
Table 4.1 Continued
Nutraceutical Physiological level Dietary level Metabolites Flaxseed/␣-linolenic acid18 10–30 g/mL –
Flaxseed/␣-linolenic acid21 – 1.5 g/day ALA씮DHA
Conjugated linoleic acid22 – – Elongated and desaturated CLA metabolites
Conjugated linoleic acid23 – 350–430 mg/day –
Flax lignans24 Diet dependent Diet dependent SDG씮enterolactone
Pycnogenol25 N/A N/A Ferulic acid, taxifolin, ␦-(3,4-dihydroxyphenyl)
and (3-methoxy 4-hydroxy phenyl) gamma- valerolactones
Resveratrol26 N/A 0.1–2.3 mg/L wine Piceatanol
Resveratrol27 N/A 0.1–2.3 mg/L wine –
Resveratrol28 N/A 0.1–2.3 mg/L wine Piceatanol, plus another tetrahydroxystilbene
Resveratrol29 N/A 0.1–2.3 mg/L wine Dihydroresveratrol
Grape seed N/A N/A Catechin/proanthocyanidin metabolites, mainly proanthocyanidin extract30 3-hydroxyphenylpropionic acid
Lycopene31 N/A 2–5 mg/day 5,6-Dihydroxy-5,6-dihydrolycopene
Lycopene32 N/A – Lycopene epoxides, cyclocopene diols,
cyclocopene epoxides Lutein33 10–12 g/g, testes, – –
adrenal
Zeaxanthin34 N/A 5–26 ng/day Zeaxanthin씮lutein
Zeaxanthin35 N/A 5–26 ng/day Zeaxanthin씮lutein
Lipoic acid36 Minimal Minimal Dihydrolipoic acid, 3-ketolipoic acid,
bisnorlipoic acid, 3-methoxylipoic acid
Table 4.1 Continued
Nutraceutical Physiological level Dietary level Metabolites
Lipoic acid37 Minimal Minimal Bisnorlipoic acid, hydroxybisnorlipoic acid,
tetranorlipoic acid, 4,6-bismethylthio-hexanoic acid, 6,8-bismethylthio-octanoic acid, 2,4- bismethylthio-butanoic acid
Dehydroepiandrosterone38 – – Testosterone, 5-androstenediol
Dehydroepiandrosterone39 1–5 g /L 0.2–1% in foods Oestradiol, oestrone
Soy isoflavones, N/A Diet dependent Unidentified daidzein/genistein40
Soy isoflavones41 N/A 15–20 mg/day by specific 18 demethylated and hydroxylated metabolites
consumers
Soy isoflavones25 N/A 15–20 mg/day by specific Daidzein씮equol and intermediates
consumers
Green tea catechins, N/A Diet dependent, minimal in 4–O-Methyl-epigallocatechin, valerolactones EGCG, EGC, EC, ECG42 low dose green tea
Green tea catechins, N/A – 3 and 4-O-methyl-EC, EGC and EGCG, EGCG, EGC, EC, ECG43 valerolactones
Green tea catechins, N/A 18–50 mg/day – EGCG, EGC, EC, ECG44
Creatine45 1 g/day produced Present 5 g/kg meat Creatinine, phosphocreatine
N/A, not available endogenously.
ALA,␣-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; CLA, conjugated linoleic acid; SDG, secoisolariciresinol diglucoside; DHEA, dehydroepiandrosterone; EC, (—)-epicatechin; ECG, (—)-epicatechin gallate; EGC, (—)-epigallocatechin; EGCG, (—)-epigallocatechin gallate.
73
Table 4.2 Oral bioavailability in humans after single-dose administration of nutraceuticals (except where stated)
Nutraceutical Dose Bioavailability Increased serum levels
Glucosamine46 7.5 g 26%, 44% incorporation –
into globulin
Chondroitin4 3 g 13% –
Coenzyme Q106 30 mg – 35% increase in serum levels at 6 hours
Coenzyme Q1048 30 mg – 2.7–6 times normal level
Melatonin27 2–4 mg 15% –
Melatonin49 250g 10–56% 240–620 pg/mL
Melatonin50 1–6 g 5–18% –
Carnitine51 2 g/12 hours 14–16%
Carnitine11 0.5–0.6 g 14–18%
Acetyl-L-carnitine11 2 g/day 43% increase
Octacosanol/policosanol12 – 5–12% (rats) –
S-Adenosyl methionine15 2⫻ 200 mg – 3.5–6 times
Docosahexaenoic acid52 11.6% of 9 g fresh oil – 2 times normal levels
Eicosapentaenoic acid52 18.2% of 9 g fresh oil – 5–6 times normal levels
Resveratrol53 50 mg/kg 38% (rats) –
Resveratrol29 Almost zero
Lycopene, lutein, zeaxanthin, 1 mg 4% –
astaxanthin34 10 mg 20%
Lipoic acid37 600 mg/day for 4 days 30% –
Lipoic acid36 1 g 20–38% –
Dehydroepiandrosterone54 200 mg – 5–6 times normal
Green tea extracts42 20 mg/kg body weight Low –
EGC 15.5 mg 0.8% 179 ng/mL peak serum level
EC 36.5 mg 0.7%
EGCG 16.7 mg 0.1%
ECG55 31.1 mg 0.09% 1.7% in total
Creatine56 2–3 g 5–6 times normal
absence of data for some major nutraceuticals, such as methylsulfonyl- methane (MSM), ␥-linolenic acid (GLA) and grape seed proantho- cyanidin extract (GSPE), means that there is no guidance for optimal dosage levels.
Further evidence for the different bioavailability of different formu- lations and complex mixtures only allows the individual con- sumer/patient/clinician to use the most detailed/only available published data. Detailed comparative data for some individual nutraceuticals have been published (e.g. Co Q10,57 creatine45), and in these cases com- parison of a range of studies is possible. In the study on the bio- equivalence of Co Q10 formulated products, 180 mg doses of four products were evaluated in nine individuals. Although the absolute bioavailability of Co Q10 is not known, it has been found to be strongly lipophilic, practically insoluble in aqueous solution, and has poor bioavailability. A range of products have been formulated with emulsi- fying agents and oil-based vehicles, as well as fully solubilised formula- tions, in an attempt to improve bioavailability. An increased serum concentration and area under the curve (blood concentration–time profile) (AUC) of about 50% was recorded for the oil suspension in soft gelatin capsule when compared with a standard dry formulation.58
Research into the variability of ten Co Q10 products available in New Zealand showed that there was at least fourfold variation in the increase in plasma Co Q10 levels achieved by the different products, and patients showed no increase in levels with the least effective products.59 Bioequivalence comparison of four products showed the best to be the one containing the reduced form of Co Q10, ubiquinol, which was even superior to solubilised formulations.57
In a review of the pharmacokinetics of 17 formulated creatine products taken from six published studies, accumulated data allow direct comparison of the data on single dose use of 5 mg formulated products.45 There is a wide variation in the levels of quoted pharmaco- kinetic parameters: the maximum concentration (blood concentra- tion–time profile) (Cmax) varies from 67 to 160 mg/L, AUC from 183 to 340 mg h/L, half-life (t1
-2) from 0.89 to 1.7 hours, clearance from 14 to 27 L/hour, and the volume of distribution from 18 to 47 L. Overall, these levels show variations of the order of 100%, and even comparable data from a single study using different volunteer groups (young or elderly) exhibited variations of up to 50%.
In addition to formulation differences, it has been reported that various dietary factors also affect the bioavailability of certain nutra- ceuticals. The absorption of lycopene has been reported to improve
following ingestion of a combined dose of -carotene and lycopene, instead of lycopene alone.60 Optimal intestinal uptake of lutein esters has been reported to require higher dietary fat levels than other carotenoids, and with concomitant intake of high fat supplementation, plasma lutein uptake more than doubled.61 Lutein-containing yellow carrots caused significantly increased lutein concentrations in humans, and did not result in the decrease of -carotene concentrations that normally accompanies administration of lutein.62 Further evidence of the effect of the food matrix on the bioavailability of lutein was shown when present in spinach.63 Dietary fat levels have also been shown to affect absorption of lutein beneficially, high levels resulting in five times higher absorption.64
Pharmacokinetic data
Pharmacokinetic data for a number of nutraceuticals have been reported. This is of great importance in deciding optimum dosage levels and frequency of administration of the particular entities. Comparison of data available for different nutraceuticals is extremely difficult due to the wide range of possible parameters available and published. Table 4.3 lists some of the major pharmacokinetic parameters for many of the major nutraceuticals. Some of the most important parameters (Cmax, time of Cmax(tmax)), t-12, maximum AUC at ⬁ (AUC⬁)) have been reported, but only rarely is the whole pharmacokinetic picture available. Compari- sons between nutraceuticals, even nutraceuticals of similar type, are extremely difficult due to lack of data, different dosage levels (different dimensions and units in published works) and wide variations between different volunteer/patient groups involved. Cmax gives an idea of maximal serum concentration after dosing. The half-life, t-1
2, is sometimes available, but this varies if above saturation dose. AUC⬁is often quoted, but not invariably, sometimes AUC24h or another timescale is used. AUC⬁is an acccepted indicator of bioavailability, but takes no account of dosing level used.
From Table 4.3 it would appear that glucosamine, chondroitin, eicosapentaenoic acid (EPA), GLA and creatine have far better bioavail- ability (as seen from AUC values) than other nutraceuticals. However, the dosages used were usually far greater as well, although they were in the normal therapeutic range. Bioavailability appears to be very low for carnitine, lipoic acid, dehydroepiandrosterone (DHEA) and tea catechins. The tmaxand t-12values indicate a comparatively low retention for melatonin and lipoic acid. The n-3 fatty acids docosahexaenoic acid Pharmacokinetic data 7 5
stated)
Nutraceutical Number of Dose Cmax tmax(h) t-12(h) AUC⬁
subjects Glucosamine65 8 beagles 1500 mg 1.5 1.52 178.1 g.h/mL Chondroitin66 20 4 g (bovine) 12.7 g/mL 2.4 179.1 g.h/mL (48 h) Chondroitin3 20 4 g (ickthyc) 4.87 g/mL 8.7 141.4 g.h/mL (48 h) Coenzyme Q1057 9 180 mg 1.03 g/mL 6.2 51.67 g.h/mL Melatonin49 12 250 g 125 pg/mL 0.38 255 pg.h/mL Melatonin67 16 0.5 g/kg 0.79 377 pg.h/mL Carnitine51 15 2 g every 12 h 12.4 g/mL 0.12 g.h/mL
S-Adenosyl methionine68 6 100 mg i.v. 1.35 78 g.h/mL
6 500 mg i.v. 1.68 425 g.h/mL Docosahexaenoic acid69 12 1200 mg 131 g/mL Eicosapentaenoic acid69 12 1140 mg 126 g/mL Eicosapentaenoic acid70 10 1 g 50 g/mL 4.7 645 g.h/mL ␥-Linolenic acid70 10 1.5 g 73 g/mL 3.4 674 g.h/mL ␥-Linolenic acid19 6 240 mg 21.7 g/mL 3.6 137.1 g.h/mL Flax lignans71 12 0.9 mg/kg SDG 4.4 280 g.h/mL 12 0.9 mg/kg SDG 12.6 525 g.h/mL Lycopene72 25 10 mg 0.04 g/mL 16.6 28.1 2.74 g.h/mL 25 120 mg 0.11 g/mL 32.6 40.9 9.70 g.h/mL Zeaxanthin34 10 10 mg 1 g/mL 15 13 1.6 g.h/mL Astaxanthin73 3 100 mg 1.3 mg/mL 6.7 21 42 g.h/mL Astaxanthin74 8 40 mg 55 g/mL 8 16.7 1.35 g.h/mL Lipoic acid36 12 200 mg 70.8 g/mL 1.8 0.66 0.66 g.h/mL
77
Table 4.3 Continued
Nutraceutical Number of Dose Cmax tmax(h) t1-2(h) AUC⬁
subjects
Dehydroepiandrosterone38 12 Men 25 mg/day for 8 days 27.7 26 0.16 g.h/mL
12 Women 25 mg/day for 8 days 27.7 26 0.20 g.h/mL Daidzein40 10 (20 g soybean) 214 000 g/mL 2.6 g.h/mL 13 mg daidzein Daidzein75 10 7.47 mg SR 0.05 g/mL 7.4 11.4 1.07 g.h/mL Genistein40 10 (20 g soybean) 0.31 g/mL 4.4 g.h/mL 20 mg genistein Genistein75 10 22.3 mg SR 0.04 g/mL 6.7 10.2 0.97 g.h/mL
Green tea extracts76 5 400 mg 0.11 g/mL 1.8 2.7 2124 g.h/mL
epigallolocatechin gallate
Green tea catechins77 12 910 mg total 159 500 g/mL 2.3 4.8 0.64 g.h/mL
catechin derivatives
Black tea catechins77 12 300 mg total 49 300 g/mL 2.2 6.9 0.15 g.h/mL
catechin derivatives
Black tea catechins 12 300 mg total 52 200 g/mL 2 8.6 0.17 g.h/mL (with milk)77 catechin derivatives
Creatine45 1 10 g 120 g/mL 1.25 0.94 360 g.h/mL
(DHA) and EPA exhibit comparable data in the same study, but astaxanthin shows widely different data (Cmax, AUC) from the two studies quoted. As one would expect, hydrophobic substances often exhibit longer half-lives, and the data shown for DHEA and carotenoids confirm this.
Half-lives are available for some of the published nutraceuticals, which should allow dosage regimens to be designed. Comparative data45 published for creatine show a wide variation in half-life values, both within single studies, of the order of 2.5 times, and also between different studies using the same dosage regimen. If pharmacokinetic experimentation was available from similarly designed studies, derived data may be useful in comparing the effectiveness of nutraceuticals used for the same therapeutic application (e.g. in the case of glycoaminogly- cans (GAG)), and one should be able to compare dosing of individual compounds and thereby select the best individual entity for the appli- cation.
Recently, the comparable bioavailability of a number of poly- phenols has been studied.44 Comparable data from 28 studies on catechin bioavailability were reported, and there are marked differences between different individual entities. When supplementation with single pure catechins was studied it was found that galloylation of catechins reduces their absorption. It was also shown that 77–90% of (—)-epigal- locatechin gallate (EGCG) is present in plasma in the free form, although other catechins are highly conjugated with glucuronic acid and/or sulfate groups. The valerolactone metabolites of the catechin derivatives are of microbiological origin, and were mainly found in plasma and urine in conjugated forms. These metabolites represented 6–39% of (—)-epigal- locatechin (EGC) and (—)-epicatechin (EC), and were present in concen- trations 8–25 times higher than those of the free compounds. It is likely that as these appear later than the catechins in plasma, and have long half-lives, they may prolong the action of the catechins. Very limited absorption of polymeric proanthocyanidins has been shown to occur, but their activity may be via direct action on the intestinal mucosa, protecting it from oxidative stress or carcinogens. Alternatively, these polymers usually occur in conjunction with their monomers at levels of 5–25%, and these may be responsible for the activity.
Similar comparative bioavailability studies have also been carried out on soy phytoestrogens, using 15 published studies.78Unfortunately, contradictory results were obtained: one particular study had indicated that there was greater bioavailability for the glucoside forms, another that there was greater bioavailability for the aglycone form, and two
showed no differences in the absorption rates for the two forms. Production of the metabolite equol was shown to be greater for daidzin than for daidzein, and the bioavailability of genistein was higher than that of daidzein, but glycitein was higher still.
Overall, data for metabolites produced from most nutraceuticals are now available, and bioavailability data have been published for the majority. Detailed pharmacokinetic data have not been published for MSM, octacosanol/policosanol, CLA, Pycnogenol, resveratrol, GSPE, and any of the isolated components from complex products such as CLA, Pycnogenol or GSPE.
Dosage levels that have been used for collection of the data are largely intuitive, and more studies involving greater dosage ranges are needed.
It needs to be borne in mind that dosage regimens used in reported clinical trials and pharmacokinetic work may not have been the most effective for treating symptoms, and also that different researchers have often used different regimens. Pharmacokinetic data from trials involving wide dosage levels and regimens may supply extremely worthwhile information for planning future clinical trials of nutra- ceuticals, particularly in cases where there is a possibility of side-effects, for example with the caffeine content of green tea.79
Some scientists would question the validity of carrying out pharmacokinetic evaluation of those nutraceuticals which are them- selves endogenous constituents of living tissue. A number are also possible or probable components of individual diets, for example soy products, green tea and n-3 fatty acids, and may either be consumed at variable levels or not at all, thus compromising other data.
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