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Arch. Pharm. Res.

DOI 10.1007/s12272-014-0517-z

REVIEW

Interactions between herbs and antidiabetics: an overview


of the mechanisms, evidence, importance, and management
Shaheed Ur Rehman • Min Sun Choi •

Kevin Choe • Hye Hyun Yoo

Received: 26 February 2014 / Accepted: 10 November 2014


Ó The Pharmaceutical Society of Korea 2014

Abstract Complementary and alternative therapies are hypertension, pain syndromes, and anxiety, as well as a
quickly gaining importance because they are perceived to desire for good health, collectively lead to the use of herbal
be free of side effects due to their natural origin. However, medicines (Tachjian et al. 2010). Herbal medicines are
herbal remedies are complex mixtures of bioactive entities, quickly gaining importance because they are perceived to
which may interact with prescription drugs through phar- be free of side effects due to their natural origin (Walker
macokinetic or pharmacodynamic mechanisms and some- and Donovan 1999). However, herbal remedies are com-
times result in life-threatening consequences. In particular, plex mixtures of organic chemicals and have many
diabetes patients are often treated with multiple medica- potential adverse effects owing to their active ingredients
tions due to different comorbidities, and such patients use and the interactions of these ingredients with conventional
antidiabetic medications for their entire lives; thus, it is drugs, which can sometimes have life-threatening conse-
important to make the public aware of herb interactions quences (Bent et al. 2005). It has been well documented
with antidiabetic drugs. In this paper, we summarize the that significant effects on pharmacokinetics and/or phar-
reports available on the interaction of herbal remedies with macodynamics can occur through herb–drug interaction
oral hypoglycemic agents and describe mechanisms, pre- (Butterweck and Derendorf 2008; Tarirai et al. 2010),
clinical or clinical evidence, importance, and management which has led to increased concern regarding the safety of
strategies. co-administration of herbal products with drugs (Chavez
et al. 2006; Hafner-Blumenstiel 2011; Izzo and Ernst 2009;
Keywords Herb–drug interaction  Antidiabetics  Marchetti et al. 2007; Skalli et al. 2007).
Mechanism  Evidence  Management Unlike conventional drugs, herbal products contain a
complex mixture of bioactive entities, each of which may
or may not provide therapeutic activity. Often a complete
Introduction characterization of all the chemical constituents from a
natural product is unavailable. Additionally, the chemical
The use of medicinal plants to treat diseases is probably the makeup of a natural product may vary depending on the
first method used by humanity to cope with illness, and part of the plant processed (stems, leaves, roots), season-
medicinal plants are used therapeutically around the world ality, and growing conditions. While the complex nature of
as important components of various traditional medicine natural products complicates determination of drug–herb
systems (Solimene et al. 2007). In particular, the high interactions, the manufacturing process also contributes to
prevalence of chronic disorders such as obesity, the complexity of these processes.
The potentially dangerous effects of herbs in patients
already taking prescription medications is a significant
S. Rehman  M. S. Choi  K. Choe  H. H. Yoo (&) concern, particularly for those patients currently taking
Institute of Pharmaceutical Science and Technology and College
multiple medications, which are often prescribed by mul-
of Pharmacy, Hanyang University, Ansan,
Gyeonggi-do 426-791, Republic of Korea tiple physicians who may or may not be in communication
e-mail: yoohh@hanyang.ac.kr with each other regarding their medical reasoning.

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S. Rehman et al.

Table 1 Important CYP isonzymes subfamilies and their acting herbs


CYP Interacting nature Acting herb References

CYP1A2 Inhibitor Melatonin Yeleswaram et al. (1999)


CYP1A2 Substrates Sweet wormwood Greenblatt et al. (2006 and Williamson et al. (2013)
CYP2C8 Inducer Flavonoids Cermak and Wolffram (2006), Choi et al. (2004), Kim et al. (2005)
Substrate Goldenseal Mohutsky et al. (2006) and Williamson et al. (2013)
Quercetin Choi et al. (2004)
CYP2C9 Inducer Ginkgo Etheridge et al. (2007), Gaudineau et al. (2004), Moltke et al.
(2004), Sugiyama et al. (2004a, b), Yale and Glurich (2005)
St. John’s wort Xu et al. (2008)
Inhibitor Isoflavones (puerarin) Guo et al. (2014)
Substrate Resveratrol Yu et al. (2003b)
CYP2C19 Inducer Ginkgo Etheridge et al. (2007), Gaudineau et al. (2004), Moltke
et al. (2004) and Sugiyama et al. (2004b)
Inhibitor Resveratrol Yu et al. (2003b)
CYP2D6 Inducer Valerian Hellum et al. (2007) and Vale (1998)
Inhibitor Aloe vera Djuv and Nilsen (2012)
Substrate Goldenseal Gurley et al. (2005, 2008)
CYP3A4 Inducer Danshen Qiu et al. (2010, 2008)
Ginseng (panax) Malati et al. (2012)
St. John’s wort Goey et al. (2014)
Turmeric Hou et al. (2007) and Sugiyama et al. (2006)
Goldenseal Beckert et al. (2007), Budzinski et al. (2000, 2007),
Chatterjee and Franklin (2003)
Inhibitor Andrographis Ooi et al. (2011)
Elder Langhammer and Nilsen (2014)
Aloe vera Djuv and Nilsen (2012)
Isoflavones (puerarin) Guo et al. (2014)
Substrate Rooibos Matsuda et al. (2007)
Echinacea Gilbert (1997), Gorski et al. (2004), and Rowin and Lewis (1996)

Furthermore, an increasing percentage of the public is particular, many people often take herbal remedies with
taking herbs, often without their physician’s knowledge. oral hypoglycemic agents without sufficient caution.
Therefore, it is important for clinical practitioners, herb- However, coadministered herbs may alter the pharmaco-
alists, and patients to understand the nature of herb–drug kinetic profile of hypoglycemic agents or potentiate/
interactions to avoid any undesirable side effects cause by antagonize their pharmacological effects, and thus lead to
coadministration of herbal medicines and drugs. side effects resulting from failure to regulate blood sugar
Diabetes mellitus (diabetes) is a group of chronic met- levels. These risks are particularly serious due to the long-
abolic diseases characterized by high blood sugar levels term nature of therapy for diabetic patients. Therefore, this
over a prolonged period. Untreated diabetes can cause paper reviewed herb–drug interactions involving antidia-
many complications, which range from acute effects such betic drugs, with a focus on mechanisms, clinical evidence,
as diabetic ketoacidosis and nonketotic hyperosmolar coma importance, and management strategies.
to more serious complications such as heart disease, stroke,
kidney failure, foot ulcers, and damage to the eyes (Walker
et al. 2013). Therefore, continuous management of blood Mechanisms of herb–drug interactions
sugar levels is important in patients with diabetes, and such
control can be achieved through diet, exercise, and use of The basic concept of interaction is that consumption of two
appropriate medications with insulin injections or oral an- substances (herbs, drugs, nutrients, foods) at the same time,
tidiabetics. As the number of people with diabetes increa- or within a short time, will result in physiological effects
ses, so does the number of those who try alternative means that are different from a simple summation of the effects of
to manage the disease, including the use of herbs. In either substance alone.

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Interactions between herbs and antidiabetics

Overlapping substrate specificity in the biotransforma- taken together. Such products include aloe gel, flaxseed,
tional pathways of physiological systems is seen as the marshmallow, psyllium, and rhubarb (Samson 1982).
major reason for drug–drug, food–drug, and herb–drug These herbals can bind to drugs and prevent absorption,
interactions (Marchetti et al. 2007). The ability of different and thus reduce systemic availability. Drug displacement
chemical moieties to interact with receptor sites and alter of highly protein-bound drugs by other compounds may
the physiological environment can explain pharmacody- result in increased activity of the displaced drug. Although
namic drug interactions, while pharmacokinetic interac- displacement of protein-bound drugs has been described as
tions arise from altered absorption and interference in a source for potential drug interactions, there are no doc-
distribution patterns, as well as changes in, and competition umented reports of herb–drug interactions attributable to
for, metabolic and excretory pathways (Izzo and Ernst displacement of drugs from protein-binding sites (Wang
2009). It is therefore convenient to consider separately the and Chou 2010). Altered renal clearance is another
mechanisms involved in pharmacokinetic and pharmaco- potential mechanism underlying herb–drug interactions, in
dynamic interactions. which herbal products capable of interacting with renal
functions alter renal drug elimination. Changes in renal
Pharmacokinetic herb–drug interactions function can result from inhibition of tubular secretion,
tubular reabsorption, or glomerular filtration (Isnard Bagnis
The major underlying mechanisms of pharmacokinetic et al. 2004). Herbal products consumed as diuretics are
drug–herb interaction, as with drug–drug interaction, are often capable of altering renal function, but their mecha-
the induction and inhibition of intestinal and hepatic met- nisms of herbal diuresis are complex and non-uniform.
abolic enzymes such as those of the CYP enzyme family, Some herbs increase the glomerular filtration rate, but do
as well as drug transporters and efflux proteins (Meijerman not stimulate electrolyte secretion, while others act as
et al. 2006; Yoo et al. 2007; Nowack 2008; Yoo et al. direct tubular irritants (Al-Ali et al. 2003; Crosby et al.
2008). In particular, the pre-systemic activity of CYP 2001). Thus, herbs that can interfere with the renal clear-
enzymes often influences oral bioavailability of drugs, thus ance of a drug should be considered to have the potential to
the modulating activity of co-administered herbal products produce pharmacokinetic herb–drug interactions (Wang
on CYP function has been shown to result in pronounced and Chou 2010), and representative examples are discussed
changes in the blood levels of the affected drugs (Brown below.
et al. 2008). In vitro assessments with allicin, fresh garlic, or com-
The CYP system is a family of monooxygenase mercially prepared garlic supplements showed that they
enzymes mainly found in intestinal and liver cells that had modest inhibitory activities (\50 %) against human
catalyzes several phase I metabolic processes, including CYP2C9, CYP2C19, and CYP3A4 isoforms (Foster et al.
oxidation, hydroxylation, S-and O-demethylation, and 2001; Zou et al. 2002; Kim et al. 2012). It has been well
oxidative deamination of more than 70 % of prescription established that St. John’s wort (SJW) can modulate CYP
drugs (Karyekar et al. 2002). The CYP superfamily is subfamilies 2C and 3A, as well as several ABC efflux
involved in biotransformation of a wide range of xenobi- transporters (Kober et al. 2008; Madabushi et al. 2006;
otics and endogenous compounds (Hiratsuka 2012; Nebert Whitten et al. 2006; Zhou and Lai 2008). More than 70 %
and Russell 2002). CYP enzymes belonging to families 1, of all prescription medications are susceptible to SJW-
2, and 3 are principally involved in xenobiotic metabolism, mediated interactions, the consequences of which include
while others play a major role in the formation and elim- decreased oral bioavailability, enhanced systemic clear-
ination of endogenous compounds such as hormones, bile ance, and reduced drug efficacy (Williamson et al. 2013).
acids, and fatty acids (Amacher 2010; Norlin and Wikvall Ginkgo biloba has a modest inhibitory effect on CYP
2007). The most important CYP enzymes responsible for activity (Smith et al. 2001; Sun et al. 2002; Uchida et al.
drug metabolism in humans are CYP1A2, CYP2A6, 2006; Fan et al. 2009a, b), and induces expression of
CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A4 (Jiang et al. 2006), CYP2C9 (Greenblatt et al.
CYP3A5 (Ono et al. 1996; Boullata 2005). Because some 2006), and CYP2C19 (Yin et al. 2004). In vitro, a Devil’s
herbs and drugs may be substrates of the same CYP iso- claw (genus Harpagophytum) extract moderately inhibited
enzymes, they may inhibit or induce the activity of these the activity of CYP2C8, CYP2C9, CYP2C19, and
CYP isoenzymes when ingested concomitantly (Wang and CYP3A4 (Unger and Frank 2004).
Chou 2010; National Institutes of Health Office of Dietary
Supplements 2013). The important CYP subfamilies and Pharmacodynamic herb–drug interactions
herbs on which they act are shown in Table 1.
Absorption of drugs can be impaired when herbs that Some constituents from herbs may act on identical drug
contain hydrocolloidal fibers, gums, and mucilage are target molecules (e.g. receptors or enzymes), resulting in

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S. Rehman et al.

synergistic or antagonistic herb–drug interactions (Asdaq Thus, this patient group is at an increased risk of harmful
and Inamdar 2010; Dasgupta et al. 2010; Van den Bout-van drug–drug interactions and herb–drug interactions.
den Beukel et al. 2008; Kim et al. 2010; Nivitabishekam Based on both in vitro and pharmacogenetic data, DDIs
et al. 2009). Synergistic or additive (enhanced) effects may and HDIs involving oral antidiabetics and the main CYP
lead to toxicity and complicate the dosing regimens of enzymes, including CYP2C8, CYP2C9, CYP2C19, and
long-term medications, while antagonistic interactions may CYP3A4, have been identified. This indicates the need for
result in decreased efficacy and therapeutic failure (Ma increased understanding of the effects of many clinically
et al. 2009). important HDIs on the pharmacokinetics of oral antidia-
betics. Available clinical and experimental evidence shows
that pharmacodynamic interactions are also a major class
Synergistic or additive interactions
of herb–antidiabetics interactions.
An herb might produce the same effect as a drug and thus
enhance this effect upon coadministration (Kang and Park
Antidiabetic–herb interactions
2010; Scott and Elmer 2002; Williamson et al. 2013).
Therefore, herbal sedatives, anticoagulants, antihyperten-
The most common interactions of herbs with antidiabetic
sives, and other drugs could increase the effects of con-
drugs are those that result in a rise or fall in blood glucose
ventional drugs taken simultaneously for the same purpose.
levels, thereby disturbing the control of diabetes. Antidia-
For example, additive blood-glucose-lowering effects are
betic drugs that have been found to have a probability of
produced when agrimony extract is taken with anti-dia-
interacting with coadministered herbal products include
betics (Gray and Flatt 1998; Swanston et al. 1990). The
CYP2C8 substrates pioglitazone, repaglinide, and rosiglit-
hypnotic activity of benzodiazepines is increased by vale-
azone; CYP2C9 substrates glibenclamide, glimepiride,
rian, and the anticoagulant action of warfarin is enhanced
glipizide, nateglinide, and rosiglitazone; CYP2C19 sub-
by gingko, garlic, and ginger (Kuhn 2002; Scott and Elmer
strate proguanil; and CYP3A4 substrates pioglitazone and
2002; Fetrow et al. 1999).
repaglinide (Bertram 2012; Anthony and Gregory 2014).
Herb–drug interactions related to antidiabetic drugs are
Antagonistic interactions summarized in Table 2. The herb–drug interactions of
several selected herbs are described in detail below.
An herb might produce an effect that is contrary to the
effect desired by a coadministered drug, thereby reducing Aloe vera
the effect of the drug (Scott and Elmer 2002; Williamson
et al. 2013). Ephedra or caffeine-containing herbs (cola nut, In diabetic patients, treatment with A. vera has been shown
guarana, mate, green tea), often used in combination to to cause significant reduction in blood glucose and blood
produce additive cardiovascular effects in many herbal pressure, as well as to improve the lipid profile (Choudhary
weight-loss products, may antagonize the effects of anti- et al. 2014). Due to its hypoglycemic nature, A. vera
hypertensive medications (Scott and Elmer 2002; Wil- interacts with anti-diabetics.
liamson et al. 2013).
Diabetes is a growing epidemic that affected more than Evidence of herb–drug interaction
350 million people worldwide in 2011, and its prevalence
is expected to increase to approximately 550 million by In obese individuals with prediabetes or early untreated
2030 (Whiting et al. 2011). The pharmacological treatment diabetes mellitus, treatment with an A. vera gel complex
of hyperglycemia in patients with type 2 diabetes mellitus reduced the body weight, body fat mass, and insulin
(T2DM) is usually initiated with oral antidiabetic drug resistance (Choi et al. 2013). Diabetic patients treated with
monotherapy, but combination therapy with different oral A. vera juice with or without glibenclamide showed
antidiabetics or parenteral therapy with insulin may be reduced blood-glucose levels (Bunyapraphatsara et al.
needed as the disease progresses. Moreover, to reduce 1996; Yongchaiyudha et al. 1996). Yagi showed a possible
cardiovascular morbidity and mortality, multitargeted effect of long-term ingestion of A. vera gel metabolites on
treatment, including antihypertensive, lipid-lowering, and insulin sensitivity (Yagi 2014). In high-fat diet-induced
antiplatelet drugs, is often employed in T2DM patients mice, 3 weeks of treatment with aloesin and aloesinol
(Gaede et al. 2008). Owing to different comorbidities, decreased plasma insulin levels by 37.9 and 46.7 %,
T2DM patients are often treated with multiple medications respectively. In diabetes (db/db) mice, a chromone-stan-
in a practice referred to as polypharmacotherapy, which is dardized aloe-based composition decreased fasting tri-
especially common in the elderly (Caughey et al. 2010). glyceride and plasma glucose levels by 33.7 and 46.0 %,

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Interactions between herbs and antidiabetics

Table 2 Herb–drug interactions related to antidiabetic drugs


Interacting Herb–drug Mechanism type Possible interacting antidiabetic References
herb interactions severity drugs
(Williamson et al.
2013)

Aloe vera ??? Pharmacokinetics (CYP3A4) Pioglitazone, repaglinide Djuv and Nilsen (2012) and
Pharmacodynamics (enhancement Tseng-Crank et al. (2013)
in adipose tissue insulin signaling
pathway)
Andrographis ?? Pharmacokinetics (Inhibit Glibenclamide, glimepiride, Pan et al. (2011a, b), Ooi et al.
paniculata CYP2C9, CYP2C19, CYP2D6, glipizide, nateglinide, (2011) and Yu et al. (2003a)
CYP3A4) rosiglitazone, pioglitazone,
Pharmacodynamics (glucose repaglinide
transporter (GLUT4))
Cassia ? Pharmacokinetics (inhibit CYP Glibenclamide, glimepiride, Appiah-Opong et al. (2008)
1A2, 2C9, 2D6 and 3A4) glipizide, nateglinide,
Pharmacodynamics (inhibit the rosiglitazone, pioglitazone,
glucose absorption from the small repaglinide
intestine)
Ginseng ?? Pharmacokinetics (CYP3A4) Pioglitazone, repaglinide Anderson et al. (2003), Liu
Pharmacodynamics (stimulate and et al. (2013a) Sen et al.
increase in insulin action and (2013), Sun et al. (2014) and
secretion; decrease in b-cell Kim et al. (2012)
mass)
Karela ?? Pharmacokinetics (CYP, through Glibenclamide, glimepiride, Appiah-Opong et al. (2008),
CYP2C9 and glutathione glipizide, nateglinide, Raza et al. (1996, 2000) and
S-transferase) rosiglitazone Raman and Lau (1996)
Pharmacodynamics (insulin-like
effects and stimulate insulin
secretion)
Lycium ?? Pharmacokinetics (improve glucose Glibenclamide, glimepiride, Zhao et al. (2005), Lam et al.
transport, CYP2C9 inhibitor) glipizide, nateglinide, (2001) and Williamson et al.
Pharmacodynamics (improving rosiglitazone (2013)
GLUT4 trafficking and
intracellular insulin signaling)
St. John’s ?? Pharmacokinetics (CYP 1A2, 2C9, Glibenclamide, glimepiride, Hruska et al. (2005) and Goey
wort 2C19, 2D6 and 3A4; Activator of glipizide, nateglinide, et al. (2014), Obach (2000),
the pregnane X receptor) rosiglitazone, pioglitazone, Xu et al. (2008), Moore et al.
Pharmacodynamics repaglinide (2000), Menegazzi et al.
(2008), and Richard et al.
(improving beta-cell function and
(2012)
survival; inhibitors of
adipogenesis of 3T3-L1 cells)
1
For interactions that are not considered to be of clinical significance, or where no interaction occurs
11
For interactions where there is doubt about the outcome of concurrent use, and therefore it may be necessary to give patients some guidance
about possible adverse effects, and/or consider some monitoring
111
For interactions where there is a potentially hazardous outcome, but where, perhaps, the data is poor and conclusions about the interaction
are difficult to draw

respectively, after 10 weeks of oral treatment (Yimam Mechanism


et al. 2013). Similarly, enhanced improvement in plasma
insulin levels and a statistically significant reduction in The metabolites of aloe polymannose, such as a man-
triglyceride levels were observed in animals treated with nooligosaccharide and short chain fatty acids, synergisti-
the same chromone-standardized aloe-based composition cally modulate insulin sensitivity in tissues with a
(Yimam et al. 2014). combination of phenolics, such as aloesin, aloe emodin,

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S. Rehman et al.

and salicylate (Yagi 2014). Nutrigenomic studies were Mechanism


conducted to elucidate the mechanism of the hypoglycemic
and insulin-sensitizing effects of A. vera, and the results Potentially additive pharmacological effects are present.
showed that A. vera reduced hepatic fat accumulation and Andrographolide enhanced the uptake of radioactive glu-
enhanced insulin signaling in adipose tissue. This study cose in the isolated soleus muscle of STZ-diabetic rats in a
provided a mechanistic explanation for the in vivo effects concentration-dependent manner. Moreover, mRNA and
of enhanced insulin sensitivity and decreased blood glu- protein levels of the glucose transporter 4 (GLUT4) in
cose in mouse diabetes and prediabetes models (Tseng- soleus muscle were increased after repeated intravenous
Crank et al. 2013). Moreoever, A. vera was found to exert administration of andrographolide for 3 days (Yu et al.
inhibitory effects on CYP3A4 and CYP2D6 (Djuv and 2003a).
Nilsen 2012). Antidiabetic drugs pioglitazone and repa- Andrographis paniculata ethanolic extract also resulted
glinide are substrates of CYP3A4. in significantly lower levels of thiobarbituric acid-reactive
substances in the liver and kidney in comparison with
vehicle-treated rats, while significantly increasing the
Importance and management
activity of superoxide dismutase and catalase enzymes, as
well as hepatic glutathione concentrations, in diabetic rats
Aloe vera could be used to facilitate the maintenance of
(Zhang and Tan 2000). Ethanolic and methanolic extracts
healthy blood glucose levels (Yimam et al. 2013), and it is
of A. paniculata showed potent inhibitory effects on
clear that some oral preparations of A. vera might have
CYP3A4 and CYP2C9 activities (Ki values below 20 lg/
clinically important blood-glucose-lowering effects.
mL) (Pan et al. 2011a). The diterpenoids andrographolide
Indeed, A. vera has traditionally been used to treat diabetes.
and 14-deoxy-11,12-didehydroandrographolide reduced
It might therefore be prudent to increase the frequency of
the mRNA and protein levels of CYP2D6 and CYP3A4
blood-glucose monitoring if patients taking antidiabetic
(Ooi et al. 2011). Andrographis paniculata inhibited
medication wish to try oral A. vera preparations (Wil-
CYP2C19 activity (Pan et al. 2011b). Glibenclamide,
liamson et al. 2013).
glimepiride, glipizide, nateglinide, and rosiglitazone are
substrates of CYP2C9, and pioglitazone and repaglinide
Andrographis paniculata
are substrates of CYP3A4.
Andrographis paniculata is an herb that is commonly used
Importance and management
by diabetic patients (Reyes et al. 2006). Due to its hypo-
glycemic nature, it interacts with conventional anti-
These experimental studies provide limited evidence of the
diabetics.
possible blood-glucose-lowering properties of Androgra-
phis. Furthermore, because of the nature of the evidence,
Evidence of interaction applying these results in a clinical setting is extremely
difficult. However, if a patient taking antidiabetic drugs
Experimental evidence shows that water extract of A. wishes to take A. paniculata, it may be prudent to discuss
paniculata significantly prevents orally administered glu- these potential additive effects (Williamson et al. 2013).
cose-induced hyperglycemia in nondiabetic rabbits without
affecting epinephrine-induced hyperglycemia (Borhanud- Cassia
din et al. 1994). Ethanolic extract of A. paniculata
administered orally twice daily for 14 days to streptozo- Cassia fistula and Cassia occidentalis are ethnomedicinal
tocin-induced diabetic rats significantly reduced fasting plants that are widely used in Indian and Chinese medicine
serum glucose and increased body weight in a dose- to treat diabetes.
dependent manner (Zhang and Tan 2000). Andrographo-
lide at the effective dose (1.5 mg/kg) significantly attenu- Evidence of interaction
ated the increase in plasma glucose induced by an
intravenous glucose challenge test in normal rats. This Wild leguminous seeds of C. fistula were investigated by
result suggests that andrographolide can increase glucose Singh and Bharadwaj for their hypoglycemic activity, and
utilization to lower plasma glucose in diabetic rats lacking were found to have marked hypoglycemic activity in nor-
insulin (Yu et al. 2003a). According to Reyes et al., the mal albino rats, but not in alloxan-induced diabetic albino
anti-diabetic potential of A. paniculata was demonstrated rats (Singh and Bharadwaj 1975). Nirmala et al. (2008)
by its restoration of impaired estrous cycle in alloxan- reported the hypoglycemic and hypocholesterolemic
induced diabetic rats (Reyes et al. 2006). effects of the hexane extract of stem bark of C. fistula in

123
Interactions between herbs and antidiabetics

normal and streptozotocin induced diabetic rats, and found and anti-obesity effects by improving sensitivity to insulin
that the effect of the extract at 0.45 g/kg was found to be and leptin in KK-Ay mice. Rb1 may be the primary
comparable with that of glibenclamide, the reference drug. hypoglycemic component of PNS extract (Zhong et al.
The antioxidant and polyphenol contents of the extracts 2014). Due to their hypoglycemic nature, ginseng constit-
might contribute to their antihyperglycemic and antilipi- uents interact with conventional anti-diabetics.
demic properties (Nirmala et al. 2008). Acute and chronic
oral dosing of aqueous bark extract of C. fistula in nor- Interaction evidence
moglycemic and streptozotocin-induced diabetic rats sig-
nificantly lowered fasting blood glucose levels and rapidly Twelve weeks of supplementation with a selected Korean
caused marked improvement in the oral glucose tolerance ginseng treatment safely maintained good glycemic con-
test (Ratnasooriya et al. 2004). Cassia occidentalis exhib- trol, improved plasma glucose levels, and enhanced plasma
ited significant antihyperglycemic activity in normal and insulin regulation beyond that achieved by normal therapy
alloxan-induced diabetic rats. The antidiabetic activity of in people with well-controlled type 2 diabetes. Further
C. occidentalis may be due to the presence of flavonoids investigation with similarly selected Korean ginseng
(Malpani et al. 2010). treatments may support their clinical efficacy (Vuksan
et al. 2008).
Mechanism In a study of nondiabetic subjects, no differences were
found in postprandial glycemia between those treated with
Aqueous bark extract significantly inhibited glucose placebo and ginseng when these compounds were admin-
absorption from the small intestine and induced glycogen istered together with a glucose challenge. When ginseng
accumulation in liver and skeletal muscle (Ratnasooriya was taken 40 min before the glucose challenge, significant
et al. 2004). Catechin from C. fistula possesses hypogly- reductions were observed. Thus, for nondiabetic subjects,
cemic, glucose oxidizing, and insulin mimetic activities to prevent unintended hypoglycemia it may be important
(Daisy et al. 2010). Cassia inhibited the enzyme activities that Panax quinquefolius (American ginseng; AG) be taken
of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (Appiah- with a meal (Vuksan et al. 2000a). Two-way analysis of
Opong et al. 2008). Glibenclamide, glimepiride, glipizide, variance (ANOVA) demonstrated that treatment (0, 3, 6,
nateglinide, and rosiglitazone are substrates of CYP2C9, and 9 g AG), but not time of administration (120, 80, 40, or
and pioglitazone and repaglinide are substrates of 0 min before the glucose challenge), significantly affected
CYP3A4. postprandial glycemia, with significant interaction for area
under the curve (AUC). Therefore, it was concluded that
Importance and management AG reduced postprandial glycemia irrespective of dose and
time of administration (Vuksan et al. 2000b). AG taken at
Findings from animal studies indicate that C. fistula and C. different times did not have an additional influence on
occidentalis extract possess antihyperglycemic properties, postprandial glycemia. In nondiabetic individuals, 3, 6, or
and these results lend credence to the traditional ethno- 9 g of AG taken 40, 80, or 120 min before a glucose
medical uses of the plant in the management of T2DM (Ali challenge similarly improved glucose tolerance (Vuksan
et al. 2012). Due to the antidiabetic properties of C. fistula et al. 2000c). AG also showed enhanced antioxidative and
and C. occidentalis, their combination with conventional antihyperglycemic effects. In another study, glycogen and
antidiabetics requires proper caution and careful manage- high density lipoprotein (HDL) content were significantly
ment. Furthermore, coadministration of CYP substrate increased, while levels of plasma cholesterol and low
antidiabetic drugs with C. fistula and C. occidentalis may density lipoprotein (LDL) were significantly decreased, in
lead to herb–drug interactions. the AG-treated group (Yoo et al. 2012).
Sen et al. investigated the effects of North American
Ginseng ginseng (NAG) root extract on type 1 and type 2 diabetes
and the mechanisms underlying such effects. NAG reduced
Ginsenosides are major bioactive constituents of ginseng blood glucose and glycated hemoglobin levels in the
that are thought to be the main components responsible for groups with type 1 and type 2 diabetes NAG (Sen et al.
its antidiabetic effect (Xiong et al. 2010). Some ginseno- 2013).
sides, such as Rb1, Rb2, Rc, Re, Rg3, Rh2, and compound Intraperitoneal injection of an aqueous extract of the
K have been shown to possess anti-diabetic activities crude drug ‘‘shigoka’’ (Siberian ginseng) remarkably
(Xiong et al. 2010; Cho et al. 2006; Lai et al. 2006; Lee diminished plasma glucose levels in mice. Activity-guided
et al. 2006, 2010; Kim et al. 2009; Li et al. 2012). Panax fractionation of the extract yielded seven glycans (eleu-
notoginseng saponins (PNS) produced anti-hyperglycemic therans A, B, C, D, E, F, and G) that exerted marked

123
S. Rehman et al.

hypoglycemic effects in normal and alloxan-induced controlled with karela curry, provides some evidence that the
hyperglycemic mice (Hikino et al. 1986). Malonyl ginse- blood glucose-lowering effect of karela and conventional oral
nosides (MGR) are natural ginsenosides found in both fresh anti-diabetics can be additive (Aslam and Stockley 1979).
and air-dried ginseng. Administration of MGR to high fat Karela produces significant improvement in glucose tolerance
diet/streptozotocin diabetic rats significantly reduced fast- in patients with T2DM when they were taking chlorpropamide
ing blood glucose levels, improved glucose tolerance, and (Leatherdale et al. 1981), tolbutamide (Leatherdale et al. 1981),
enhanced insulin sensitivity, without affecting body weight glibenclamide (Leatherdale et al. 1981; Tongia et al. 2004),
(Liu et al. 2013b). glymidine (Leatherdale et al. 1981) or metformin (Tongia et al.
2004), as well as when they are not taking antidiabetics (Akhtar
Mechanism 1982; Srivastava et al. 1993; Welihinda et al. 1986). However,
one randomized study showed no significant effect on glycated
Data indicate that NAG may produce a protective effect hemoglobin (HbA1c) and no change in FBG (Dans et al. 2007).
against diabetes through regeneration of b-cells, which A case report on two young non-diabetic children reported
results in enhanced insulin secretion (Sen et al. 2013). hypoglycaemic coma and seizures after they were given karela
Treatment with ginseng polysaccharides resulted in a sig- tea (Hulin et al. 1988). In an experiment with rats, the combi-
nificant decrease in serum malondialdehyde levels and sig- nation of an alcoholic extract of karela with 2 or 5 mg/kg ros-
nificant increases in serum insulin, superoxide dismutase iglitazone caused a greater reduction in serum glucose levels
activity, and hepatic glycogen content, and these mecha- than either dose of rosiglitazone alone (Nivitabishekam et al.
nisms may underlie the anti-diabetic activity of intra-gastric 2009). The blood glucose-lowering effects of karela may be due
ginseng polysaccharides (Sun et al. 2014). Ginseng poly- to its bioactive constituent polypeptide P (Khanna et al. 1981),
saccharides affect fasting blood glucose levels by stimulat- which is effective when administered subcutaneously (Baldwa
ing insulin secretion to promote glycogen synthesis (Lee et al. 1977). However, the oral activity of polypeptide P is not
et al. 2012). In addition, ANG increased the expression of well-characterized (Raman and Lau 1996). Other constituents
insulin and decreased the expression of uncoupling protein 2, of karela with blood glucose-lowering effects include the sterol
Bax, and poly ADP-ribose polymerase, which may be the glucoside mixture, charantin, which is found in the fruit, and the
primary targets of Korean ginseng that result in increased pyrimidine nucleoside vicine, which is found in the seeds
insulin action and secretion, decreased b-cell mass, and (Raman and Lau 1996).
normalized glucose homeostasis (Kim and Kim 2012).
Panax ginseng appeared to induce CYP3A activity in Mechanism
the liver and the gastrointestinal tract (Malati et al. 2012).
Ginseng activated CYP3A4 in vitro (Anderson et al. 2003). Karela can produce insulin-like effects and stimulate insulin
Pioglitazone and repaglinide are substrates of CYP3A4. secretion (Raman and Lau 1996), and thus has additive effect
with conventional antidiabetics. Momordica charantia
Importance and management inhibited CYP2C9 with IC50 values between 63.4 and
425.9 lg/mL (Appiah-Opong et al. 2008). Raza et al. reported
These studies show that P. ginseng, P. quinquefolius, and that changes in hepatic phase I and phase II drug-metabolizing
other species of ginseng might possess blood-glucose- enzyme activities in streptozotocin (STZ)-induced diabetic
lowering activity, but a multiple-dose study showed that animals may be associated with altered expression of CYP and
this effect was not clinically relevant in patients with well- glutathione S-transferase (GST) isozymes (Raza et al. 1996,
controlled diabetes (Jellin et al. 2014, Williamson et al. 2000). Glibenclamide, glimepiride, glipizide, nateglinide, and
2013). rosiglitazone are substrates of CYP2C9.

Karela Importance and management

The blood glucose-lowering effects of antidiabetics can be The blood glucose-lowering activity of karela appears to be
increased by Karela (Momordica charantia) (Williamson established, although the best controlled clinical study on
et al. 2013). Due to its hypoglycemic effect, Karela inter- karela found its effects to be minimal. The aqueous extract
acts with conventional anti-diabetics. powder of M. charantia, an edible vegetable, appears to be
a safe alternative blood glucose-lowering agent for diabetic
Evidence of interaction patients (Virdi et al. 2003). Health professionals should
therefore be aware that patients could be using karela, as
One report of a diabetic patient, whose diabetes was poorly well as conventional drugs, to control their diabetes (Jellin
controlled by diet regulation and chlorpropamide, but well et al. 2014; Williamson et al. 2013).

123
Interactions between herbs and antidiabetics

Lycium CYP2C8-mediated clearance of rosiglitazone after a single


administration, and the magnitude of the effect of SJW is
Plants of the genus Lycium have also been used in tradi- not influenced by CYP2C8 genotype (Hruska et al. 2005).
tional medicine as treatments for diabetes (Ahmed et al. Consumption of SJW for 14 days had no clinically sig-
2009; Muhammad et al. 2006; Tiwari et al. 2010). nificant effect on the pharmacokinetics and pharmacody-
namics of repaglinide (Fan et al. 2011). Tolbutamide
Evidence of interaction metabolism is not affected by SJW (Arold et al. 2005;
Wang et al. 2001).
Knowledge of the interaction between Lycium and antidi-
abetics is based on experimental evidence only. The extract
Mechanism
of the root bark of Lycium barbarum is known to produce
antidiabetic effects in rabbits that are associated with
SJW extract (containing hyperforin) at low concentrations
reduced blood glucose levels (Ahmed et al. 2009). Lycium
targets key mechanisms of cytokine-induced beta-cell
barbarum polysaccharides (glycoconjugates), containing
injury, thereby improving beta-cell function and survival.
several monosaccharides and 17 amino acids, are major
Thus, SJW may have value as a treatment to prevent or
bioactive constituents that produce hypoglycemic effects.
limit beta-cell loss in diabetes (Menegazzi et al. 2008).
In addition, polysaccharides and vitamin antioxidants from
Adipocytes are insulin-sensitive cells that play a major role
L. barbarum fruits may produce hypolipidemic effects
in energy homeostasis. SJW extracts inhibit adipogenesis
(Luo et al. 2004). The effects of Lycium barbarum poly-
in 3T3-L1 cells and insulin-sensitive glucose uptake in
saccharide (LBP) on improvements in insulin resistance
mature fat cells (Richard et al. 2012). Therefore, the effects
and lipid profiles were studied in a rat model of non-insulin
of SJW are additive with conventional antidiabetics.
dependent diabetes mellitus (NIDDM), and it was found
Long-term SJW administration resulted in a significant
that LBP ameliorated insulin resistance (Zhao et al. 2005).
and selective induction of CYP3A activity in the intestinal
wall (Wang et al. 2001). The SJW constituent hyperforin
Mechanism
activates the pregnane X receptor (PXR) (Moore et al.
2000), which results in increased transcription of CYP3A4
The antidiabetic mechanism of Lycium may involve
and the drug efflux transporter ABCB1 (P-glycoprotein)
increasing levels of GLUT4 at the cell surface, improving
(Hruska et al. 2005). Induction of CYP3A4 and/or ABCB1
GLUT4 trafficking, and enhancing intracellular insulin
increases the metabolism and excretion of drug substrates,
signaling (Zhao et al. 2005). Lycium appears to reduce
eventually leading to decreased systemic exposure and
blood-glucose levels by improving glucose transport and
possibly decreased therapeutic efficacy (Goey et al. 2014).
increasing insulin signaling; therefore, these effects may be
Several in vitro experiments with components of SJW
additive with conventional antidiabetics (Williamson et al.
extracts showed that hyperforin and hypericin influenced
2013). In vitro studies suggest that Lycium may be a weak
enzyme activity differently. Hyperforin markedly inhibited
inhibitor of CYP2C9 (Lam et al. 2001).
the activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6,
and CYP3A4, whereas hypericin inhibited CYP2D6 only
Importance and management
(Obach 2000). Gliclazide is a substrate of CYP2C9, and the
authors suggest that SJW induces this enzyme, thereby
The limited experimental evidence suggests that lycium
increasing the metabolism of gliclazide and reducing its
may have antidiabetic properties, and this finding is sup-
systemic exposure (Xu et al. 2008). Other substrates of
ported by the traditional use of Lycium to treat diabetes.
CYP2C9 include glibenclamide, glimepiride, glipizide,
Therefore, there is a theoretical possibility that lycium may
nateglinide, and rosiglitazone. Pioglitazone and repaglinide
enhance the blood-glucose-lowering effects of conven-
are substrates of CYP3A4.
tional antidiabetics (Williamson et al. 2013).

St. John’s wort Importance and management

Evidence of interaction As mentioned above, SJW extract inhibits CYP2C9 and


CYP3A4. Therefore, conventional antidiabetics that are
Treatment with SJW significantly increases the apparent substrates of CYP2C9 and CYP3A4 have significant
clearance of gliclazide and modestly decreases the glicla- pharmacokinetic interactions with SJW. Glibenclamide,
zide AUC, and this effect is independent of CYP2C9 glimepiride, glipizide, nateglinide, and rosiglitazone are
genotype (Xu et al. 2008). SJW also significantly increases substrates of CYP2C9, whereas pioglitazone and

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S. Rehman et al.

Table 3 Micellaneous herbs Interacting Herb–drug Mechanism type References


which may cause interactions herb interactions
with antidiabetic drugs severity
(Williamson
et al. 2013)

Agrimony ?? Pharmacodynamics (insulin-releasing and Ahn et al. (2011), Gray


insulin-like activity) and Flatt (1998) and
Swanston et al. (1990)
Alfalfa ?? Pharmacodynamics (stimulation of insulin Gray and Flatt (1997)
secretion from the BRIN-BD11)
? Cocoa ?? Pharmacodynamics (improve insulin signaling Cordero-Herrera et al.
For interactions that are not
and modulate glucose uptake) (2013)
considered to be of clinical
significance, or where no Coffee ?? Pharmacodynamics (improve glucose tolerance Van Dam et al. (2004)
interaction occurs and metabolism) and Van Dam (2006)
?? Elder ?? Pharmacodynamics (enhance insulin secretion, Gray et al. (2000) and
For interactions where
there is doubt about the outcome increased 2-deoxy-glucose transport, glucose Williamson et al. (2013)
of concurrent use, and therefore oxidation and glycogenesis)
it may be necessary to give Fenugreek ?? Pharmacodynamics (affecting an insulin Williamson et al. (2013)
patients some guidance about signaling pathway)
possible adverse effects, and/or Flaxseed ?? Pharmacodynamics (increase in liver glucose- Dusane and Joshi (2013)
consider some monitoring 6-phosphate dehydrogenase enzyme activity
???
For interactions where and normal glycogenesis, and formation of
there is a potentially hazardous new islets)
outcome, but where, perhaps, Holy basil ?? Pharmacodynamics (stimulate and activate Narendhirakannan et al.
the data is poor and conclusions insulin) (2006) and Hannan
about the interaction are et al. (2006)
difficult to draw

repaglinide are substrates of CYP3A4. Actos, a maker of Ingredients derived from herbs or other natural sources
pioglitazone, recommends caution when prescribing piog-
litazone with drugs that induce CYP2C8 (Actos, Summary This part deals with possible interactions between several
of product characteristics 2011; Komoroski et al. 2005; representative ingredients from herbs or natural products
Williamson et al. 2013). The concurrent use of SJW should and antidiabetic drugs, which are summarized in Table 4.
be monitored when patients are also given antidiabetic
drugs that are substrates of CYP2C8, CYP2C9, or Glucosamine
CYP3A4. Treatment with SJW significantly increases the
apparent clearance of gliclazide, and this effect is inde- Evidence of interaction A study by Scroggie et al. pro-
pendent of CYP2C9 genotype. People with diabetes vided evidence that glucosamine-chondroitin supplemen-
receiving this combination should be closely monitored to tation (glucosamine hydrochloride 1.5 g daily with
evaluate possible signs of reduced efficacy (Xu et al. 2008). chondroitin sulfate sodium 1.2 g daily) for 90 days in
osteoarthritis patients with diabetes does not pose a sig-
Miscellaneous herbs nificant risk of worsening glycemic control in the form of
elevated hemoglobin A1c levels (Scroggie et al. 2003). In
Numerous herbs have been traditionally used for the 2000, the Canadian Adverse Drug Reaction Monitoring
treatment of diabetes in addition to those described above, Programme (CADRMP) reported that unexpected increases
including agrimony, alfalfa, cocoa, coffee, elder, fenu- in blood-glucose levels had occurred in diabetic patients
greek, flaxseed, and holy basil (Table 3). These herbs may taking glucosamine sulfate or glucosamine with chondroi-
lead to pharmacodynamic interactions when they are co- tin (Persiani et al. 2009). In one case study, glucosamine
administered with antidiabetic therapeutic drugs due to was reported to reduce hypoglycemic episodes in a patient
their antidiabetic effects, but there is limited clinical and with metastatic insulinoma (Chan et al. 2001).
experimental evidence regarding such interactions. There-
fore, caution should be paid to possible drug interactions Mechanism Endogenous glucosamine plays a role in
between these herbs and antidiabetic drugs in the context of glucose metabolism and may increase insulin resistance.
diabetic control. The lack of a negative impact of glucosamine on glycemic

123
Interactions between herbs and antidiabetics

Table 4 Ingredients derived from herbs or other natural sources which may cause interactions with antidiabetic drugs
Interacting Herb–drug Mechanism type Possible interacting References
herb interactions antidiabetic drugs
severity
(Williamson
et al. 2013)

Glucosamine ??? Pharmacodynamics (glucose metabolism, No specification Chan et al. (2001) and
increase insulin resistance; endogenous insulin Jain and McCormick
secretion in response to a possible increase in (2004)
insulin resistance)
Isoflavones ?? Pharmacokinetics (CYP2C9 and CYP3A4) Glibenclamide, glimepiride, Guo et al. (2014), Chen
Pharmacodynamics (activate a1-adrenoceptors to glipizide, nateglinide, et al. (2004), Hsu et al.
enhance the secretion of b-endorphin, decrease rosiglitazone, pioglitazone, (2003) and Fu et al.
of plasma glucose; increased glucose repaglinide (2006)
transporter (GLUT4), and preventing islet cells)
Levocarnitine ?? Pharmacokinetics (CYP2C9 and CYP3A4) Glibenclamide, glimepiride, Guo et al. (2014) and
Pharmacodynamics (depressed in the insulin glipizide, nateglinide, Mingrone et al. (1999)
resistant by activation of pyruvate rosiglitazone, pioglitazone,
dehydrogenase) repaglinide
?
For interactions that are not considered to be of clinical significance, or where no interaction occurs
??
For interactions where there is doubt about the outcome of concurrent use, and therefore it may be necessary to give patients some guidance
about possible adverse effects, and/or consider some monitoring
???
For interactions where there is a potentially hazardous outcome, but where, perhaps, the data is poor and conclusions about the interaction
are difficult to draw

control may be due to increased insulin resistance (Jellin dose-dependent manner in STZ-induced diabetic rats. In
et al. 2014). this study, puerarin at a dose of 15.0 mg/kg significantly
attenuated the increase in plasma glucose induced by an
Importance and management The effect of glucosamine intravenous glucose challenge in normal rats. In the iso-
on glycemic control in patients at an early stage in the lated soleus muscle of STZ-induced diabetic rats, puerarin
course of diabetes may be explained by a compensatory enhanced the uptake of radioactive glucose in a concen-
increase in endogenous insulin secretion in response to a tration-dependent manner. Moreover, mRNA and protein
possible increase in insulin resistance. These results may levels of GLUT4 in soleus muscle were increased after
not hold true in patients in a later stage of the disease, who repeated intravenous administration of puerarin in STZ-
may lack the ability to compensate for the effects of glu- induced diabetic rats for 3 days (Hsu et al. 2003).
cosamine because of their inability to increase insulin
secretion. Confirmation of these results in a wider spectrum Mechanism The pharmacokinetic interactions of puerarin
of diabetic patients could validate glucosamine as an with antidiabetics in rats are mediated by its inhibitory
osteoarthritis treatment option (Jain and McCormick 2004). effects on CYP2C9 and CYP3A4 activities (Guo et al.
Therefore, it may be prudent to increase monitoring of 2014). Puerarin may also activate a1-adrenoceptors in the
blood-glucose in patients if glucosamine supplements are adrenal gland to enhance the secretion of b-endorphin
taken (Jellin et al. 2014; Williamson et al. 2013). (Chen et al. 2004). Liang et al. suggest that puerarin pro-
tects islet cells against oxidative stress by stimulating the
Isoflavones activities of antioxidant enzymes. Moreoever, puerarin
may protect islet cells from the toxic action of reactive
Evidence of interaction Knowledge of the interaction oxygen species in diabetes (Fu et al. 2006).
between isoflavones and antidiabetics is based on experi-
mental evidence only. Puerarin at a dose that lowered Importance and required management Isoflavones might
plasma glucose increased plasma b-endorphin-like immu- have additive effects when they are combined with anti-
noreactivity (BER) in STZ-induced diabetic rats (Chen diabetic drugs, and thus antidiabetic doses might need to be
et al. 2004). In another study, a bolus intravenous injection adjusted. Furthermore, due to the inhibitory effects of
of puerarin decreased plasma glucose concentrations in a puerarin rat CYP2C9 and CYP3A4 enzyme activities,

123
S. Rehman et al.

puerarin interacts with antidiabetics that are substrates of receiving insulin or oral antidiabetics might result in
these enzymes (Guo et al. 2014). Glibenclamide, glimepi- hypoglycemia, and regular monitoring of plasma glucose
ride, glipizide, nateglinide, and rosiglitazone are substrates concentrations in these patients may be required.
of CYP2C9. Pioglitazone and repaglinide are substrates of
CYP3A4.
Conclusion
Levocarnitine
As herbal therapies are increasingly being used around the
Carnitine derivatives have been tested in patients with world because they are perceived to be free of side effects,
diabetes for a variety of indications, including treatment of it is important to be aware of their possible harm and herb–
diabetic neuropathy and improvement in lipid profiles drug interactions. The solution for this trend is not to avoid
(Williamson et al. 2013), as well as to try to improve or suppress the use of herbal medicines, but rather to
insulin sensitivity. Due to its hypoglycemic effect, carni- induce rational, safe, and effective use. Furthermore, it may
tine interacts with conventional anti-diabetics. be desirable to apply safe adjunctive treatment or co-
administration of herbal medicines with prescription med-
Evidence of interaction Rahbar et al. investigated the ication in some conditions where separate use of conven-
effects of oral L-carnitine administration on fasting plasma tional drugs seems to be inappropriate. Therefore, it is
glucose (FPG), HbA1c, and lipid parameters to evaluate its necessary to educate practitioners and consumers on the
effect on insulin sensitivity and lipid profiles in subjects importance of herb–drug interactions and appropriate
with T2DM taking metformin or glibenclamide (glybu- treatment management. Ideal treatment strategies for her-
ride). In patients with T2DM, oral L-carnitine (1 g bal therapy could be achieved based on a complete bio-
administered 3 times daily for 12 weeks) significantly logical and clinical database for natural products, as well as
lowered FPG, but increased fasting triglyceride levels its standardization. However, clinical and experimental
(Rahbar et al. 2005). data on herb–drug interactions, including antidiabetic-herb
In a randomized, placebo-controlled study in patients interactions, is limited, and attention must be focused on
with T2DM not taking any antidiabetic medications, oral L- collecting and preserving clinical evidence and performing
carnitine administration (1 g administered 3 times daily experiments using animal models. Therefore, more
before meals for 4 weeks) had no effect on insulin sensi- research should be conducted to ensure rational use of
tivity or lipid profiles (Gonzalez-Ortiz et al. 2008). Con- herbal medicines both alone and in combination with
stant infusion of L-carnitine improved insulin sensitivity in conventional medicines.
insulin resistant diabetic patients, and a significant effect Owing to different comorbidities, diabetes patients are
on whole body insulin-mediated glucose uptake was often treated with multiple medications in a practice
observed in normal subjects (Mingrone et al. 1999). In referred to as polypharmacotherapy, which is especially
patients with poorly controlled diabetes taking oral antid- common in the elderly (Caughey et al. 2010). As these
iabetics or insulin, treatment with oral L-carnitine (2 g medications are used for the duration of their lives by this
daily) and either sibutramine (10 mg) or orlistat slightly patient group, they are at increased risk of harmful herb–
improved diabetic control in comparison with sibutramine drug interactions and drug–drug interactions. These inter-
or orlistat alone (Derosa et al. 2010a, b). actions could produce acute hypoglycemic/hyperglycemic
conditions that require emergency management. For these
Mechanism In diabetic patients taking L-carnitine, glu- reasons, particular attention should be paid to interactions
cose taken up by the tissues appears to be promptly utilized of herbs with anti-diabetic drugs.
as fuel, because glucose oxidation is increased during L-
carnitine administration. Significantly reduced plasma Acknowledgments This work was supported by the research fund
of Hanyang University (HY-2013-G).
levels of lactate after L-carnitine administration suggest
that this effect might be exerted through pyruvate dehy-
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