Pharmacokinetics in herbal medicine
Pharmacokinetics can be defined as the study of the absorption, distribution, metabolism and elimination of pharmacologically active agents in the body. This discussion is not intended to be a primer on the principles of pharmacokinetics (there are appropriate texts for this purpose); however, certain basic issues will be discussed where there is particular relevance to plant chemicals.
One important issue that should underlie much of the study of herbal pharmacokinetics is that herbs are not usually directly introduced into the bloodstream by injection or other means, but rather the traditional oral or topical routes of administration are preferred. This renders the study of bioavailability of paramount importance for active constituents in plants. Bioavailability can be defined as the degree of absorption of active substances into the bloodstream after oral doses. Hence bioavailability is also a factor of the preparation that is used to deliver the dose of active substance. Conventional drugs intended for oral use are designed to have good bioavailability. In contrast, phytochemicals are of natural origin and may exhibit unusual or poor bioavailability that may be further compounded by the choice of dosage preparation.
In this discussion, the issue of the bioavailability of several of the archetypal plant constituents will be emphasised. For pharmacokinetic details related to specific herbs, see the monograph section (Part Three) of this book.
Herbal clinicians and students sometimes question the value of studying herbal pharmacokinetics. The following premises should be considered:
• If it is accepted that medicinal plants act at a chemical level in the body (as well as possibly other levels of activity), then knowledge of how their chemicals behave in the body is vital.
• Given that, with a few exceptions in some countries, oral and topical doses are used for herbal medicines, a better knowledge of bioavailability is critical to meet the challenge of future health problems.
Specifically the information derived from the detailed study of herbal pharmacokinetics can deliver:
• information to further assess the traditional and anecdotal uses of a medicinal plant
• better information on which to base rational dosages
• a better interpretation of scientific information, particularly in vitro research or in vivo studies where the active compounds are administered by injection. There is an abundance of misinformation in the herbal literature related to excessive extrapolation from such studies, with no consideration of bioavailability
• a better appreciation of the safety and toxicity of a plant
• anticipation of potential herb-drug interactions
• supporting evidence for the synergistic nature of herbal medicine
• ways to optimise the bioavailability and hence efficacy of herbal medicines.
The study of herbal pharmacokinetics is a unique and extraordinarily complex field. This is for the following reasons:
• The chemical complexity of plant medicines and the potential interactions between constituents
• The differing bioavailability of different compounds
• Often large polar molecules are involved that might be expected to have poor and unpredictable bioavailability
• The active components are often not known, so the components in the plant that should be studied cannot be identified
• Unlike drugs, herbal medicines are not designed for predictable pharmacokinetic behaviour, and in particular natural compounds are often metabolised in the digestive tract – that is, they are pro-drugs; this key feature is emphasised in this chapter.
But this does not mean to imply that the existing information is without value. On the contrary, many studies now provide a better understanding of this topic and inform clinical practice.
Before particular examples of the pharmacokinetics of plant constituents are discussed, it is worthwhile to examine some of the key issues pertaining to bioavailability. The bioavailability of a molecule depends on several factors that determine how it traverses the barrier of the gastrointestinal tract and survives into the bloodstream. These include:
• the pharmaceutical preparation
• the size of the molecule – very large molecules still have some bioavailability (about 1% or less) which may be due to pinocytosis
• the fat (lipid) solubility of the molecule – the more fat-soluble, the better the bioavailability (see Table 2.2515 for examples of how fat solubility influences bioavailability for cardioactive glycosides)
• the water solubility of the molecule – if a molecule is both water- and fat-soluble it will exhibit very good bioavailability because it will dissolve in the digestive juices and then cross lipid membranes; otherwise, purely water-soluble molecules can be expected to have poor bioavailability; ionisation of a molecule usually denotes poor bioavailability
• specific factors related to crossing the gut wall, such as active transport
• factors within the gut – interaction with food, stability in the gut, gastric emptying
• metabolism in the gut and first-pass metabolism by the liver
• individual factors in the patient, including the influence of genetic and pathological factors.
Table 2.2 Effect of lipid solubility on bioavailability515
| Cardiac glycoside | P | B% |
|---|---|---|
| g-Strophanthin | 0.01 | 6.6 |
| Convallatoxin | 0.33 | 13.6 |
| Digoxin | 18.2 | 26.4 |
| Digitoxin | 70 | 74.9 |
| Oleandrin | 338 | 86.0 |
B = bioavailability; P = partition between water and octanol, an indication of fat solubility.
Food is known to affect the bioavailability of conventional drugs (see Tables 2.3 and 2.4516 for examples). The presence or absence of food may also influence the absorption and bioavailability of plant constituents. For example, acetyl-11-keto-beta-boswellic acid (AKBA) from Boswellia serrata exhibits better bioavailability with a high fat meal,517 whereas a high fat meal reduces the bioavailability of resveratrol from Polygonum cuspidatum.66
Table 2.3 Drugs with absorption enhanced by food516
| Drug | Mechanism |
|---|---|
| Carbamazepine | Increased bile production; enhanced dissolution and absorption |
| Diazepam | Food enhances enterohepatic recycling; increased dissolution secondary to gastric acid secretion |
| Griseofulvin | Drug is lipid soluble; enhanced absorption |
| Metoprolol | Food may reduce first-pass extraction and metabolism |
| Phenytoin | Delayed gastric emptying and increased bile production improve dissolution and absorption |
Table 2.4 Drugs with absorption decreased by food516
| Drug | Mechanism |
|---|---|
| Isoniazid | Food raises gastric pH preventing dissolution and absorption; also delayed gastric emptying |
| Captopril | Mechanism unknown |
| Chlorpromazine | Drug undergoes first-pass metabolism in gut; delayed gastric emptying affects bioavailability |
| Tetracyclines | Bind with calcium ions or iron salts forming insoluble chelates |
Grapefruit juice (GFJ) is a plant substance that can exert a marked effect on bioavailability. For example, in early studies it increased the bioavailability of oral 17-beta-oestradiol and its metabolite oestrone.518 GFJ also substantially increased the bioavailability of the following drugs: felopidine,519 caffeine,520 nifedipine and similar drugs,521 cyclosporine522 and triazolam523 and similar drugs. The major interaction seems to be in the gut wall with enzymes belonging to various cytochrome P450 subfamilies.524 It also appears to inhibit renal 11-beta-hydroxysteroid dehydrogenase in humans and could therefore potentiate the side effects of licorice.525 Although the flavonoids naringin and naringenin were at first implicated, they are probably not the active components.526,527 In fact, the furanocoumarin bergamottin and related compounds appear to be largely responsible for this activity.528 This ability of plant furanocoumarins to inhibit drug-metabolising enzymes was first noted by Korean researchers in 1983.529 A 2011 review noted that GFJ demonstrated multiple interactions with drugs leading to loss of therapeutic effects or increased side effects.530 GFJ decreases presystemic metabolism through competitive or mechanism-based inhibition of gut wall CYP3A4 isoenzymes and P-glycoprotein. In addition multidrug resistance protein-2 or organic anion-transporting polypeptide inhibition may play a role. The review confirmed that, although GFJ contains high amounts of flavonoids (such as naringin, naringenin), furanocoumarins (especially 6′,7′-dihydroxybergamottin and bergamottin) are the main phytochemicals involved in the pharmacokinetic interactions. As compounds of GFJ show additive or synergistic effects, all the major furanocoumarins are necessary for the maximal inhibitory effect. Related citrus fruits or other plants containing furanocoumarins may also present pharmacological interactions yet to be discovered.
This phenomenon raises the question of how other plants and their phytochemicals might influence the bioavailability of both drugs and herbal constituents. The example of hyperforin in St John’s wort is now well studied in this regard (see the St John’s wort monograph).
Bioavailability is also affected by the preparation used to deliver the dose of the medicine. This area of study has been largely neglected for herbal medicines. However, some general statements about aqueous preparations such as infusions and decoctions can be proposed. Infusions and decoctions extract water-soluble compounds from plants. Many of these will have poor bioavailability. One important exception is plants containing essential oils taken by infusion. Here the hot water acts almost as a distillation medium and the oil will collect on the surface of the water. The addition of saponin-containing herbs to the mixture may increase the solubility of compounds not as water-soluble, which may then have better bioavailability. However, this advantage has been disputed (see previously under saponins). This practice is often observed in traditional Chinese medicine, a therapeutic system that relies heavily on aqueous preparations. Changes in water-soluble compounds in the digestive tract, most significantly the conversion of glycosides to aglycones in the caecum and large bowel, will render them more lipid-soluble. They can then be absorbed as the aglycone. In general, however, bioavailability and solubility considerations suggest that infusions and decoctions are inferior preparations for the extraction and delivery of herbal actives. The exception is where those actives are largely water-soluble anyway, such as some saponins, tannins, polysaccharides and proteins. However, only small quantities of these relatively large molecules will be absorbed as such (see later).
Salicin
A good starting point in the study of herbal pharmacokinetics is those archetypal plant constituents that have been relatively well investigated. The phenolic glycoside salicin and the anthraquinone glycosides are two such examples.
Salicin and its conversion products are illustrated in Figure 2.2 and a schematic diagram of the pharmacokinetics of salicin is provided in Figure 2.3.531,532 As shown in Figure 2.3, salicin derivatives are first converted into salicin in the stomach or small intestine. The salicin may then be absorbed in the small intestine, but in humans it is mainly carried to the distal ileum or colon where gut flora convert the glycoside into its aglycone, known as salicyl alcohol. The salicyl alcohol is absorbed and oxidised in the blood, tissue and liver to give salicylic acid, the main active form. The excretion of these various products is also outlined in Figure 2.3.
Despite the elaborate route by which salicin (and indeed willow bark) delivers salicylic acid into the bloodstream, the relative bioavailabilities of sodium salicylate and salicin are remarkably similar (Fig. 2.4531). The curve for salicin is slightly lower and flatter, indicating a greater half-life. The rapid absorption of salicin as salicylic acid additionally implies that its conversion is also rapid, suggesting the distal ileum or caecum as the site of conversion rather than the large intestine (orocaecal transit time is typically up to a few hours).
Figure 2.4 Relative bioavailabilities of salicin and salicylic acid (doses are approximately equivalent).531
At this point, it is worth reflecting upon the traditional use of willow bark and the history of aspirin. When scientists in the 19th century began to investigate the antipyretic and anti-inflammatory effects of willow bark, salicin was isolated as the active compound. Salicylic acid was more readily synthesised and was adopted into mainstream therapy, but had the drawback of being a strong irritant to the stomach. This led to the development of aspirin, a derivative of salicylic acid, in an attempt to minimise the gastric irritation. (Unfortunately, aspirin was still a gastric irritant, but it was more active than salicylic acid as an analgesic and antiplatelet agent.) Had the early scientists instead preferred salicin, they might have recognised that nature had already designed a derivative of salicylic acid that gave a good yield of bioavailable salicylic acid and was kind to the stomach.
This proposition is supported by an in vivo study.533 When salicin was administered orally to rats, salicylic acid appeared slowly in the plasma and levels increased gradually, in contrast to the rapid appearance observed after oral administration of sodium salicylate or saligenin. However, oral salicin still significantly reduced yeast-induced fever, producing a normal body temperature. Salicin did not induce gastric lesions, even at a high dose; conversely sodium salicylate and saligenin induced severe gastric lesions in a dose-dependent manner. When given to germ-free rats around 20% of the salicin was recovered intact from the digestive tract and no saligenin was found. These results provided clear evidence that salicin is a pro-drug, as discussed above, that is gradually transported to the lower part of the intestine and hydrolysed to saligenin by intestinal bacteria, producing its therapeutic effects without gastric injury.
Anthraquinone glycosides
Early research on the laxative properties of anthraquinones and their glycosides baffled researchers. When equivalent doses were used, only the glycosides were active orally, not their aglycones. However, when equivalent doses were administered by injection, the reverse situation applied: the aglycones were more active. Equally intriguing were the observations that oral doses of the anthraquinone glycosides took 6 to 8 h to exert their laxative effect and the effective dose for laxation often varied dramatically from person to person.
The modern understanding of the pharmacokinetics of anthraquinone glycosides provides a simple explanation for these paradoxical observations. This is illustrated schematically in Figure 2.5.534
As anthraquinone glycosides pass through the digestive tract, a significant proportion undergoes polymerisation to inactive polymers. Any remaining glycoside is unchanged and unabsorbed until it reaches the large intestine. There the action of certain bowel flora converts the glycosides into their anthrone aglycones. These active aglycones then exert a laxative action in situ in the colon.534
Hence, the anthraquinone glycoside given by injection exerts less activity, because this is not the active form. On the other hand, the aglycone given orally also exerts little activity because it is broken down or absorbed before it reaches the colon. (Some modern laxative drugs are anthrone aglycones, but they are administered orally in quite high doses.) The 6 to 8 h lag-time for activity reflects the time it takes for ingested anthraquinone glycosides to reach the appropriate part of the colon for conversion into aglycones.
We can only wonder at this elegant and, when one considers the quantities of liberated anthrone aglycone involved, exquisitely sensitive mechanism designed by nature. One inference from this example is that the composition of an individual’s bowel flora is highly relevant to the pharmacokinetic equation and hence to the final pharmacological effect.534 This is a common theme for several of the archetypal plant constituents and emphasises the herbal clinician’s obsession with the health of the gut, not just as the central focus for restoring robust health, but also for delivering effective therapy.
Glycosides and gastric modification
A number of plant glycosides are modified by the action of gastric acid or the alkaline conditions of the duodenum. The following examples and their implications serve to illustrate this phenomenon.
Harpagoside from devil’s claw (Harpagophytum procumbens) has oral anti-inflammatory activity (Fig. 2.6). However, when it is incubated with gastric acid, which generates harpagogenin from harpagoside, it tends to lose this activity in oral dose models.535 While harpagoside may not be the final bioavailable form, this research suggests that the action of gastric acid is detrimental to the anti-inflammatory activity of devil’s claw. Preparations of this herb should therefore be enterically coated or at least taken between meals to optimise the bioavailability of anti-inflammatory components. (See the devil’s claw monograph for a further discussion of this topic.)
The valepotriates (Fig. 2.7) of valerian have cytotoxic activity when administered by injection, but do not exhibit this effect after oral doses. The former observation initially raised concerns about the safety of valerian, but it is now clear that valepotriates are quite unstable in aqueous solution and are decomposed by gastric acid. The breakdown products of the valepotriates still possess some sedative activity.536 (See the valerian monograph for more details.)
The following example is not of therapeutic significance but it does illustrate that the empirical basis for the traditional use of plants sometimes reflects an implicit understanding of pharmacokinetic issues. Salvia divinorum is a species of sage with hallucinogenic properties. Traditionally the fresh leaves are chewed for this effect, which led to the belief that the hallucinogenic component(s) were inactivated by drying the herb. Research has revealed that this is not the case. The active hallucinogenic component in Salvia divinorum is salvinorin A (Fig. 2.8).537 This is converted by gastric acid into salvinorin B, which is inactive. Hence the chewing of leaves by the shamans was in fact a delivery mechanism for salvinorin A that bypassed decomposition in the stomach. That the hallucinogenic quantities of salvinorin A can be absorbed through the oral mucosa underlines the potent activity of this compound.
Flavonoid glycosides and enteric modification
Flavonoid glycosides are a common component of many plants and are a significant class of archetypal plant constituents with pharmacological activity. However, in vitro models dominate the pharmacodynamic research on flavonoids and their glycosides. This is of concern because an understanding has existed for some time (and has been repeatedly confirmed) that flavonoids tend to have poor bioavailability as such, because they are largely decomposed by bowel flora.
Studies have shown that flavonoid-O-glycosides are converted into the aglycone by bowel flora. But the decomposition can extend further than this; the aglycones undergo further breakdown by a process known as C-ring fission (the C-ring is the central ring in the flavonoid structure) to give two different phenolic products. An example of C-ring fission is illustrated in Figure 2.9. The ring fission products for several common flavonoids, flavonoid glycosides and related products are summarised in Table 2.5538 and a general scheme for the pharmacokinetics of many flavonoid glycosides is outlined in Figure 2.10.
Table 2.5 Flavonoid ring fission metabolites538
| Flavonoid administered | Ring fission products |
|---|---|
| Quercetin, rutin | 3,4-dihydroxphenylacetic acid,3-methoxy-4-hydroxyphenylacetic acid,m-hydroxyphenylacetic acid |
| Hesperidin, diosmin, eriodictyol, homoeriodictyol | m-hydroxyphenylpropionic acid,m-coumaric acid (rat), 3-hydroxy-4-methoxyphenyl-hydracrylic acid (human) |
| (+)-Catechin | delta-(hydroxphenyl)-gamma-valerolactones,m-hydroxyphenylpropionic acid,m-hydroxybenzoic acid,m-hydroxyhippuric acid |
| Kaempferol | delta-(p-hydroxyphenyl)-gamma-valerolactone,p-hydroxyphenylacetic acid |
| Myricetin, myrictrin | 3,5-dihydroxyphenylacetic acid |
| Tricetin, tricin | m-hydroxyphenylacetic acid,3,5-dihydroxyphenylpropionic acid,m-hydroxyphenylpropionic acid |
Studies have also shown the following:
• Oral doses of flavonoid aglycones are less bioavailable (as the flavonoid) than their glycosides because they are more susceptible to ring fission
• Levels of a flavonoid aglycone in the bloodstream will vary according to:
This picture of flavonoid pharmacokinetics needs to be modified in one specific area following the work of a German group of scientists early this century. Their study of the bioavailability of quercetin in various forms provided new and important information about the pharmacokinetics of flavonoids.540–542 The pharmacokinetics of two quercetin glycosides, and plant extracts containing these, were investigated in 12 healthy volunteers in a crossover study.540,542 This was because prior investigation had indicated that the bioavailability of quercetin may actually be improved by the presence of a sugar on the molecule. That is, certain quercetin glycosides can deliver quercetin more effectively into the bloodstream, presumably via active uptake by enterocytes. (Even this enhanced bioavailability was only about 5% of the amount ingested.)541
Each volunteer received an onion extract (containing quercetin-4′-O-glucoside) or pure quercetin-4′-O-glucoside, both equivalent to 100 mg of quercetin; or buckwheat tea (containing quercetin-3-O-rutinoside) or pure quercetin-3-O-rutinoside (rutin), both equivalent to 200 mg of quercetin. Pure quercetin was not detected in the human plasma samples. Instead, four different quercetin glucuronides (QG) were detected. These were presumably formed following uptake by the action of enterocytes.
The form of the flavonoid greatly influenced the rate and extent of QG appearance in the bloodstream. After administration of quercetin-4′-O-glucoside or onions, maximum plasma levels of QG were reached after 0.5 to 1 h. But only 5 to 10 h after administration of rutin or buckwheat tea did QG appear in volunteers’ bloodstreams. Despite the fact they were given at half the dose, the levels of QG achieved from onions and quercetin-4′-O-glucoside were about four times those achieved from rutin and buckwheat tea. The plant matrix enhanced the rate and extent of QG appearance, but to a much lesser extent than the form of the flavonoid.
These simple and elegant findings add a new dimension to our understanding of the pharmacokinetics of flavonoids:
• Aglycones (such as quercetin) have poor or even zero bioavailability
• There is an active uptake and metabolism of flavonoid glycosides by enterocytes that is determined by the nature of their sugar (with a preference for glucose)
• Before the flavonoid is taken up by the enterocyte, it is probably hydrolysed to the aglycone by a membrane-bound beta-glucosidase
• Quercetin-4′-O-glucoside is taken up in the small intestine, whereas rutin (which has a glucose and a mannose = rutinoside) is not
• Presumably rutin travels to the large intestine (hence the lag in QG appearance), where the terminal mannose is removed by bacteria, exposing the glucose which then results in uptake by enterocytes
• Measurement of the renal elimination of flavonoids suggested that at least 6% of the flavonoid dose was absorbed when given as onions.
QG have slightly more antioxidant activity than quercetin, but will not exert much effect in plasma as antioxidants because they are tightly bound to plasma proteins. However, they could well become active at target tissues, especially after removal of the glucuronide group.
The above study could provide no information on the uptake of C-ring fission compounds, since these are also metabolites naturally found in the bloodstream and it was therefore difficult to detect any changes in their levels above the natural background.
A 2011 review supported this perspective, albeit with some subtle modifications.543 As described above, lactase phlorizin hydrolase (LPH), a membrane-bound beta-glucosidase, is able to liberate aglycones into the intestinal lumen, where they passively diffuse across the small intestinal membrane. However, cytosolic beta-glucosidase may also be involved. As this particular enzyme is located intracellularly in the enterocyte, active transport of the flavonoid glycoside via the sugar transporter SGLT-1 (sodium-dependent glucose transporter) is first required. Flavonoid glycosides that are not substrates of LPH or SGLT-1 will pass to the colon where bacterial hydrolysis will produce the aglycone and C-ring fission products. Of course, the action of LPH or SGLT-1 is not quantitative, with much of the flavonoid glycosides that are their substrates still passing unchanged to the colon. In other words, the actions of LPH and SGLT-1 only render a small percentage of a flavonoid glycoside bioavailable in the small intestine.
Once absorbed, the flavonoid aglycones are subject to three main types of conjugation: methylation, sulphation and glucuronidation.543 The extent of conjugation is high and only a small percentage of free flavonoid aglycones is present in the plasma.543,544 The presence of conjugated metabolites in the portal blood of rats suggests that conjugation first occurs in the enterocytes before further metabolism in the liver.543,545
The issue of the bioavailability of the flavonoid aglycone quercetin is controversial. Many nutritional supplement companies market products containing quercetin. The rationale for including quercetin in such products is often largely based on in vitro research or in vivo models following dosage by injection (although there are also clinical trials demonstrating positive effects from high doses - see previous). The consensus of studies is that the bioavailability of quercetin (as quercetin) is poor. This is due to its propensity to undergo C-ring fission. Following the Zutphen Elderly Study and the Netherlands Cohort Study where flavonol and flavone dietary intakes were inversely associated with mortality from coronary heart disease and risk of stroke, Dutch researchers once again studied quercetin bioavailability.546 Conclusions from their study on ileostomy patients were uncertain because they did not measure quercetin in the bloodstream.547 It was assumed that, because of the ileostomy, any unrecovered quercetin was absorbed. But significant microbial degradation could also have occurred. This is supported by the minimal level of quercetin (0.5% of original dose) found in subjects’ urine. Nonetheless, this study has been misinterpreted by many authors as unequivocally demonstrating a high oral bioavailability for quercetin. More recent studies tend to confirm the relatively low and variable bioavailability of intact quercetin.230,544 Gut flora metabolism might account for a large part of this variability.
One study of the C-ring fission products of quercetin found that 3,4-dihydroxyphenylacetic acid possessed significant antioxidant activity.548 In vitro antiplatelet activity is also suggested in another.549 Pharmacodynamic research on flavonoids should include more studies on their C-ring fission products, which in many instances are probably the main bioavailable and active form of this important group of archetypal plant constituents.550
Isoflavones
As noted earlier, the isoflavones are a group of archetypal plant constituents attracting increasing attention because of their affinity for oestrogen receptors. The principal isoflavones are the glycosides genistin and daidzin and their aglycones genistein and daidzein, from the soya plant, and the aglycones formononetin and biochanin A from red clover (see Fig. 2.11). Formononetin can be converted to daidzein, which in turn can be metabolised to equol by bowel flora. This is a significant reaction pathway from a pharmacodynamic perspective, because equol has substantially more oestrogenic activity than its precursors. However, equol appears to be produced to different degrees in different people. Table 2.6551 illustrates that individuals can be grouped into high and low equol producers. The high equol producers are likely to experience significantly greater oestrogenic effects from the consumption of soya or red clover.
Table 2.6 Comparison of the urinary excretion rates of daidzein and two daidzein551 metabolites in individuals over a 3-day period following soya challenge*
Early studies also found the following:
• Soya isoflavones are 85% degraded in the intestine552
• Differences in faecal flora account for the differing metabolism of soya isoflavones553
• Faecal flora could completely degrade genistein and daidzein553
• Differences in faecal excretion of isoflavones profoundly altered isoflavone bioavailability: higher faecal excretion was correlated with higher bioavailability. Such people may have fewer bacteria that degrade isoflavones, leaving more intact for absorption.548 Bioavailability varied from 13% to 35% depending on the individual gut microflora553
• Soya protein (containing isoflavone glycosides) increased follicular phase length in women, while miso (containing isoflavone aglycones) did not.554 This suggests that the glycosidic group delays the degradation of isoflavones, resulting in higher bioavailability of their aglycones or equol.
These earlier studies served to emphasise the importance of bowel flora in determining the bioavailability and hence pharmacodynamic activity of isoflavones.
Recent reviews of the pharmacokinetics of isoflavones have noted similar mechanisms to flavonoids. LPH on the enterocyte cell membrane is thought to play a key role in the removal of sugar from isoflavone glycosides. However, in contrast to the flavonoid glycosides, there is no evidence that isoflavone glycosides are transported by SGLT-1 (or other transmembrane transporters) into the enterocyte cytoplasm.555 Any glycoside not remaining after passage through the small intestine is converted to the aglycone by colonic bacteria.
Contradictory results have been recorded for the differences in bioavailability between isoflavone aglycones and glycosides.556 However, a review of 16 human pharmacokinetic studies determined that genistin (the glycoside) was about 60% more bioavailable than genistein (the aglycone). Similarly, daidzin was around 80% more bioavailable than daidzein.557 These reviewers stated that some comparative studies used different food sources to compare aglycone versus glycoside bioavailability (for example, comparing tempeh with soya bean pieces), yielding contradictory results that were confounded by food matrix effects. Both reviews confirmed that isoflavones possess substantially higher relative bioavailabilities than flavonoids.556,557
Equol production was significantly higher after ingestion of daidzin than daidzein, but this has not been confirmed in every study, again possibly because of food matrix effects. Genistin and daidzin exhibit relatively similar bioavailabilities, as do genistein and daidzein. It was thought that the greater urinary excretion of daidzein metabolites reflected its greater bioavailability compared with genistein. However, the explanation for this finding is that a greater fraction of genistein is eliminated via bile.556,557
The nature of isoflavone metabolites in plasma is the same after glycoside or aglycone ingestion. Glycosides are not found. Unconjugated aglycones represent about 5% of the total level in plasma, together with their main metabolites the 7-O-glucuronides and 4′-O-glucuronides, with smaller proportions of sulphate esters. Additional metabolites include equol, dihydroequol and dihydrogenistein. Equol itself possesses good bioavailability and is excreted as the glucuronide.555,556
Saponins
If a saponin exhibits good fat solubility it can be absorbed unchanged in significant quantities in the small intestine. This is the case for many cardiac glycosides, a related chemical group. If saponins are not absorbed, they will pass to the large intestine where the gut flora will convert them to the sapogenin (aglycone). The sapogenin usually has better lipid solubility and will be absorbed to some extent. Hence, in these cases the saponin acts as a pro-drug. Since the bioactivity of saponins may be due to their aglycone, the extrapolation of in vitro results for saponins is potentially unreliable.
Glycyrrhizin (GL) is a triterpenoid saponin with hepatoprotective activity in vitro and by injection. It also has antiviral activity, even against HIV-1. This has led to suggestions that oral doses of licorice might be used as a systemic antiviral treatment or for hepatoprotective activity. Early pharmacokinetic experiments with licorice or GL demonstrated that the aglycone glycyrrhetinic acid (GA) was the predominant form absorbed into the bloodstream after oral doses.558,559 GL is converted to GA by human intestinal flora.560 Some GL may be absorbed, although this could also be recycled GA-glucuronide being misread as GL on chromatograms.558,561 So licorice may possess antiviral activity after oral doses, but only if the GA-glucuronide or GA itself possesses this activity. GA has been shown to be more hepatoprotective than GL,562 so licorice may also prove to be a valuable hepatoprotective herb (this awaits clinical confirmation for oral doses). (For a further discussion of the pharmacokinetics of glycyrrhizin, with a focus on the human data, see the licorice monograph.)
Other triterpenoid saponins appear to follow a similar pathway, for example the ginsenosides.563 The bacterial metabolism and subsequent pharmacokinetics of ginsenosides are complex, because these saponins typically contain several sugars bonded at various positions on the triterpenoid structure. Hence, metabolism by the gut flora usually occurs in several stages as sugars are progressively stripped from the molecule. (For a discussion of the key issues pertaining to the pharmacokinetics of the ginsenosides, see the ginseng monograph.) Some studies on the bioavailability of steroidal saponins have also been published. Ruscus extract (1 g), containing 60 mg degluconeoruscin and other steroidal saponins, was orally administered to three human volunteers.564 Plasma analysis showed significant absorption: degluconeoruscin concentrations peaked after about 90 minutes. Hence, some steroidal saponins may therefore show good bioavailability (this work does need to be repeated). However, others probably follow the same pattern as glycyrrhizin; the aglycone formed after colonic bacterial metabolism is the absorbed form. This is supported by extensive historical work on cardioactive glycosides showing that some glycosides, such as digitoxin, are quantitatively absorbed (the oral dose of digitoxin is the same as the intravenous dose). In contrast, ouabain (from Strophanthus) exhibited poor and erratic oral absorption and was only given by injection.
Tannins and catechins
Because of their large size, high affinity to bond with proteins and poor lipid solubility, tannins have negligible bioavailability as such. Hence, the activity of tannins (and the herbs that contain them) should be explained in terms of local effects. This poor bioavailability of intact tannins is important, since hydrolysable tannins absorbed into the bloodstream can cause hepatotoxicity. Many common herbs would be poisonous if tannins were highly bioavailable. Also tannins injected subcutaneously cause cancers, so it is also fortunate that they do not penetrate the skin. Breakdown products of tannins produced in the colon by gut flora (and perhaps spontaneously in the small intestine in the case of hydrolysable tannins) are absorbed and probably explain many of the modern uses of tannin and OPC-containing herbs (see previous).
Early in vitro experiments found that ellagic acid was liberated from condensed tannins at pH 7 to 8 (not at pH 2) and also by microflora when in contact with caecum contents (ellagic acid has antioxidant and anticancer properties).565 About 95% of orally administered tannic acid is decomposed (as assessed by faecal excretion).566 Tannic acid is a hydrolysable tannin that probably releases gallic acid and other compounds on decomposition. Condensed tannins, OPCs and green tea polyphenols show more complex decomposition patterns, but microflora again produce smaller bioavailable phenolic compounds (see below).567
The probable behaviour of tannins as they pass through the digestive tract is summarised in Figure 2.12. Apart from antioxidant activity and other systemic effects from the decomposition products of tannins, all the other possible effects are due to local activity at the designated site. The remote astringency and antihaemorrhagic properties sometimes attributed to oral doses of tannin-containing herbs must be in doubt (in other words, tannins given orally will not, for example, astringe lung tissue or staunch uterine bleeding, unless such effects are due to their smaller breakdown products).
Because of their widespread occurrence in many foods and beverages (for example berries, nuts and wine), the bioavailability and metabolism of ellagitannins has been the subject of several studies and a 2010 review.568 The review noted the following:
• In vitro digestion studies have shown that in general ellagitannins are stable under stimulated stomach conditions
• Under the physiological conditions of the small intestine (neutral to mild alkaline pH) there is hydrolysis and release of free ellagic acid
• Microbial metabolites of ellagic acid are then formed, mainly urolithins (A to D), which are largely absorbed and glucuronidated by enterocytes and in the liver (in both humans and rodents)
• Low levels of intact ellagitannin and ellagic acid may also be absorbed, although results are inconsistent
• In human studies large interindividual variability has been observed in levels of urolithins (probably related to gut flora variability)
• The urolithins undergo enterohepatic circulation and their conjugates are the main metabolites detected in plasma and urine.
As stated earlier, OPCs are a part of the archetypal group known as condensed tannins. Products high in OPCs, such as pine bark and grapeseed extracts, enjoy enormous popularity as antioxidants and even cure-alls. This popularity was originally based on the work of the French scientist Masquelier, although there is now an impressive body of accumulated clinical data (see previous).
One feature of the early work is the reputed high bioavailability of OPCs, which were even said to cross the blood-brain barrier. Masquelier conducted pharmacokinetic studies on OPCs using radioactively labelled compounds. On the basis of these studies, he concluded that OPCs have good bioavailability and cross the blood-brain barrier. However, the bioavailability of OPCs observed by Masquelier was probably that of their smaller decomposition products, since his study only measured radioactivity, not the chemical entity carrying that radioactivity.
This assertion was certainly supported by a 2005 review556 which concluded that polymeric procyanidins (condensed tannins) are not absorbed as such and even the absorption of OPC dimers was very minor, about 100-fold lower than the flavonol monomers (catechin and epicatechin).556 The review pointed out that commercial extracts such as those from grape seed and pine bark contain a substantial percentage of monomers that could be largely responsible for the observed therapeutic effects. In addition, gut flora metabolites of OPCs might also deliver biological effects. Similar to flavonoids, OPCs are degraded by the microflora into various aromatic acids such as m-hydroxyphenylpropionic acid, m-hydroxyphenylacetic acid and their p-hydroxy isomers.
A rat study found that the extent of degradation into aromatic acids decreased as the degree of polymerisation increased. In other words, tannins will tend to resist microbial degradation (presumably because they tend to inactivate the very enzymes that might decompose them).
An in vitro study published since the review found that procyanidin B dimers are metabolised by human gut bacteria to yield 2-(3,4-dihydroxyphenyl) acetic acid and 5-(3,4-dihydroxyphenyl)-gamma-valerolactone (DHPV) as the major metabolites.569 This finding was corroborated by an investigation in 11 healthy volunteers given a single dose of 300 mg of pine bark extract.570 Catechin, taxifolin, caffeic acid, ferulic acid and DHPV were the major compounds present in plasma, together with 10 unknown compounds. Analysis of steady state plasma samples after chronic dosing revealed significant phase II metabolism.
Green tea is rich in polyphenols such as epigallocatechin (EGC) and epigallocatechin gallate (EGCG). Black tea is fermented green tea. During fermentation, the simple polyphenols undergo polymerisation leading to more complex molecules, such as theaflavins and therarubigens (MW 500 to 3000). Green and black tea have marked antioxidant activity in vitro, but green tea is about five times more potent than black. Adding milk has no effect. Early human experiments using oral doses demonstrated that:571
• green tea and black tea cause a significant increase in the antioxidant activity of plasma
• green tea is only about 50% stronger than black tea in vivo
• the effect is rapid, peaking at about 30 minutes after consumption for green tea and 50 minutes for black tea
• in contrast to the in vitro study, adding milk completely destroys this effect in people.
One possible explanation is that the tea polyphenols undergo spontaneous decomposition in the gut and the smaller antioxidant molecules are then absorbed. This would explain the similar activities of green and black tea in vivo. Adding milk causes protein binding, which would inhibit this decomposition. This implies that only tea without milk will render significant antioxidant activity in the bloodstream. However, this study did not monitor plasma antioxidant activity after more than a few hours. It is possible that the tannin-protein complexes formed after milk is added are decomposed further down in the gut and bacterial action on the liberated tannins (or just spontaneous breakdown) leads to absorption of antioxidant phenolics from the colon into the bloodstream.
Another possible explanation is that the observed antioxidant effects in plasma were due to absorption of unchanged tea phenolics. Both EGC and EGCG have been detected in the plasma of healthy human volunteers 90 minutes after they consumed capsules containing green tea extract.572 However, as might be expected for such large polar molecules, levels detected corresponded to only 0.2% to 2.0% of the ingested amount.
The 2005 review quoted above reflected that bioavailability differs markedly among catechins.556 Galloylation of catechins reduces their absorption. Epigallocatechin (EGC) is methylated on absorption, with 4′-O-methyl-epigallocatechin accounting for 30% to 40% of the total metabolites. EGCG is also methylated, as is catechin itself. EGCG is the only green tea polyphenol present in plasma mainly as the free form, although its overall bioavailability is low (about one-third of catechin and one-tenth of EGC). The other catechins are highly conjugated with glucuronic acid and/or sulphate. Microbial metabolites similar to those found after ingestion of herbal OPC extracts, namely various valerolactone derivatives (mostly in conjugated forms) were identified in the plasma and urine of human volunteers after ingestion of green tea. These metabolites accounted for 6% to 39% of ingested EGC and epicatechin and were 8 to 25 times the levels measured for the unchanged compounds. Galloylated catechins are only eliminated via the bile. These findings were corroborated in a later 3-month study in human volunteers.573
Polysaccharides
In some modern herbal literature, great emphasis is placed on the role of polysaccharides as immune-enhancing agents, particularly in the context of herbs such as Echinacea and the medicinal mushrooms. However, the main evidence for this is in vitro research. Polysaccharides are polymers based on sugars and uronic acids. They are found in all plants, especially as a component of the cell wall. However, some plants particularly accumulate polysaccharides. Any herbal extract prepared in 50% ethanol or stronger will not contain significant quantities of polysaccharides because of their insolubility in ethanol. Since they are large water-soluble molecules, which may even carry an ionic charge, polysaccharides will have low (but not zero) bioavailability. Pharmacokinetic considerations therefore dictate that if a herb is to be used as a source of polysaccharides it must be rich in these compounds, be prepared in a way to preserve or extract the polysaccharides and be administered in sufficient doses to compensate for the poor bioavailability. Such considerations will only apply in special cases and probably do not apply for oral doses of any Echinacea preparation (examples might include high doses of aqueous extracts of medicinal mushrooms and Astragalus). Unabsorbed polysaccharides will pass into the large intestine where they are broken down by bowel flora (and may have an effect on flora balance).
Whole-leaf Aloe vera preparations appear to be one good source of active polysaccharides, provided they are prepared to contain high levels of acemannan (about 1%). Acemannan is a polysaccharide found under the skin in Aloe vera leaves and is often not present in Aloe gel or juice preparations, because the outer leaf is not incorporated or enzymes used during manufacture have destroyed the acemannan. Doses of 50 to 100 mL/day of this concentrate can provide significant doses of acemannan. In a little-known, open, uncontrolled clinical study, 29 AIDS patients received Aloe vera whole-leaf juice, essential fatty acids and nutrients.574 The Aloe dose was the equivalent of 1200 mg/day of acemannan. Karnofsky scores improved in 100% of these patients after 180 days. Although this study had many design flaws, it does suggest that this type of preparation as a source of polysaccharides is worthy of further study.
While medicinal mushroom polysaccharide preparations such as PSK from Coriolus versicolor show activity after oral doses,575 others such as lentinan from Lentinus edodes are clinically administered by injection, presumably because of poor oral bioavailability.576 However, an oral formulation of lentinan (superfine dispersed lentinan) has recently become available.577
Optimising efficacy
Hopefully the above discussion demonstrates that knowledge of factors influencing bioavailability can lead to the more effective use of herbal medicines. In particular, the bowel flora characteristics that can optimise the efficacy of many herbal treatments need to be better understood, as highlighted in two recent reviews.578,579 This factor probably underlines the importance of a wholesome diet and adequate fibre intake, which will lead to healthy bowel flora. Other issues to be considered in the context of optimising efficacy include the following:
Lipophilic components will probably be better absorbed with a high fat meal and polar (hydrophilic) compounds will probably be better absorbed with a low-fat meal• saponins can be used to improve absorption
• some foods can be used to inhibit gut biotransformation, for example grapefruit juice
• the frequency of dosage should be based on bioavailability and metabolism.
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