Download The Complexity of Herb-Drug Interaction Research

No. 145 July 2011
The Complexity of Herb-Drug Interaction Research
by Michelle Morgan
Key Points at a Glance
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Herb-drug interactions (HDIs) are a modern safety issue.
Research on HDIs is increasing.
Results from clinical studies are not always easy to interpret.
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Statistical significance does not necessarily mean clinical significance.
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There may not be enough or suitable information provided to assess the clinical relevance.
Best clinical research includes measuring pharmacodynamic effects as well as the pharmacokinetics.
Clinical trials investigate potential interactions with specific drugs or with cytochrome P450 (CYP) enzymes (using probe drugs).
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CYP enzymes are involved in drug metabolism.
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A herb shown in a trial to interact with a CYP enzyme will not automatically interact with drugs metabolised by that CYP enzyme.
Many factors affect the risk of interactions, including genetic polymorphisms.
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Some clinical trials investigate potential herb-drug interactions in people of different genotypes. This information is not usually
clinically relevant (who knows what genotype they are?).
In vitro data is not necessarily indicative of clinical outcomes.
Information on HDIs is not always accurate. Reliable sources exist.
A modern safety issue for herbal practice is the potential
for herbs to interact with drug medications. In recent years
there has been an increase in clinical research in this area,
not the least because it is relatively inexpensive to conduct
– requiring small numbers of volunteers or patients (ideally
at least 10) for relatively short duration (ideally treatment
periods of 2 weeks).
Despite the explosion of research, and although there is
improvement, misinformation still permeates the medical
literature (the media and popular thought).
• Chamomile, apparently on the basis of containing a
‘coumarin constituent’, is said to potentially interact
with warfarin. This inaccurate information is still being
reported.
• A recent review noted that motherwort (species
undefined) has a synergistic effect with
benzodiazepines and may lead to coma.1 No evidence
or reference is provided. Even if this is based on
animal studies (rather than in vitro), can it be
extrapolated to clinical practice? What were the
preparation, dosage and route of administration?
Where are the case reports of such a dramatic side
effect?
• Ginkgo is often assumed to interact with antiplatelet
and anticoagulant drugs and thereby increase the risk
of bleeding. This is despite several reviews
Not for Public Distribution. For Education of Health Care Professionals Only.
highlighting the absence of unequivocal primary
evidence to support such a claim.
Herb-drug interactions (HDIs) are studied scientifically from
the perspective of drug-drug interactions by investigating:
(1) the pharmacokinetics of a particular herb and drug
combination and (2) the interaction with cytochrome P450
enzymes (such as with probe drugs). Information about
herb-drug interactions also comes from case reports, but
the report needs to be well documented and preferably
showing at least probable causality.
Pharmacokinetics: Specific Interactions
Measurement of drug exposure or bioavailability (using
area under the serum concentration-time curve, AUC) and
plasma drug level (using maximum plasma concentration,
Cmax) are the most useful pharmacokinetic parameters
when evaluating potential interactions. The interpretation
of these results however, is not straightforward. While
statistical significance (the p value) is valuable in assessing
efficacy trials it is of limited value in HDI trials. For
example, in a trial in which treatment with a herb
produces a statistically significant improvement in
symptoms compared to placebo treatment, the herb is
likely to be efficacious. If the plasma levels of a drug are
changed by say 10%, after taking a herb compared to the
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Herb & Drug
Ginger & Warfarin
St John’s wort &
Quazepam
Pharmacokinetics
no effect
Drug levels and exposure in healthy volunteers
not changed.2
Dose: 3.6 g/day, dried ginger.
effect
Decreased drug levels and exposure in healthy
volunteers by about 25%.3
Pharmacodynamics
no effect
No effect observed on INR or platelet
aggregation.
Action
Interaction unlikely to
be clinically relevant.§
no effect
Herb did not reduce the sedative effects of
drug (assessed by a psychomotor test).
Interaction unlikely to
be clinically relevant,
but monitoring of
patient is advised.
Interaction may be
clinically relevant at
this dosage,† close
monitoring of patient
is advised.
no effect
effect
Mean drug levels and exposure not changed,*
Herb did not change blood pressure, but did
although nearly 2-fold increase in drug levels
increase heart rate (2–9%), and those with
occurred in 2 of the 8 volunteers.4
highest plasma drug levels had more severe
and longer-lasting headaches (characteristic
Dose: 240 mg/day of standardised extract,
side effect of drug).
equivalent to 12 g/day of dried leaf.
Table 1. Examples of clinical trial research on potential herb-drug interactions which measured pharmacodynamic as well as
pharmacokinetic effects.
Ginkgo & Nifedipine
Notes: § Although other research suggests the dosage of ginger may be relevant (higher doses may have an effect). * Although the herb was only
administered for one day – more robust results are obtained when the herb is administered for more than 7 days. † In other research, at the lower dosage of
120 mg/day of extract for 18 days, Ginkgo increased mean plasma drug concentration by 29% in healthy volunteers. Pharmacodynamic effects not
measured.5
baseline (no herb), a statistical significance might be
reached, but the decrease may have no clinical
consequences. How can the changes in AUC and Cmax be
assessed as clinically relevant? Clearly an increase or
decrease of 80% or more would be, but excluding drugs
with a narrow therapeutic index, where is the cut-off? As a
general rule of thumb, without any other information, and
excluding drugs with a narrow therapeutic index, a change
of 25–30% is considered potentially relevant. (There are
several mathematical means to assess this data, including
the geometric mean ratio of the AUC before and after
administration of the test herb (or drug in the case of
drug-drug interaction studies). But this additional data is
not always provided by the study.)
The most relevant interaction studies would measure
potential pharmacodynamic outcomes, that is, a change in
the pharmacological activity of the drug by the herb e.g. a
change in blood glucose for a hypoglycaemic drug, a
change in international normalized ratio (INR) for warfarin.
Table 1 provides examples of clinical studies that
investigated both pharmacokinetic and pharmacodynamic
effects.
Drug-Drug Interaction
Drug A induces/inhibits CYP3A4.
Drug B is metabolised mainly by CYP3A4.
So Drug A is likely to decrease/increase the effects of Drug B.
Example 1: A Herb-Drug Interaction
St John’s wort extract induces CYP3A4.‡
Cyclosporin is metabolised mainly by CYP3A4.
St John’s wort extract decreases the effects of cyclosporin (due to decreased drug levels).*
Example 2: Not a Herb-Drug Interaction
Golden seal inhibits CYP3A4.#
Indinavir is metabolised mainly by CYP3A4.
So golden seal may increase the effects of indinavir?
Golden seal had no effect on drug levels of indinavir in a clinical study6 with volunteers.§
Example 3: Herb-Drug Interaction? – Some but not all
Trials controlled for the dosage†
Midazolam, alprazolam and nifedipine are metabolised mainly by CYP3A4.
Ginkgo decreased drug levels of and exposure to midazolam.7
Ginkgo had no clinically-relevant effect on exposure to alprazolam.8
Ginkgo had no effect on drug levels of or exposure to nifedipine, but a pharmacodynamic effect was observed (see Table 1).
Table 2. Examples: Interactions with CYP3A4 may or may not predict drug interactions.
Notes: ‡ Observed in studies (year 2000) which assessed urinary 6-beta-hydroxycortisol/cortisol ratio9 and erythromycin breath test in healthy volunteers.10
* Interaction noted in credible case reports.11,12 # Clinical study of volunteers using midazolam.13 Interaction defined as weak by US Food and Drug
Administration criteria. The authors of this research concluded “significant herb-drug interactions may result from the concomitant ingestion of goldenseal and
CYP3A substrates”. § There were some differences in the trial design and brand, dosage and alkaloid content of golden seal used in the midazolam and
indinavir studies. † Each of these trials used a dosage of 240 mg/day of standardised Ginkgo extract, equivalent to 12 g/day of dried leaf.
Not for Public Distribution. For Education of Health Care Professionals Only.
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The antihypertensive drug losartan is mainly metabolised to an active more potent metabolite (which contributes significantly to the effect of
losartan).
Losartan is metabolised by CYP3A4 and CYP2C9.
CYP2C9 is the main enzyme responsible for transforming losartan to the active metabolite.
Several variants of CYP2C9 have been identified in humans: the most important mutations are CYP2C9*2 and CYP2C9*3.
The CYP2C9*3 variant shows decreased metabolic activity for many drugs metabolised by CYP2C9.
Twelve volunteers were recruited for the study: six were genotyped as CYP2C9*1/*1, six as CYP2C9*1/*3.
Genotype
Effect on drug
Effect on main, active metabolite of drug
Metabolic ratio
(AUC metabolite/AUC drug)
1*/1*
strongly increased exposure and plasma
some decrease in exposure and plasma level
decreased by 49%
level
1*/3*
no effect
some decrease in exposure and plasma level
decreased by 20%
Table 3. Effect of silymarin on the pharmacokinetics of losartan and its active metabolite in healthy volunteers with two CYP2C9
genotypes (CYP2C9*1/*1, CYP2C9*1/*3).
Cytochrome P450 (CYP) Probes
There are many CYP enzymes but CYP3A4, alone or in part,
is involved in the metabolism of about 60% of drugs. A
drug interacting with a particular CYP enzyme tells a great
deal about the probability that the drug will interact with
other drugs that are also metabolised by this CYP enzyme.
It turns out that this does not necessarily follow for herbs,
possibly because of variations in the composition of the
herbal preparations tested, but perhaps because herbs are
more compositionally complex than drugs or the
interaction is not strong enough to show an effect. See
Table 2 for examples.
Drugs may be metabolised by several CYP enzymes and
are metabolised in other ways too, such as with the
involvement of drug transporters such as P-glycoprotein or
by phase II metabolism. This adds further complexity to
the study of interactions. For example, although a herb
may interact with CYP3A4, what will be the effect on a
drug metabolised jointly by, for example, CYP3A4 and
CYP2D6? In the example of St John’s wort in Table 2, the
herb also enhances the expression of P-glycoprotein. Some
of the drugs St John’s wort interacts with such as
cyclosporin are metabolised by both CYP3A4 and Pglycoprotein.
with the CYP2C9*1/*3 genotype. (The conclusion is based
on the decrease in the metabolic ratio of losartan and the
fact that the active metabolite has higher potency and
longer half-life than losartan (so the metabolite may be
responsible for most of the antihypertensive effect)).
However, it is not known whether the decrease has any
clinical relevance.
Results from in vitro research do not necessarily translate
into interactions in vivo. Because in vitro research is less
expensive, it could be considered a first step for guiding
clinical study research, but not for providing definitive
information on HDIs.
HDI Information & Further Reading
It is difficult to find accurate, evidence-transparent,
clinically-relevant, up-to-date information on HDIs. Much of
the primary scientific research is difficult to read. Here are
some suggestions (Table 4).
Other Issues
Other factors that may modify the risk of interactions
include age, liver and kidney damage and genetic
polymorphisms. Genetic polymorphisms are not common,
and the information is usually not relevant as unless
specifically tested, patients don’t usually know if they
have a particular genotype.
An example of the variation of response depending upon
genotype is described in Table 3. The crossover trial
compared silymarin (420 mg/day) with placebo on the
effect of losartan.14 The results suggest that silymarin
inhibited the metabolism of losartan to a greater extent in
those with the CYP2C9*1/*1 genotype, compared to those
Not for Public Distribution. For Education of Health Care Professionals Only.
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MediHerb Herb-Drug Interaction chart
Review of primary research, updated annually, summarised and presented in table form, listed alphabetically by herb. Generally only includes
interactions of substantial evidence with safety consequences. Available in the product catalog and from the website (www.mediherb.com). See
also the General Prescribing Guidelines and Assessment of Risk & Recommended Action (on website only).
Textbook
Williamson E, Driver S, Baxter K (eds). Stockley's Herbal Medicines Interactions. Pharmaceutical Press, London, Chicago, 2009.
This book contains monographs on herbs, some plant constituents and other natural substances. The monographs provide more detail (than the
table format) but are easy to read and transparent as to the evidence (in vitro, animal, clinical etc). Includes CYP enzymes and ‘positive’ and null
(no) interactions (other than just safety-related ‘negative’ interactions). Has a useful index that lists by herb and by drug.
Research papers providing a general overview of evidence and risk management of herb-drug interactions
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De Smet PA. Clinical risk management of herb-drug interactions. Br J Clin Pharmacol 2007; 63(3): 258-267. Article freely downloadable from
Medline: www.ncbi.nlm.nih.gov/pubmed/17116126
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De Smet PA, Floor-Schreudering A, Bouvy ML et al. Clinical risk management of interactions between natural products and drugs. Curr Drug
Metab 2008; 9(10): 1055-1062. Abstract on Medline: www.ncbi.nlm.nih.gov/pubmed/19075622
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Coxeter PD, McLachlan AJ, Duke CC et al. Herb-drug interactions: an evidence based approach. Curr Med Chem 2004; 11(11): 1513-1525.
Abstract on Medline: www.ncbi.nlm.nih.gov/pubmed/15180581. These authors note that without critical analysis of the published data, it is
not possible to separate “interaction from over-reaction”!
Research papers providing a review of specific herb-drug interactions
Presented in table form (summarised), includes CYP enzymes and the type of information (in vitro, animal, clinical etc).
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Tarirai C, Viljoen AM, Hamman JH. Herb-drug pharmacokinetic interactions reviewed. Expert Opin Drug Metab Toxicol 2010; 6(12): 15151538. Abstract on Medline: www.ncbi.nlm.nih.gov/pubmed/21067427
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Kennedy DA, Seely D. Clinically based evidence of drug-herb interactions: a systematic review. Expert Opin Drug Saf 2010; 9(1): 79-124.
Abstract on Medline: www.ncbi.nlm.nih.gov/pubmed/20021292
Research papers reviewing the primary evidence for the reputed interaction between Ginkgo and anticoagulant drugs
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Bone KM. Potential interaction of Ginkgo biloba leaf with antiplatelet or anticoagulant drugs: what is the evidence? Mol Nutr Food Res 2008;
52(7): 764-771. Abstract on Medline: www.ncbi.nlm.nih.gov/pubmed/18214851
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Kellermann AJ, Kloft C. Is There a Risk of Bleeding Associated with Standardized Ginkgo biloba Extract Therapy? A Systematic Review and
Meta-analysis. Pharmacotherapy 2011; 31(5): 490-502. Abstract on journal website:
http://pharmacotherapyjournal.org/doi/abs/10.1592/phco.31.5.490 [not yet indexed on Medline]
Report and critique of primary research
Included sometimes in documents such as the MediHerb e-Monitor, available from the website (www.mediherb.com). See e-Monitor issues and
the MediHerb Library search engine.
Primary research on herb-drug interactions
Medline database (PubMed: www.ncbi.nlm.nih.gov/pubmed/)
As a quick start: type ‘Herb-Drug Interactions[Mesh]’ in the search field and limit to ‘Reviews’, but this won’t retrieve all HDI information. (Herbdrug interaction research is indexed on Medline as a subject heading (MeSH), but this indexing does not capture all relevant publications.)
Table 4. Herb-drug interaction information.
SELECTED REFERENCES
© Copyright 2011 MediHerb.
1
Tachjian A, Maria V, Jahangir A. J Am Coll Cardiol 2010; 55(6): 515-525
Jiang X, Williams KM, Liauw WS et al. Br J Clin Pharmacol 2005; 59(4):
425-432
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Kawaguchi A, Ohmori M, Tsuruoka S et al. Br J Clin Pharmacol 2004;
58(4): 403-410
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Yoshioka M, Ohnishi N, Koishi T et al. Biol Pharm Bull 2004; 27(12):
2006-2009
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Smith M, Lin KM, Zheng MD. Clin Pharmacol Ther 2001; 69(2): P86,
Abstract #PIII-89
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Sandhu RS, Prescilla RP, Simonelli TM et al. J Clin Pharmacol 2003;
43(11): 1283-1288
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Robertson SM, Davey RT, Voell J et al. Curr Med Res Opin 2008; 24(2):
591-599
8
Markowitz JS, Donovan JL, Lindsay DeVane C et al. J Clin
Psychopharmacol 2003; 23(6): 576-581
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Roby CA, Anderson GD, Kantor E et al. Clin Pharmacol Ther 2000; 67(5):
451-457
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Durr D, Stieger B, Kullak-Ublick GA et al. Clin Pharmacol Ther 2000;
68(6): 598-604
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Barone GW, Gurley BJ, Ketel BL et al. Ann Pharmacother 2000; 34(9):
1013-1016
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Ruschitzka F, Meier PJ, Turina M et al. Lancet 2000; 355(9203): 548-549
13
Gurley BJ, Swain A, Hubbard MA et al. Clin Pharmacol Ther 2008; 83(1):
61-69
14
Han Y, Guo D, Chen Y et al. Eur J Clin Pharmacol 2009; 65(6): 585-591
2
Not for Public Distribution. For Education of Health Care Professionals Only.
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