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Keywords:

  • Absorption;
  • bioavailability;
  • clinical trials;
  • herbal medicines;
  • pharmacokinetics

Introduction

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References

Within the past few decades the use of herbal medicines in the developed world has mushroomed into a multibillion dollar industry, which has been facilitated by less stringent regulations.1 Although the marketplace provides liberal access to a plethora of inadequately evaluated products, there has been a move in recent years to provide more evidence-based support to determine objectively the safety and efficacy of medicinal herbs.

The methodological quality of clinical trials investigating herbal medicines has steadily improved over the years, and a greater proportion of trials use standardised extracts and are randomised, placebo-controlled prospective studies.2,3 However, the literature is replete with studies that show wide variations in clinical outcome for extracts made from the same medicinal herb. It is argued here that subtherapeutic levels of ‘active’ ingredients would even undermine studies with excellent methodological design and this may account for the wide variability in studies investigating the same medicinal herb. Although the recommendation for well-designed clinical studies is warranted and should be acted upon, the pharmacokinetic nature of a herbal extract is critical to the outcome of clinical trials.

The pharmacokinetic characteristics of a few commonly used herbs, such as Hypericum perforatum (St John's wort), Echinacea and green tea made from Camellia sinensis, are being investigated but this is not common practice. Details for most herbal preparations are sparse4,5 and this gap provides the ideal opportunity for researchers in herbal medicine to inform ‘rational’ phytotherapy.

This paper explores the literature on the pharmacokinetic characteristics of popular herbal medicines in human studies as well as in vitro and in vivo systems. It is hoped that this will inform future clinical studies with implications for dosage forms and the designing of rational dosing regimens. As with synthetic medicines, pharmacokinetic considerations should be taken ‘on board’ to assess adequately the biological activity of herbal medicines.

Are we really comparing apples with apples?

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References

Most meta-analyses of herbal medicines are inconclusive, and reviewers often recommend that larger, rigorous, well-designed RCTs be conducted to determine decisively the efficacy of herbs.6 For instance, the Cochrane meta-analysis of Echinacea (for the prevention and treatment of the common cold) showed wide variability in the nature and composition of preparations used in the selected clinical trials. Although there were beneficial effects for some preparations, the variability severely restricted the overall conclusion.7 Although a recent meta-analysis of H. perforatum for major depression confirmed the superiority of H. perforatum extracts over placebo, a closer look at the selected studies showed a noticeable and significant difference in clinical responses between the STW3-VI extract and other extracts, including LI 160, WS 5572 and WS5570 (with a greater than twofold effect size).8 This observation may indicate an enhanced absorption and bioavailability of ‘active’ ingredients in the STW3-VI extracts compared with the other extracts.

What is in the product?

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References

Although most reputable manufacturers of herbal preparations indicate the amount of ‘active’ ingredients on the labels of standardised products, analytical methods have found wide variability. Standardisation involves the identification of one or more putative ‘active’ ingredients or surrogate compounds and the manufacturer's attempt to replicate similar concentrations in all batches.9 In spite of these efforts many products on the market do not contain the concentration of ‘active’ ingredient stated on the label.

In a study investigating several brands of Tanacetum parthenium (feverfew) products, analytical methods showed that parthenolide content, the putative active ingredient, was highly variable between brands and that in some products it was undetectable.10 Another report investigating different brands of Ginkgo biloba also demonstrated wide variability of flavone glycosides, terpene lactones and ginkgolic acids.11 Other studies have demonstrated considerable variability between different brands of popular products containing H. perforatum, ‘ginseng’ and Echinacea spp.12,13 An analysis of six brands of Serenoa repens (saw palmetto) available at popular pharmacies showed wide variability, with three brands containing less than 20% of the ‘active’ ingredients stated on the label.14 Similarly, commercial C. sinensis products were analysed for catechin content and the results showed that all brands tested had significantly less catechins than that stated on the labels.15 It has become necessary in clinical trials of herbal preparations to employ analytical techniques that will definitively determine the presence and quantity of ‘active’ components in products.

Extract formulation may affect the rate and extent of absorption

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References

Some studies have shown significant differences in the rate and extent of absorption and the subsequent bioavailability of ‘active’ ingredients in various extract formulations of the same medicinal herb. For instance, the absorption and time for peak plasma concentrations of hyperforin and hypericin from H. perforatum extract was significantly reduced in the hard gelatin capsule formulation compared with the soft gelatin capsule formulation.16 In recent studies using H. perforatum extract formulation STW3-VI, Laif (600 mg and 900 mg) the pharmacokinetic parameters for major ‘active’ antidepressant compounds including hyperforin and hypericin were similar;17,18 however, another study using a film-coated H. perforatum extract tablet (WS 5572, 300 mg) demonstrated that the time for maximum plasma concentration and the half-life for hyperforin were significantly different.19

Formulation modification has been shown appreciably to modulate absorption and subsequent bioavailability of ‘active’ compounds. It was recently shown that a self-emulsifying drug delivery system significantly decreased the in vitro dissolution rate and increased the absorption and bioavailability of bilabolide and ginkgolide A and B in an in vivo model.20

Pharmaceutically equivalent extracts from different manufacturers may not necessarily be bioequivalent. This was the case with two different brands of G. biloba, in which capsule dissolution rates, the rate and extent of absorption and subsequent bioavailability of major components (bilobalide and ginkgolide A and B) were markedly different following oral administration.21

It may be expected that enriched and purified products would possess superior pharmacokinetic characteristics that would directly affect biological response. A study comparing the bioavailability of ginkgolides in a standardised G. biloba extract (24/6) and an enriched extract (BioGinkgo 27/7) showed that there were significant differences in pharmacokinetic characteristics, which were attributed to a higher terpenoid content and longer half-life in the enriched extract.22 However, this was not the case with purified epigallocatechin (major polyphenol in green tea) and Polyphenon E (a standardised tea extract), in which there were similar absorption and bioavailability profiles for both interventions.23

Different Echinacea purpurea preparations, using various excipients, from the same manufacturer showed similar pharmacokinetics.24 However, Woelkart and colleagues25 showed in an earlier study that alkamides in an Echinacea tincture preparation were four times more bioavailable than in the tablet formulation. This was not in agreement with a recent study that showed similar bioavailability and pharmacokinetics of Echinacea alkamides in both liquid and tablet preparation dosage forms.26 The differences in these results may be indicative of differences in formulations, and underscore the importance of characterising the pharmacokinetics profile of herbal preparations in clinical trials.

There must be absorption for biological effect

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References

Putative ‘active’ ingredients in herbal preparations must be absorbed following oral administration and reach the site of action in sufficient quantities to elicit a biological response. A recent study linked the rapid absorption of major E. purpurea alkamides with the dose-independent downregulation of pro-inflammatory cytokines in humans.27

Active components of herbal extracts must cross the intestinal barrier to facilitate bioavailability. The Caco-2 monolayer in vitro model is a standard assay to predict oral absorption of pharmaceuticals, and this model was used to confirm the rapid absorption and bioavailability of Echinacea alkamides in humans.28,29 This in vitro model also demonstrated that caffeic acid conjugates, once thought to possess medicinal properties, did not cross the Caco-2 monolayer, which correlated well with no detection in human plasma following oral dosing. The pharmacokinetic characteristics of alkamides in Echinacea extract following oral dosing support the current one dose three times a day regimen required for steady state.30

The effect of dosing frequency and conditions on bioavailability

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References

Multiple daily doses may also affect pharmacokinetic parameters, as was the case with G. biloba extract given at 80 mg once a day and 40 mg twice a day.31 In the divided dose, half-life and mean residence time was significantly lengthened, although the single dose had a higher peak plasma concentration. Increasing the dose may not always produce a linear increase in the absorption and bioavailability of ‘active’ components, as was observed with hypericum extracts.19

The effect of food, and other dietary components, on the absorption and bioavailability of active ingredients is an important consideration that may affect biological response. Although food intake did not affect Echinacea alkamide oral bioavailability,30 there was a 3.5 times greater oral bioavailability of epigallocathecin-3-gallate (a major tea polyphenol) from a standardised Polyphenon E preparation in the fasting state compared with the fed state in humans.32 Components of commonly consumed foods may also modulate the absorption and bioavailability of active components in herbal preparations. This was the case with piperine (an alkaloid found in black pepper) in which concomitant consumption with green tea moderately increased the bioavailability of epigallocathechin-3-gallate (a tea polyphenol) in an animal model.33

The type of extract, formulation and dosage form are all factors that would affect the absorption and bioavailability of active ingredients and subsequently affect biological response. In an inconclusive meta-analysis of Echinacea preparations in the prevention and treatment of the common cold, several different preparations were used and included the three different plant species (E. purpurea, E. pallida and E. angustifolia) at varying doses as crude extracts, freeze-dried herb pressed juice, pressed herb juice, standardised and root extract.7

The effects of biotransformation on bioavailability

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References

Herbal preparations are composed of complex mixtures of compounds that undergo metabolism and biotransformation before reaching the site of action. Biotransformation could produce either active metabolites (which would contribute to the overall biological response) or inactive compounds for elimination. Metabolism may take place at various sites including the intestinal mucosa and the liver, and the extent of metabolism would determine bioavailability and subsequent biological response.

For example, ginkgolide C (a ginkgolide found in G. biloba) was not detected at any time point in plasma samples collection in human subjects following the administration of G. biloba extract.34 However, its methylated metabolite was detectable, which suggests that there was very rapid metabolism following the intestinal absorption of ginkgolide C. Free forms of C. sinensis catechins have low bioavailability35 and plasma concentrations are five to 50 times lower than those needed to produce specific biological effects in in vitro systems.36,37 However, there are substantial amounts of detectable O-methylated and conjugated forms in human plasma after green tea consumption.38 It is not known whether these metabolites retain some activity, which may contribute to the overall biological response. It may also be possible that prolonged exposure to low concentrations of putative active ingredients or moderately active metabolites may be sufficient to elicit a biological response.

Conclusions

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References

The quality of clinical trials in herbal medicines has improved significantly over the past decade, but these efforts may be thwarted by the use of herbal preparations with unspecified pharmacokinetic profiles. Phytopharmaceutical equivalence should not be interpreted as bioequivalence, as ‘similar’ products from different manufacturers show significant differences in the absorption and bioavailability of putative active ingredients. Pharmacokinetic assessment of herbal preparations should be an important consideration that would support well-designed clinical trials of herbal medicines, as data derived would aid in the rational design of dosing schedules.

References

  1. Top of page
  2. Introduction
  3. Are we really comparing apples with apples?
  4. What is in the product?
  5. Extract formulation may affect the rate and extent of absorption
  6. There must be absorption for biological effect
  7. The effect of dosing frequency and conditions on bioavailability
  8. The effects of biotransformation on bioavailability
  9. Conclusions
  10. References
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