Herbal Extracts used for Upper Respiratory Tract Infections: Are there Clinically Relevant Interactions with the Cytochrome P450 Enzyme System?

• Abstract
• Abbreviations
• Introduction
• Echinacea
• Other Widely Used Extracts
• Kan Jang
• Conclusions
• References

Abstract

The regulatory requirements for assessing potential interactions between herbal medicinal products and other medicines can cause specific, additional phytopharmaceutical problems. In this short review we assess the state of our knowledge for herbal extracts commonly used as over the counter (OTC) products for upper respiratory infections and which in many cases are considered to have immunomodulatory effects. Overall, the data on the safety of these products is still limited and only in the case of Echinacea preparations can preliminary conclusions be drawn. The available evidence points to weak cytochrome P450 inhibition which is unlikely to be of clinical relevance.

Abbreviations

CYP:cytochrome P450

HMP(s):herbal medicinal product(s)

OTC:over the counter (drugs)

Introduction

For newly developed drugs, regulatory agencies now require that interactions involving CYP isoforms be assessed before licensing. Heightened awareness of the possibility that herbal medicinal products (HMP) might also interfere with drug metabolising enzymes has led to proposals to extend such assessments to herbal medicines by regulatory authorities like the German BfArM [1].

There are limited data on interactions of herbal extracts with cytochrome P450 enzymes. While this information has been assessed by several authors (e. g., [2], [3] specifically on possible interactions with antiretroviral agents), no critical review exists regarding the interpretability of such data in the context of a product’s clinical use. For example, in the case of Echinacea, Willamson [2] concludes ”Caution [should be taken] with drugs, which are substrates of CYP3A4 and CYP1A2 (e. g., much of cancer chemotherapy drugs, phenytoin, warfarin, clozapine, theophylline, midazolam) until further evidence is available (p. 7)”. This statement and many other ones highlight the lack of a systematic procedure to evaluate the risk associated with the concomitant use of herbal medicines and chemically defined drugs. Because of their widespread OTC usage, this is of particular importance with herbal extracts used orally for the treatment of upper respiratory conditions. This review analyses such information in order to set some standards for conducting research on possible interactions of these extracts with the cytochrome P450 enzyme system.

The ideal scenario would be a systematic clinical assessment of interactions in a large patient population or in healthy volunteers. Alternatively animal studies could be conducted, but these have limited clinical relevance. However, due to the high cost of these approaches, in vitro methods for assessing modulation of CYP activity are useful for preliminary investigation of potential interactions. The results can also be used for an initial risk assessment. If such in vitro assays yield positive results, further studies can be carried out within a framework of tried and tested strategies that proceeds to higher levels of biological complexity and produces data with increasing relevance to clinically relevant scenarios. In vitro assays alone can only reveal the potential for interaction and their capacity for capturing features typical of higher order biological systems is limited.

Specifically in relation to herbal medicinal products, it is useful to distinguish five levels of evidence, and we have used these levels to group studies published in the literature.

1. Theoretical: Interactions are postulated based on the species’ constituents and their hypothetical potential to cause interactions.

2. In vitro or in vivo assessment of uncharacterised extracts.

3. In vitro assessment of chemically characterised extracts.

4. In vivo assessment of chemically characterised extracts.

5. Combined in vivo and in vitro assessment of chemically characterised extracts.

This distinction takes the chemical and thus pharmacological variability of preparations derived from one botanical drug into account.

Here we assess the evidence with respect to the ability of herbal medicinal products used for the treatment of upper respiratory conditions to inhibit cytochrome P450 isoforms. Such inhibitions can lead to interactions with other drugs, e. g., by prolonging systemic circulation of active agents, or by blocking the detoxification of unwanted metabolites. Aside from Echinacea, respiratory conditions are commonly treated with decongestants, demulcents and immune system modulators. Here we concentrate on Andrographis paniculata and Eleutherococcus senticosus (Kan Jang extract) and Astragalus membranaceus.

Echinacea

Echinacea preparations are one of the best selling HMP with a well established therapeutic use in the treatment of upper respiratory tract infections [4]. Both polysaccharides and alkylamides are considered to be of relevance for the preparations’ therapeutic use and this is corroborated by pharmacokinetic data [5]. Their consumption is increasing and in two meta-analyses the benefit of Echinacea preparations in decreasing the incidence and duration of the common cold were demonstrated [6], [7].

Information about the ability of Echinacea preparations to inhibit CYP enzymes has so far been fragmentary, and the picture is further complicated by a lack of characterisation of the extracts used for analysis ([Table 1]). The experimental approaches vary widely and in general insufficient data are available to allow a detailed comparison. For example, Budzinski and colleagues [8] demonstrated the inhibitory effects of Echinacea extracts on purified CYP3A4 preparations by using enzyme substrates that produce fluorescing metabolites. Yet, details of the procedures used for the preparation of Echinacea extracts were not provided [8] (level 2). Hellum et al. [14] evaluated the in vitro induction/inhibitory potential of six commonly used trade herbal products including Echinagard™ (Madaus AG) on CYP1A2, CYP2D6 and CYP3A4 and concluded that there is a ”general inhibitory potential”. Unfortunately the data for Echinacea are presented very briefly and in insufficient detail as is the description of the controls used [14], so no further conclusions can be made and a comparison with other studies is difficult. Consequently, it was not possible to rank this study. To our knowledge no other study on the potential direct induction of CYP 450 by Echinacea preparations is available.

Recently, Yale and Glurich [9] assessed inhibitory effects of extracts of Echinacare™ (Phytopharmica) capsules (E. purpurea - aerial portion only) on baculovirus expressed CYP isoforms (supersomes). The extract inhibited CYP3A4 and CYP2C9, but little effects were seen with CYP2D6 (level 2).

Studies with human volunteers using chemically uncharacterized extracts (level 2) have yielded conflicting results about the inhibitory activity of Echinacea preparations. Gorski et al. [10] administered drug probes specific for certain CYP isoforms together with E. purpurea root tablets (400 mg, E. purpurea root extract lot no: 47 266-05, Nature’s Bounty, Inc.) four times daily, to 12 healthy non-smokers for 8 days. There was selective inhibition of CYP3A and some inhibition of CYP1A2, but effects on CYP2D6 or CYP2C9 were not apparent. In contrast, Gurley and colleagues [11] failed to observe inhibitory effects on CYP1A2, CYP2D6, CYP3A4 and CYP2E1 with E. purpurea tablets (Wild Oats Markets, Inc.) given to twelve healthy volunteers. It is likely that variations in the composition of the Echinacea preparations used in these studies are one factor contributing to the differences in these study outcomes, but conclusive information is missing (level 3).

Modarai et al. [12] conducted a comparative study of ten Echinacea preparations commonly available on the European marked using the supersome assay with a particular focus on Echinaforce®. Inhibitory actions on CYP isoforms 1A2, 2C19, 2D9 and 3A4, were measured (supersome assays). Echinaforce® induced mild inhibition of all these isoforms, with CYP3A4 being the most, and CYP2D6 the least sensitive enzyme. To assess whether CYP inhibition might be a general feature of Echinacea preparations, nine additional commercially available preparations were screened using CYP3A4. All tested preparations were able to inhibit CYP3A4, but inhibitory potencies (expressed as median inhibitory concentrations, IC₅₀) varied by a factor of 150. The concentrations of 2E,4E,8Z,10E/Z-tetranoic acid isobutylamide and total alkylamide content were determined in all preparations and the latter was found to be associated with their CYP3A4 inhibitory potency. The chemically pure alkylamides dodeca-2E,4E,8Z,10E/Z-tetranoic acid isobutylamide and dodeca-2E,4E-dieonoic acid isobutylamide showed inhibitory activity on CYP2C19, 2D6 and 3A4. Overall, the inhibitory effect of Echinacea extracts co-varied with their content of alkylamides. However, unlike the Echinaforce® extract, the alkylamides tested did not induce CYP1A2 inhibition. Thus, other, as yet unidentified constituents also contribute to the overall weak inhibitory effects seen with Echinacea preparations in vitro (level 3).

In a study with the chemically pure alkylamides, Matthias et al. [13] observed that some alkylamides could inhibit the CYP-mediated conversion of other alkylamides in human liver microsomes.

Overall the existing data indicate that the inhibitory effects of the extracts can be primarily attributed to alkylamides, but other compounds may also be involved. However, other main classes of Echinacea constituents - caffeic acid derivatives (caftaric acid, cichoric acid and echinacoside), polysaccharides and glycoproteins, do not appear to be involved. This is currently under investigation in our laboratories. (Modarai et al. in preparation).

Other Widely Used Extracts

Kan Jang

Hovhannisyan and colleagues [15] have studied the potential interaction of Kan Jang extract on the pharmacological effects of warfarin in a total of one hundred and eight, time mated Wistar rats. In this study, each Kan Jang tablet (400 mg) contained a combination of two extracts Andrographis paniculata (85 mg) and Eleutherococcus senticosus (11.6 mg). Each day, a dose of 17 mg/kg of the active principle andrographolide was administered orally to the rats for five days. The control groups received similar volumes but with water only. This is a 17-fold higher dose than that recommended for humans and three times the dose recommended for rats. On day 5, after 60 minutes of the final dose an aqueous solution of warfarin (0.2 mg/mL) was administered to the rats at a dose of 2 mg/kg. Animals were sacrificed after various time periods and the blood samples were assessed for warfarin concentration using capillary electrophoresis, and detection at 208.1 nm and 307.5 nm. Prothrombin time was also recorded and there was no statistical difference between the two groups of rats. There was no statistical significance difference in the maximum concentration of warfarin (C_max) for the control or treated group (7.08 ± 0.46 vs. 7.59 ± 0.25, respectively p > 0.05). This study suggests no inhibitory activity of this extract on CYP2C9 which is important in the metabolism of warfarin, however further studies are required to verify this (level 2 or 3) ([Table 2]).

Pekthong et al. [16] investigated the inhibitory effect of Andrographis paniculata extract and andrographolide on rat and human hepatic microsomes. In the case of several model systems (CYP1A2-dependent ethoxyresorufin O-deethylation, CYP2B1-dependent benzyloxyresorufin O-dealkylation, CYP2B6-dependent bupropion hydroxylation, CYP2C-dependent tolbutamide hydroxylation, CYP2E1-dependent p-nitrophenol hydroxylation and CYP3A-dependent testosterone) some non-competitive inhibition was observed. A competitive inhibition on human CYP3A4 in human microsomes was also reported. Andrographolide was found not to be active in the human microsomal systems used (level 2). Therefore, Andrographis paniculata extract may cause drug-drug interactions in humans through CYP3A and 2C9 inhibition, confirming data from an earlier study with fresh plant material (i. e., not a pharmaceutical preparation) [17].

One detailed study [18] has looked at Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. which is used for a wide variety of purposes including immunostimulation/adaptogenic effects. This study indicates a low risk of interactions (level 2). Huang qi, Astralagus membranaceus (Fisch.) Bge, is used as an immune stimulant in treating and preventing colds and upper respiratory infections. No studies on the interactions of A. membranaceus with the CYP P450 enzyme system are available.

Conclusions

Robust, (though still limited) in vitro and in vivo data are only available for Echinacea preparations and mostly investigate the potential inhibitory effects. However, insufficient experimental information is available for several of the studies reviewed here limiting their usefulness. Consequently, it is also not possible to systematically compare the studies with respect to these conditions and their impact on the outcomes. An aspect that has so far received insufficient attention is the impact of inhibitions of transporter proteins such as P-glycoproteins that are important for the elimination of toxic metabolites from organ systems.

From a phytochemical-analytical perspective, assessments of interactions between HMPs and chemically defined medicines are only meaningful when either the active constituents of the HMPs are tested systematically or the extracts are characterised chemically. Unfortunately, this still seems to be the exception both in clinical studies and in in vitro studies.

In summary, additional studies may be desirable, but the overall evidence points to a good safety profile of high-quality preparations of Echinacea. In the case of Kan Jang, the limited evidence again points to a good safety profile. For the other products no information is available which would allow an assessment.

References

• 1 BfArM. Bewertung möglicher pharmakokinetischer Arzneimittel-Interaktionen mit Phytopharmaka. 2004. Available at http://www.bfarm.de/cln_042/nn_424 630/DE/Arzneimittel/besTherap/amPflanz/ampflanz-node.html. Accessed August 20, 2006. 
• 2 Williamson E M. Interactions between herbal and conventional medicines.  Expert Opin Drug Saf. 2005;  4 1-24
  CrossrefPubMedSearch in Google Scholar
• 3 Van den Bout-van den Beukel C JP, Koopmans P P, van der Ven A JAM, De Smet P AGM, Burger D M. Possible rrug - metabolism interactions of medicinal herbs with antiretroviral agents.  Drug Metabol Rev. 2006;  38 477-514
  PubMedSearch in Google Scholar
• 4 Barnes J, Anderson L A, Gibbons S, Phillipson J D. Echinacea angustifolia (D.C.) Hell. Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench: a review of their chemistry, pharmacology and clinical properties.  J Pharm Pharmacol. 2005;  57 929-54
  CrossrefPubMedSearch in Google Scholar
• 5 Woelkart K, Marth E, Suter A, Schoop R, Raggam R B, Koidl C. et al . Bioavailability and pharmacokinetics of Echinacea purpurea preparations and their interactions with the immune system.  Int J Clin Pharmacol Ther. 2006;  44 401-8
  PubMedSearch in Google Scholar
• 6 Shah S A, Sander S, White C M, Rinaldi M, Coleman C I. Evaluation of Echinacea for the prevention and treatment of the common cold: a meta-analysis.  Lancet Infect Dis. 2007;  7 473-80
  CrossrefPubMedSearch in Google Scholar
• 7 Schoop R, Klein P, Suter A, Johnson S L. Echinacea in the prevention of induced rhinovirus colds: A meta-analysis.  Clin Ther. 2006;  28 174-83
  CrossrefPubMedSearch in Google Scholar
• 8 Budzinski J W, Foster B C, Vandenhoek S, Arnason J T. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures.  Phytomedicine. 2000;  7 273-82
  CrossrefPubMedSearch in Google Scholar
• 9 Yale S H. Glurich I. Analysis of the inhibitory potential of Gingko biloba, Echinacea purpurea, and Serenoa repens on the metabolic activity of cytochrome P450 3A4, 2D6, and 2C9.  J Altern Complement Med. 2005;  11 433-9
  CrossrefPubMedSearch in Google Scholar
• 10 Gorski J C, Huang S M, Pinto A, Hamman M A, Hilligoss J K, Zaheer N A. et al . The effect of Echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo.  Clin Pharmacol Ther. 2004;  75 9-100
  PubMedSearch in Google Scholar
• 11 Gurley B J, Gardner S F, Hubbard M A, Williams D K, Gentry W B, Carrier J. et al . In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle and saw palmetto.  Clin Pharmacol Ther. 2004;  76 428-40
  CrossrefPubMedSearch in Google Scholar
• 12 Modarai M, Gertsch J, Suter A, Heinrich M, Kortenkamp A. Cytochrome P450 inhibitory action of Echinacea preparations differs widely and co-varies with alkylamide content.  J Pharm Pharmacol. 2007;  59 567-73
  CrossrefPubMedSearch in Google Scholar
• 13 Matthias A, Gillam E M, Penman K G, Matovic N J, Bone K M, De Voss J J. et al . Cytochrome P450 enzyme-mediated degradation of Echinacea alkylamides in human liver microsomes.  Chem Biol Interact. 2005;  155 62-70
  CrossrefPubMedSearch in Google Scholar
• 14 Hellum B H, Hu Z, Nilsen O G. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes.  Basic Clin Pharmacol Toxicol. 2007;  100 3-30
  PubMedSearch in Google Scholar
• 15 Hovhannisyan A S, Abrahamyan H, Gabrielyan E S, Panossian A G. The effect of Kan Jang extract on the pharmacokinetics and pharmacodynamis of warfarin in rats.  Phytomedicine. 2006;  13 318-23
  CrossrefPubMedSearch in Google Scholar
• 16 Pekthong D, Martin H, Abadie C, Bonet A, Heyd B. Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide. J Ethnopharmacol, advance online publication; doi: 10.1016/j.jep.2007.10.013
• 17 Jarukamjorn K, Don-in K, Makejaruskul C, Laha T, Daodee S, Pearaksa P. et al . Impact of Andrographis paniculata crude extract on mouse hepatic cytochrome P450 enzymes.  J Ethnopharmacol. 2006;  105 464-7
  CrossrefPubMedSearch in Google Scholar
• 18 Donovan J L, DeVane C L, Chavin K D, Taylor R M, Mardowitz J S. Siberian ginseng (Eleutherococcus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers.  Drug Metab Dispos. 2003;  31 519-22
  CrossrefPubMedSearch in Google Scholar

Prof. Dr. Michael Heinrich

Centre for Pharmacognosy and Phytotherapy

The School of Pharmacy

University of London

29/39 Brunswick Square

London WC1N 1AX

United Kingdom

Phone: +44-20-7753-5944

Fax: +44-20-7753-5908

Email: michael.heinrich@pharmacy.ac.uk

References

• 1 BfArM. Bewertung möglicher pharmakokinetischer Arzneimittel-Interaktionen mit Phytopharmaka. 2004. Available at http://www.bfarm.de/cln_042/nn_424 630/DE/Arzneimittel/besTherap/amPflanz/ampflanz-node.html. Accessed August 20, 2006. 
• 2 Williamson E M. Interactions between herbal and conventional medicines.  Expert Opin Drug Saf. 2005;  4 1-24
  CrossrefPubMedSearch in Google Scholar
• 3 Van den Bout-van den Beukel C JP, Koopmans P P, van der Ven A JAM, De Smet P AGM, Burger D M. Possible rrug - metabolism interactions of medicinal herbs with antiretroviral agents.  Drug Metabol Rev. 2006;  38 477-514
  PubMedSearch in Google Scholar
• 4 Barnes J, Anderson L A, Gibbons S, Phillipson J D. Echinacea angustifolia (D.C.) Hell. Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench: a review of their chemistry, pharmacology and clinical properties.  J Pharm Pharmacol. 2005;  57 929-54
  CrossrefPubMedSearch in Google Scholar
• 5 Woelkart K, Marth E, Suter A, Schoop R, Raggam R B, Koidl C. et al . Bioavailability and pharmacokinetics of Echinacea purpurea preparations and their interactions with the immune system.  Int J Clin Pharmacol Ther. 2006;  44 401-8
  PubMedSearch in Google Scholar
• 6 Shah S A, Sander S, White C M, Rinaldi M, Coleman C I. Evaluation of Echinacea for the prevention and treatment of the common cold: a meta-analysis.  Lancet Infect Dis. 2007;  7 473-80
  CrossrefPubMedSearch in Google Scholar
• 7 Schoop R, Klein P, Suter A, Johnson S L. Echinacea in the prevention of induced rhinovirus colds: A meta-analysis.  Clin Ther. 2006;  28 174-83
  CrossrefPubMedSearch in Google Scholar
• 8 Budzinski J W, Foster B C, Vandenhoek S, Arnason J T. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures.  Phytomedicine. 2000;  7 273-82
  CrossrefPubMedSearch in Google Scholar
• 9 Yale S H. Glurich I. Analysis of the inhibitory potential of Gingko biloba, Echinacea purpurea, and Serenoa repens on the metabolic activity of cytochrome P450 3A4, 2D6, and 2C9.  J Altern Complement Med. 2005;  11 433-9
  CrossrefPubMedSearch in Google Scholar
• 10 Gorski J C, Huang S M, Pinto A, Hamman M A, Hilligoss J K, Zaheer N A. et al . The effect of Echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo.  Clin Pharmacol Ther. 2004;  75 9-100
  PubMedSearch in Google Scholar
• 11 Gurley B J, Gardner S F, Hubbard M A, Williams D K, Gentry W B, Carrier J. et al . In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle and saw palmetto.  Clin Pharmacol Ther. 2004;  76 428-40
  CrossrefPubMedSearch in Google Scholar
• 12 Modarai M, Gertsch J, Suter A, Heinrich M, Kortenkamp A. Cytochrome P450 inhibitory action of Echinacea preparations differs widely and co-varies with alkylamide content.  J Pharm Pharmacol. 2007;  59 567-73
  CrossrefPubMedSearch in Google Scholar
• 13 Matthias A, Gillam E M, Penman K G, Matovic N J, Bone K M, De Voss J J. et al . Cytochrome P450 enzyme-mediated degradation of Echinacea alkylamides in human liver microsomes.  Chem Biol Interact. 2005;  155 62-70
  CrossrefPubMedSearch in Google Scholar
• 14 Hellum B H, Hu Z, Nilsen O G. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes.  Basic Clin Pharmacol Toxicol. 2007;  100 3-30
  PubMedSearch in Google Scholar
• 15 Hovhannisyan A S, Abrahamyan H, Gabrielyan E S, Panossian A G. The effect of Kan Jang extract on the pharmacokinetics and pharmacodynamis of warfarin in rats.  Phytomedicine. 2006;  13 318-23
  CrossrefPubMedSearch in Google Scholar
• 16 Pekthong D, Martin H, Abadie C, Bonet A, Heyd B. Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide. J Ethnopharmacol, advance online publication; doi: 10.1016/j.jep.2007.10.013
• 17 Jarukamjorn K, Don-in K, Makejaruskul C, Laha T, Daodee S, Pearaksa P. et al . Impact of Andrographis paniculata crude extract on mouse hepatic cytochrome P450 enzymes.  J Ethnopharmacol. 2006;  105 464-7
  CrossrefPubMedSearch in Google Scholar
• 18 Donovan J L, DeVane C L, Chavin K D, Taylor R M, Mardowitz J S. Siberian ginseng (Eleutherococcus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers.  Drug Metab Dispos. 2003;  31 519-22
  CrossrefPubMedSearch in Google Scholar

Prof. Dr. Michael Heinrich

Centre for Pharmacognosy and Phytotherapy

The School of Pharmacy

University of London

29/39 Brunswick Square

London WC1N 1AX

United Kingdom

Phone: +44-20-7753-5944

Fax: +44-20-7753-5908

Email: michael.heinrich@pharmacy.ac.uk