Introduced in 1960s, carbamazepine (CBZ) remains as one of the most commonly prescribed antiepileptic drugs worldwide and has established efficacy for the treatment of partial seizures, generalized tonic-clonic seizures, trigeminal neuralgia, and bipolar disorders [
Since antiepileptic regimens are normally given on a long-term basis, the opportunity of a clinical significant interaction between CBZ and coadministered substances is considerably high. Herbal medicines, dietary supplements, and food may interact with CBZ pharmacokinetically and/or pharmacodynamically which leads to potential clinical consequences. One of the contributing factors towards increasing incidence of herb-drug interaction is the increased popularity of herbal medicines [
When making clinical decisions on the use of herbal or dietary supplements, the review article is one of the major information sources for healthcare professionals [
In view of all the constraints of the existing literature, a comprehensive systematic review focusing on CBZ and overcoming the mentioned hurdles is warranted for healthcare professionals to make proper decisions. In this current report, we conducted a systematic review on interactions between CBZ and herbs, dietary supplements, and food, summarizing the scientific evidence for such interactions and providing recommendations for the combinational use. In addition to the usual databases (e.g., Medline and Embase), we also included several Chinese databases to identify reports of interactions between CBZ and TCM which are written in Chinese. The aim of this review is to provide a clear and systematic presentation of herb and food interactions with CBZ to alert and provide guidance for medical professionals when prescribing CBZ.
A computer-based search of the following English databases was conducted: AMED (1985–Oct. 2012), CINAHL Plus (1937–Oct. 2012), Cochrane Database of Systematic Reviews (2005–Dec. 2011), CENTRAL (Oct. 2012), Embase (1947–Oct. 2012), Medline (1946–Oct. 2012), and SciFinder Scholar (1907–Oct. 2012). The keyword search terms for carbamazepine (“Carbamazepine”, “Tegretol”, “Tegretol XR”, “G-32883”, “5H-Dibenz[b,f]azepine-5-carboxamide”) were combined, using the combination term AND, with a comprehensive list of keywords and MeSH search terms for herbs, food, and dietary supplements (Table
Keyword and MeSH search terms for herbs, food, and dietary supplements.
Keywords | MeSH terms |
---|---|
(i) alter* medic* |
(i) exp Chinese drug |
The selection of relevant reports and evaluation of article eligibility was carried out by two reviewers independently (Fong and Gao). Articles were considered eligible for evaluation if they contained original data involving herb, food, or dietary supplement interactions with CBZ without restriction for
We grouped the natural products into four categories: TCM, other herb/botanical, vitamin/mineral/amino acid, and food. We categorized the mechanisms for pairs of interactions into three types: pharmacokinetics, pharmacodynamics, and both. In order to standardize the names of the included TCMs, the official compendium Pharmacopoeia of the People’s Republic of China 2010 (Chinese Pharmacopoeia) was consulted and their Latin names (for herbs) or Chinese pinyin names (for herbal formulae) were presented.
A total of 3179 articles was initially found through database searches while an addition of 14 articles were obtained from scrutinizing the bibliographies of relevant literatures. 196 articles fulfilling the inclusion criteria were selected for further evaluation with perfect agreement between the two authors. Finally, seventy-four articles with full text, including 40 original articles and 34 review articles, were qualified to undergo an in-depth review (Figure
Summary of the included
Types of herbal product* | Herbal products | Study type | Subject/model (number) | Study design | Outcome measures | Effect | Mechanism | References |
---|---|---|---|---|---|---|---|---|
TCM |
|
Animal | Male Wistar rats with pentylenetetrazole-induced seizure model |
Randomized controlled study | PK and PD parameters | No effect on plasma level of CBZ |
Increased GABAergic activity | Katyal et al. 2012 [ |
| ||||||||
TCM | Berberine (active compound in Coptidis rhizome) | Animal | Male Wistar rats (5 in each group) | Randomized parallel design | PK parameters | No effect on pharmacokinetic parameters of CBZ or CBZ 10,11-epoxide | Did not affect |
Qiu et al. 2009 [ |
| ||||||||
TCM |
|
Animal | Male Wistar rats (10 in each group) | Randomized crossover design | PK and PD parameters | No significant effect on CBZ plasma level |
N.D. | Thabrew et al. 2004 [ |
| ||||||||
TCM |
|
Animal | Male Wistar rats (10 in each group) | Randomized crossover design | PK and PD parameters | Increased plasma level of CBZ |
N.D. | Thabrew et al. 2004 [ |
| ||||||||
TCM | Chai-hu-jia-long-gu-mu-li- tang | Animal | Wistar rats |
Randomized parallel design | PK parameters | No effect on pharmacokinetic parameters or protein binding of CBZ or CBZ 10,11-epoxide | Did not alter |
Ohnishi et al. 2001 [ |
| ||||||||
TCM | Ginsenoside |
|
Human liver microsomes |
N/A | PK parameters | Increased CBZ metabolism | Activated CYP3A4 activity by interacting with CBZ in the active site | Haop et al. 2008 [ |
| ||||||||
TCM |
|
Animal | Rats |
Randomized parallel design | PK parameters | Decreased bioavailability and increased rate of elimination of CBZ | N.D. |
Chandra et al. 2009 [ |
| ||||||||
TCM | Hu-gan-ning pian | Animal | Male Sprague-Dawley rats |
Randomized parallel design | PK parameters | Decreased bioavailability |
Decreased absorption but not metabolism of CBZ | Zheng et al. 2009 [ |
| ||||||||
TCM |
|
Human | Healthy subjects |
Open label study | PK parameters | No effect on PK parameters of CBZ | Autoinduction or greater clearance by CBZ | Burstein et al. 2000 [ |
| ||||||||
HP | Ispaghula Husk |
Human | Healthy male volunteer (4) | Open label study | PK parameters | Decreased bioavailability by reducing absorption and plasma levels of CBZ | Decreased amount of biological fluid in GI tract and thereby reduced dissolution rate of CBZ Also adsorb CBZ onto their surfaces |
Etman 1995 [ |
| ||||||||
TCM | Jia-wei-xiao-yao-san | Human | Patients with major depression or bipolar disorder (61) | Randomized double-blinded control trial | PK parameters | Decreased plasma level of CBZ | Increased metabolism of CBZ by inducing CYP3A | Zhang et al. 2007 [ |
| ||||||||
HP | Mentat | Animal | New Zealand white rabbits |
Randomized parallel design | PK parameters | Increased bioavailability of CBZ | N.D. | Tripathi et al. 2000 [ |
| ||||||||
TCM | Paeoniae Radix | Animal | Male Sprague-Dawley rats |
Randomized parallel design | PK parameters | Decreased |
Improved dissolution of CBZ |
Chen et al. 2002 [ |
| ||||||||
TCM | Piperine |
Human | Patients with epilepsy |
Open label, crossover study | PK parameters | Increased bioavailability of CBZ |
Decreased metabolism/ elimination and/or increased absorption of CBZ | Pattanaik et al. 2009 [ |
| ||||||||
TCM | Platycodonis Radix | Animal | Rabbits |
Randomized parallel design | PK parameters | Increased plasma level of CBZ | Improve CBZ absorption by increasing its solubility and stimulating bile secretion | Liu and Wei 2008 [ |
| ||||||||
TCM |
|
Animal | Male Sprague-Dawley rats |
Randomized crossover design | PK parameters | Increased level of CBZ and CBZ 10,11-epoxide in plasma, brain, liver, and kidney |
Inhibited CYP3A in intestine and MRP2 in the kidney | Chi et al. 2012 [ |
| ||||||||
HP | Septilin | Animal | Male rabbits |
Randomized crossover study | PK parameters | Decreased absorption of CBZ | Affected gastric emptying time or intestinal transit time | Garg et al. 1998 [ |
| ||||||||
TCM | Xiao-cha-hu-tang | Animal | Female Sprague-Dawley rats |
Randomized parallel design | PK parameters | Increased |
Decreased GI absorption of CBZ by decreasing gastric emptying rate | Ohnishi et al. 2002 [ |
| ||||||||
TCM | Xiao-qing-long-tang | Animal | Male Wistar rats (4–6 in each group) | Randomized parallel design | PK parameters | Increased |
Decreased gastric emptying rate and accelerated metabolism of CBZ | Ohnishi et al. 1999 [ |
| ||||||||
TCM | Xiao-yao-san | Human | Patients with major depression or bipolar disorder | Randomized double-blinded control trial | PK and PD parameters | Decreased plasma level of CBZ and increased incidence of dizziness, blurred vision, skin rash, and nausea | N.D. | Li et al. 2005 [ |
*Types of herbal product: traditional Chinese medicines (TCM)/other herbal products (HP); N.D.: not determined by authors; N/A: not applicable.
Summary of the included
Dietary supplement (DS)/food | Dietary products | Study type | Subject/model (number) | Study design | Outcome measures | Effect | Mechanism | References |
---|---|---|---|---|---|---|---|---|
Food | Alcohol | Animal | Male CD-1 mice (10 in each group) | Randomized parallel design | PD parameters | Additive neurotoxicity (ethanol-induced motor incoordination and loss of righting reflex potentiated ) | Nonadenosinergic action | Dar et al. 1989 [ |
| ||||||||
Food | Alcohol | Human | Healthy volunteers (8) | Open label crossover study | PK parameters | No effect on pharmacokinetics of CBZ | Low ethanol level in subjects |
Sternebring et al. 1992 [ |
| ||||||||
Food | Alcohol | Human | Alcoholics (7) | Open label crossover study | PK parameters | Increased AU |
Acute inhibition of CBZ metabolism and/or accelerated CBZ metabolism in abstinence phase due to enzyme induction by previous ethanol abuse |
Sternebring et al. 1992 [ |
| ||||||||
Food | Butter | Animal | New Zealand white rabbit |
Crossover study | PK parameters | Increased bioavailability of CBZ | Improved solubility and dissolution of poorly soluble CBZ | Sidhu et al. 2004 [ |
| ||||||||
Food | Caffeine | Human | Healthy male volunteers (6) | Open label crossover study | PK parameters | Decreased bioavailability and increased |
Involving metabolism by mixed function oxidase | Vaz et al. 1998 [ |
| ||||||||
Food | Caffeine | Animal | Albino Swiss male mice with maximal electroshock seizure model |
Randomized controlled parallel study | PK and PD parameters | Acute caffeine decreased antiepileptic efficacy of CBZ but had no effect on plasma level of CBZ | N.D. | Czuczwar et al. 1990 [ |
| ||||||||
Food | Caffeine | Animal | Swiss male mice with maximal electroshock seizure model |
Randomized controlled study | PK and PD parameters | Chronic caffeine dose-dependently decreased anti-epileptic efficacy of CBZ but had no effect on plasma level of CBZ | May induce changes in neurotransmitter system causing sensitization effect | Gasior et al. 1996 [ |
| ||||||||
Food | Coca-Cola | Human | Healthy male volunteers (10) | Randomized two-way crossover design | PK parameters | Increased bioavailability of CBZ; no change in elimination |
Enhanced dissolution of CBZ by its acidity | Malhotra et al. 2002 [ |
| ||||||||
DS | Folinic acid | Animal | Male Sprague-Dawley rats |
Randomized parallel controlled design | PK parameters | No effect on plasma or brain level of CBZ | N.D. |
Simth and Carl 1982 [ |
| ||||||||
Food | Grapefruit juice | Human | Patients with epilepsy (10) | Randomized crossover study | PK parameters | Increased bioavailability of CBZ | Inhibited CYP3A4-mediated intestinal and hepatic metabolism of CBZ | Garg et al. 1998 [ |
| ||||||||
Food | Honey | Animal | Angora grey rabbit |
Nonrandomized design | PK parameters | Decreased bioavailability of CBZ | Decreased metabolism of CBZ by inducing CYP enzymes |
Koumaravelou et al. 2002 [ |
| ||||||||
Food | Honey | Human | Healthy volunteers |
Randomized crossover study | PK parameters | Single dose of honey has no effect on pharmacokinetics of CBZ | N.D. | Malhotra et al. 2003 [ |
| ||||||||
Food | Honey | Human | Healthy male volunteers (12) | Open label crossover study | PK parameters | Multiple doses of honey have no effect on pharmacokinetics of CBZ | Flavanoids in honey may not affect human CYP3A4 activity | Thomas et al. 2007 [ |
| ||||||||
Food | Kinnow Juice | Human | Healthy male volunteers (9) | Randomized crossover study | PK parameters | Increased bioavailability of CBZ | Inhibited CYP3A activity | Garg et al. 1998 [ |
| ||||||||
DS | Melatonin | Animal | Female Swiss mice |
Randomized parallel design | PK and PD parameters | Potentiated the anticonvulsant activity of CBZ but impair long-term memory but no effect on plasma and brain levels of CBZ | Enhanced GABAergic transmission in CNS | Borowicz et al. 1999 [ |
| ||||||||
DS | Melatonin | Human | Children with epilepsy (28) | Double-blind randomized control study | PK and PD parameters | Increased glutathione reductase (antioxidant) activity but no effect on plasma level of CBZ and its metabolite | Antagonized CBZ-triggered reactive oxygen species accumulation | Gupta et al. 2004 [ |
| ||||||||
DS | Melatonin | Animal | Male Swiss albino mice with maximal electroshock seizure model |
Randomized parallel design | PK and PD parameters | Synergistic anti-epileptic effect but no effect on plasma level of CBZ | N.D. | Gupta et al. 2004 [ |
| ||||||||
DS | Nicotinamide | Human | Children with epilepsy (2) | Case report | PK parameters | Increased plasma level of CBZ and decreased clearance of CBZ | N.D. | Said et al. 1989 [ |
| ||||||||
Food | Pomegranate juice | Animal | Male Wistar rats (5-6 in each group) | Randomized parallel design | PK parameters | Increased |
Inhibited enteric but not hepatic CYP3A activity | Hidaka et al. 2005 [ |
| ||||||||
Food | Pomegranate juice |
|
Male Wistar rats (3 in each group) |
|
PK parameters | Decreased intestinal transport of CBZ | Induced enteric CYP3A4 | Adukondalu et al. 2010 [ |
| ||||||||
Food | Soybean | Animal | Albino Wistar rats |
Randomized parallel design | PK parameters | Decreased bioavailability of CBZ, increased plasma clearance and |
Decreased gastric emptying and enhanced elimination of CBZ |
Singh and Asad 2010 [ |
| ||||||||
Food | Star Fruit Juice | Animal | Male Wistar rats (6 in each group) | Randomized parallel design | PK parameters | Increased |
Inhibited enteric but not hepatic CYP3A activity | Hidaka et al. 2006 [ |
N.D.: not determined by authors.
Flow chart of literature search.
Nineteen of the included original articles documented the interactions between 20 different herbal products and CBZ, where TCMs in the form of crude drug, extract, or single TCM compound were the major studied herbal products (
A total of twenty-one original literatures covering 13 different dietary supplement/food-CBZ interaction studies were recorded in the current review. These included beverages (
Patients on antiepileptic therapy are usually on a long-term basis. Several antiepileptic drugs require therapeutic drug monitoring and are prone to drug interactions which may lead to serious consequences. CBZ is one of the antiepileptic drugs that are on the “watch-list”. With the increased popularity of herbal products as well as dietary supplement, prescribers may need to be aware of the potential herb-drug or food-drug interactions when prescribing and monitoring CBZ therapy. In this study, we had conducted a systematic review and summarized the up-to-date evidence of the interactions between CBZ and herbal products/food/dietary supplements that have been reported in primary literature.
In order to achieve a comprehensive literature search, a total of eleven databases were searched. These included two conventional databases (EMBASE and MEDLINE), five other English databases (AMED, CINAHL Plus, Cochrane Database of Systematic Reviews, CENTRAL, and SciFinder Scholar) four Chinese databases. We had also consulted some relative tertiary literatures including Stockley’s Herbal Medicines Interactions and Natural Medicines Comprehensive Database in case of any additional information. The keywords used for the search were optimized and refined in an attempt to include most of the relevant literatures (Table
There were altogether 33 different herbal products/food/dietary supplements identified from literature in which their effects on CBZ were studied. These included 17 TCMs, 3 other herbs/botanicals, 10 foods, and 3 dietary supplements. The large number of studies involving TCM-drug interactions implies that TCM warrants special attention when coadministered with CBZ. However, the nonstandardized naming and multiple constituents of TCMs often confuse prescribers when anticipating such interaction. After extracting the herbal names from the original articles, we standardized the herbal names in Latin according to the Chinese Pharmacopoeia 2010 (Table
Synonyms of the included TCM products.
Herbal products | Synonyms |
---|---|
|
Sweet flag, Zhang-chang-pu |
|
Ballon vine, Winter cherry, Heartseed, Dao-di-ning |
|
Avaram, Senna auriculata, Tanner's Cassia, Er-ye-fan-xie |
|
St John’s wort |
Paeoniae Radix | Peony, Shao-yao |
Platycodonis Radix | Jie geng, Platycodon Root, Balloon flower |
|
Japanese knotweed, Hu-zhang |
Composition of individual herbs in the included herbal formulae.
Herbal formula | Other name | Herbs | Content |
---|---|---|---|
Chai-hu-jia-long-gu-mu-li-tang | Saiko-ka-ryukostsu-borei-to | Bupleuri Radix |
5 parts |
| |||
Hu-gan-ning pian | Huganning tablet | Sedi Herba |
850 g |
| |||
Jia-wei-xiao-yao-san | Free and easy wanderer plus | Bupleuri Radix |
12.5% |
| |||
Mentat | BR 16A |
|
Not known |
| |||
Xiao-cha-hu-tang | Sho-saiko-to | Bupleuri Radix |
7 parts |
| |||
Xiao-qing-long-tang | Sho-seiryu-to extract | Pinelliae Tuber |
6 parts |
| |||
Xiao-yao-san | Free and easy wanderer | Bupleuri Radix |
2 parts |
No fatal or severe interactions between CBZ and herbal products/food/dietary supplement were found from the literature search. Majority of the studied interactions were pharmacokinetic-based, where the oral bioavailability or plasma level of CBZ was significantly altered by the natural products (Table
Pharmacokinetic and pharmacodynamic interactions of herbal products/food/dietary supplements with CBZ by direction of interactions.
Pharmacokinetic interactions with CBZ | ||
---|---|---|
Oral bioavailability/plasma level of CBZ | ||
Increased | Decreased | No effect |
|
Septilin |
|
*In alcoholics, not healthy volunteers; study type: human study (
Pharmacodynamic interactions with CBZ | |||||
---|---|---|---|---|---|
Antiepileptic efficacy of CBZ | Side effects related to CBZ | ||||
Potentiation | Inhibition | No effect | Potentiation | Reduction | No effect |
|
Caffeine |
|
|
Study type: human study (
On the other hand, nine natural products diminished the oral bioavailability/plasma level of CBZ significantly with four of them having clinical evidences: Ispaghula husk, Xiao-yao-san, Jia-wei-xiao-yao san, and caffeine (Table
Furthermore, CBZ has poor water solubility; consequently, its absorption time and extent are thus easily affected by coadministration of substances that may alter gastric conditions. For example, Xiao-cha-hu-tang and Xiao-qing-long-tang delayed the time for CBZ to reach peak plasma concentration by decreasing the gastric emptying rate. By improving the dissolution of CBZ, Paeoniae Radix allowed faster absorption while butter and Platycodonis Radix increased the extent absorption of CBZ.
Any changes of the plasma level of CBZ-10,11 epoxide caused by the simultaneous administration of herbal products/food/dietary supplements with CBZ should also be noted. Formed through the CYP3A4-mediated metabolism in intestine and liver, CBZ-10,11 epoxide is the principle metabolite of CBZ which is pharmacologically active and may contribute to the toxicities of CBZ [
Compared to pharmacokinetic interactions, there were fewer studies reporting pharmacodynamic-based interactions between herbal products/food/dietary supplements and CBZ. Pharmacodynamic interaction refers to the alteration of efficacy (antiepileptic activity) and/or the adverse effects of CBZ in the presence of natural products. Melatonin and
In this study, the documented evidence of interactions between CBZ and herbal products/food/dietary supplements was systematically reviewed from the published literature. The intention of this review was to provide guidance to assist healthcare professionals in identifying patients taking CBZ that are more susceptible to these interactions and make proper actions. A total of 33 unique herbal products/dietary supplement/food-CBZ interacting pairs were identified from this review. Considering the popularity and frequent usage of both CBZ (as first-line epilepsy regimen) and herbal products/food/dietary supplements, the number of studied interactions is considerably small. More evidence and reports are needed from research studies and, preferably, from adverse report system in clinical setting. Of course, the importance of therapeutic drug monitoring of CBZ is again emphasized while most pairs of natural products-CBZ interactions remained unknown. On the other hand, the amount of documented CBZ-herbal products/food/dietary supplements interactions might be underreported in this review due to several limitations, including publication bias and language restrictions. We had attempted to reduce language bias by including four evidence-based Chinese databases. However, the evidence regarding complementary alternative medicine or folk therapies, which were published in other languages (e.g., Japanese, Indian, and French), might be missing. Another limitation of this review was that it included all relevant information identified in the literature, regardless of the evidence types or quality of the studies. Such arrangement aimed to gather as much useful information regarding studies on interactions between CBZ and the natural products. Although species differences existed, human pharmacokinetic parameters and pharmacodynamic behavior could be successfully extrapolated from animal studies [
This review provides a structured summary of the evidence of the documented interactions between CBZ and herbal products/food/dietary supplements. These findings should be helpful for healthcare professionals to identify potential herb-drug and food-drug interactions while prescribing CBZ and would also facilitate them to communicate these documented interactions to their patients, thus preventing potential adverse events and improving patients’ therapeutic outcomes.
Grant from Hospital Authority of Hong Kong (Reference no. L/M (Q08-040) to HAHO(S)/P/45).