REVIEWInteractions between medicines and functional foods or
dietary supplements
Noriaki Ohnishi and Teruyoshi Yokoyama
Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University
Kyoto, Japan(Received for publication on January 7, 2004)

Abstract. Recently, the demand for supplements has steadily been increasing with the diffusion ofalternative and supplemental medicines throughout the world. Therefore, the supplements have frequently been taken with many drugs. Here, we have introduced the pharmacokinetic and pharmacological interactions between them. (Keio J Med 53 (3): 137–150, September 2004)
Key words: drug interaction, functional food, dietary supplement, cytochrome P450 (CYP), Pglycoprotein

Introduction
Recently, so-called health foods, including functional
foods and dietary supplements, are being increasingly
used world-wide as part of complementary and alternative medicine or self-medication (Fig. 1). With thisprevalence of health foods, the possibility of their concomitant use with synthetic chemicals (medicines) ingeneral has also increased (Fig. 2).1 However, there
is little information based on scientiﬁc evidence concerning the interactions between medicines and healthfoods.
Concerning mechanisms of interactions among medicines, pharmacokinetic interactions are the most frequent, and interactions in the metabolic processes are
particularly important. Most of such metabolic interactions are considered to be related to inhibition or induction of the drug metabolizing enzyme cytochrome
P450 (CYP).2 In addition, there are many isoforms of
CYP. CYP3A4, in particular, is present at high levels in
the intestines and liver, and is involved in the metabolism of about 50% of the clinically used drugs, so that
it is an isoform that needs particular attention in druginteractions.3
By setting the establishment of combination therapy using medicines and effective and safe traditional
herbal medicines as the ﬁnal goal, our laboratory has
conducted basic research on pharmacokinetic inter-actions between them in which CYP3A4 is involved. Aspart of our research accomplishments, we could demonstrate an enhancement of metabolism of carbamazepine, an antiepileptic drug and a substrate of CYP3A
after 1-week repeated oral administration of Shoseiryu-to in rats.4 We have also reported that the possibility of the occurrence of interactions among thesedrugs is small in humans.5 Moreover, we are continuing research on pharmacokinetic interactions between
medicines and various health foods (i.e., Ginkgo biloba
leaf extract, Agaricus blazei Murill extract, propolis extract, and pomegranate juice) with the same objective
as our study of traditional herbal medicines.
The Ministry of Health and Welfare (presently Ministry of Health, Labor and Welfare) announced in the‘‘Information concerning the safety of drugs and medical instruments No. 160 (May, 2000)’’ that the plasma
concentrations of various medicines that are substrates
of CYP3A are reduced with consequent reductions intheir effects by the ingestion of St. John’s wort (Seiyootogiri-so in Japanese) extract. We believe that this announcement is of profound signiﬁcance in that it urges
keen awareness of physicians, pharmacists, and nutritionists about the necessity for attention to interactions
not only among medicines but also between medicinesand health foods.
In this article, we ﬁrst explain the deﬁnition andclassiﬁcation of so-called health foods. Next, we de-Presented at the 1322nd Meeting of the Keio Medical Society in Tokyo, July 18, 2003.
Reprint requests to: Dr. Ohnishi, Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University,
5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan, e-mail: ohnishi@mb.kyoto-phu.ac.jp
137

138

Ohnishi N and Yokoyama T: Interactions between drugs and supplements

39.7

60.3

Fig. 1 Results of a questionnaire about the percentage of healthfood users in the opinion pole about health by the Tokyo Metropolitan Government. Subjects: 2,113 males and females aged 20 years andabove living in Tokyo (September, 2000). A question: Are you taking
health foods (drinking health beverages) besides conventional foods?
o, Yes; k, No.

scribe cases of interactions between medicines and St.
John’s wort or grapefruit juice, and interactions between medicines and other typical health foods and the
management of patients in case of such interactions.6
Finally, we will present part of the results of basic
research concerning pharmacokinetic interactions between medicines and health foods obtained at ourlaboratory.
Deﬁnition and Classiﬁcation of Health Foods
Most of so-called health foods are foods manufactured and sold by business enterprises claiming thatthey are ‘‘better for the health than regular foods’’.
Among those available in this country are St John’swort extract, grapefruit juice, Ginkgo biloba leaf extract, Agaricus blazei Murill extract, Phellinus linteus
Aoshima extract, propolis extract, pomegranate juice,chlorella, collagen, Curcuma Longa L., Ginseng, royaljelly, vitamins, and minerals. The Ministry of Health,
Labor and Welfare deﬁnes health foods as foods soldfor supplementation of nutritional elements or for speciﬁc health uses, composed of conventional foods, andprepared in the forms of conventional foods or tablets,and capsules. Presently, however, there is no particular
law that systematically controls or regulates healthfoods, and they are dealt with by multiple related laws
similarly to conventional foods. Also, it is well-known
that health foods cannot claim to be effective for particular indications, and they are treated as unapproved/
unauthorized medicines and are regarded as violationsof the Pharmaceutical Affairs Law once the product is
purport to have a particular effect.
The Ministry of Health, Labor and Welfare started
the ‘‘Health and Functional Foods System’’ in April,
2001, and so-called health foods came to be classiﬁed
into health-protecting or health-promoting functional
foods and health foods or supplements, which are
regarded as conventional foods. Furthermore, healthprotecting or health-promoting functional foods wereclassiﬁed into (1) conventional foods for speciﬁc healthuses (individually approved type) and (2) newly categorized nutritional functional foods (speciﬁed andstandardized type) (Fig. 3 and Table 1). Also, of theseso-called health foods, those in the forms of tablets or
capsules are categorized as dietary supplements. Many
dietary supplements that contain herbs, vitamins, andminerals are put on the market, and are used by a large
number of people.
Interactions Between Medicines and St. John’s Wort
(SJW) and Their Management

(A)
(B)
9.6
52.1
47.9
90.4

Fig. 2 Results of two questionnaires about the percentages of users
experiencing the history of concomitant intake of health foods andmedicines.1 Period, May–June, 2000; Subjects: 453 outpatients at
Tsukuba University Hospital. (A) The ﬁrst question: Have you taken
medicines prescribed by hospitals or clinics with health foods? o,Yes; k, No. (B) The second question for the persons who answered‘‘yes’’ in the ﬁrst question: Did you tell it to the physician? o, Yes; k,No.

SJW is an erect perennial plant of the family Guttiferae distributed primarily from Europe to Central
Asia. Its scientiﬁc name is Hypericum perforatum. SJW
has also been used in Europe from ancient times for
insominia and depression, and as it has recently beenreported to have an effect similar to those of existing
antidepressants,7,8 it is popular particularly in the
United States and Europe. In Japan, also, SJW is soldas a health food by many companies. SJW contains
more than 20 natural components, and hyperforin has
been shown to have the strongest antidepressant activity among them.9
Although no clinical case that suggests interaction
between SJW and medicines has been reported to datein our country, caution against the concomitant use with
SJW was added in 2000 to the precautions for use of thefollowing medicines. SJW has been reported to reduce

Keio J Med 2004; 53 (3): 137–150

139

Foods
Foods forspecificuses

So-called health foods
Functional foods

Quasi drugs

Foods forspecific
healthDrugs

Nutritionfunctional
foods

Supplementary
healthSpecifications
and standards
set by the
Ministry of
Health, Laborand Welfare(2001-)

Specifications
and standards
set bythe JHFA(1986-)

Required
to indicate:(1) that theitem is anutritionfunctional food(2) contents ofnutritional
components(3) functions(4) recommended
quantity andmethod of intake(5) warnings

Required
to indicate:(1) that theitem is a healthpromoting foodapproved by theJHFA(2) contents ofnutritional
components(3) warnings[17 components][54 food groups]

uses

Health Other
foods

foods

Required
to indicate:(1) that the item
is a food forspecific healthuse(2) contents ofnutritional
components(3) specifichealth uses
(4) recommended
quantity andmethod of intake

Foods inconventional forms

Divided into
2 groups

foods

Individually
approved by
the Ministryof Health,
Labor andWelfare(1991-)

Foods forpatients

Generalfoods

Tablets,
capsules, etc.

Required
to indicate:(1) contentsof nutritional
components

Dietary
Supplements(2) warnings(5) warnings[about 410 items]

Fig. 3 Deﬁnitions and classiﬁcation of health foods in our country (4/’04).23 Forms of drugs generally include powder, granules, tablets,troches, capsules, ointment, cream, and liquids. Among them, Ensure Liquid1, an enteral nutritional preparation in a liquid form, appears
identical with canned soft drinks sold as conventional foods. Moreover, Vicks Medicated Drops1 and Asada Ame1, which are OTC drugs, lookexactly the same as drops and candies prevalent as foods. Lipovitan D1, which is a quasi drug, is sold in a form difﬁcult to distinguish frombottled beverages in general. Among foods other than health foods, some (e.g., lemonade-ﬂavored candies) are sold in the forms of tablets,troches, etc.  Presently, warning against the concomitant use of St. John’s wort is printed on packages and package inserts.

Table 1

Outline of Foods for Speciﬁc Health Uses and Nutrition Functional Foods
Foods for speciﬁc health uses

Nutrition functional foods

Deﬁnition (Partially omitted)

Foods that are indicated on theirpackages that they are expected to
produce speciﬁc health-promoting or
health-protecting objectives for those
who consume them for the statedobjectives according to a nutritional
regimenFoods that are indicated on theirpackages to have the functions of thespeciﬁc nutritional components that the
foods are stated to contain according to
the standards set by the Minister of
Health, Labor and Welfare (fresh foods
other than chicken eggs excluded)

Sales regulations

Individually approved (scientiﬁc dataneeded)Regulated by speciﬁcations or standards(Upper and lower limits of the intake
determined)

Number of items [Components]

About 410 (4/’04)[Vitamins 12, Minerals 5]

ExamplesAmyl S1, Yakulut 400, Bansorei-cha,
Econa1 Cooking Oil

Vitamins A, B, C, D, and E, foric acid,
pantothenic acid, biotin, niacin, Ca, Fe

Commercial name

Origo-de-shikkari-Ca (Meiji Seika)

Tennen-koka-karushiumu (House Foods)

Active components

Fructooligosaccharides, CaCa

Description

Fructooligosaccharides promote theabsorption of Ca and make strong
bones and teeth

Calcium is a nutrient necessary for theformation of bones and teeth

Speciﬁc examples

140

Ohnishi N and Yokoyama T: Interactions between drugs and supplements

Fig. 5 Course of digoxin trough levels in 25 healthy volunteers
treated either with hypericum extract (L1160) or placebo (mean
G SEM). Daily oral digoxin dose was 0.25 mg. P Values represent
statistical signiﬁcance between the two medication groups. (Reproduce from, Johne A, et al: Clin Pharmacol Ther 1999; 66: 338–345,
Copyright 6 (1999), with permission from Mosby, Elsevier Ltd.)

Fig. 4 Ciclosporin concentrations in two patients after heart transplantation. Treatment with St John’s wort was associated with a dropin ciclosporin values below the therapeutic range and acute transplant
rejection. Hypericin, one of the biologically active constituents of St
John’s wort extract, which is an antidepressant chemical compound;
ISHT, the grading determined by International Society of Heart andLung Transplantation. (Reproduce from, Ruschitzka F, et al: Lancet
2000; 355: 548–549, Copyright 6 (2000), with permission from THE
LANCET Publishing Group, Elsevier Ltd.)the plasma concentrations of ciclosporin (Fig. 4),10
indinavir,11 and ethynylestradiol, which are metabolized
by CYP3A4, theophylline,12 which is metabolized by
CYP1A2, and warfarin, which is metabolized by bothof these isozymes.13 Moreover, it has been concluded
that CYP3A4 is induced by hyperforin as it directly
binds with hormone receptor pregnane X receptor(PXR) to activate PXR.14 SJW has also been reported
to induce not only some CYP isoforms but also Pglycoprotein (MDR1), which is a drug efﬂux transporterand involved in multiple drug resistance of cancer
cells.15 Indeed, reductions of the plasma concentrationof digoxin, which is a substrate of MDR1, have beenreported (Fig. 5).15
For the above reasons, the concomitant use of SJWcontaining foods and medicines should be avoided,in principle. Also, when physicians and pharmacistsprescribe or prepare and dispense such medicines,
they must check whether the patients consume SJWcontaining foods. If they do, the physicians and pharmacists must try to persuade the patients to immediately stop consuming the SJW-containing foods andstart the medication after a period. If they discover
patients who have been concomitantly using SJWcontaining foods and the above medicines over a relatively long period, they must lead the patients to eventually give up consuming the SJW-containing foods
while paying sufﬁcient attention to the patients, because if the patients suddenly stop consuming the SJWcontaining foods on their own judgments, adverse
reactions associated with rapid increases in the plasma
concentrations of the medicines may appear. Therefore,
providing sufﬁcient information from physicians or
pharmacists to patients is indispensable, and accumulation of reliable information is an urgent requirement.
Interactions Between Medicines and Grapefruit Juice(GFJ), and Their Management
Increases in the blood drug concentrations due to theintake of GFJWhen particular medicines metabolized by CYP3A4
are taken simultaneously with GFJ, their plasma con-

Keio J Med 2004; 53 (3): 137–150

centrations may increase, occasionally causing unexpected adverse reactions. This interaction is mentioned
in the package inserts of a total of 26 drugs as of theend of September, 2002. They include calcium blockers(nisoldipine, felodipine, and nifedipine), antipsychotics(pimozide), antiplatelet agents (cilostazol), immunosuppressants (ciclosporin and tacrolimus), anticancer
drugs (geﬁtinib and imatinib), and antiviral agents(saquinavir). Also, GFJ increases the plasma concentrations of the antihyperlipidemic agents simvastatin,
atorvastatin, and lovastatin, but it shows no interaction
with pravastatin (which is not a substrate of CYP3A4
or MDR1). Figure 6 shows a typical case of interaction, in which the plasma concentration of simvastatin
was increased by the concomitant intake of GFJ.16 As
shown in this ﬁgure, the peak concentration increased
about 12-fold, indicating great danger of the concomitant use. As for the mechanism of inhibition by GFJ, it
has been concluded that frunocoumarins, particularly
their dimers, contained in GFJ inhibit CYP3A4 in intestinal epithelial cells, causing a marked increase in
the intestinal absorption of the drug.17 Moreover, by
this inhibition mechanism, which is called mechanismbased inhibition (inhibition by direct binding of ametabolite or intermediate metabolite of the inhibitorwith CYP3A4), intestinal CYP3A4 is inactivated, or irreversibly inhibited, and its protein level is reduced.
In addition, the degree of interaction between GFJ
and medicines not only vary widely among medicines ofthe same categories (e.x. calcium blockers) but also aremarkedly affected by factors such as the quantity of intake, brand, and timing of intake of GFJ. Even worse,
as GFJ irreversibly inhibits CYP3A4, a single dose of
GFJ has been shown to produce an inhibitory actionthat may continue for several days (Table 2).18
Therefore, this interaction cannot be prevented by
avoidance of simultaneous intake of GFJ, and it is best
to completely abandon all intake of GFJ. However,
only simultaneous intake is prohibited, and concomitant use is not, in many package inserts. Moreover, despite the presence of reliable literature that indicatesthe danger of concomitant use, it is not reﬂected inmany package inserts. Therefore, utmost caution basedon the latest information is required to physicians andpharmacists.
Decreases in the blood drug concentrations due to theintake of GFJ
Recently, there has been a very shocking report ofinteractions of GFJ. The plasma concentration of fexofenadine, an antiallergic agent, after its oral administration decreases markedly by a massive intake of GFJ(Fig. 7).19 Moreover, this decrease has been shown tooccur even with an intake of GFJ at a conventional

141

Fig. 6 Mean serum concentrations of simvastatin (upper panel) andsimvastatin acid (lower panel) in 10 healthy volunteers after single
oral doses of 40 mg simvastatin. Simvastatin was taken with 200 mL
water (open circles), with 200 mL double-strength grapefruit juice after ingestion of 200 mL grapefruit juice three times daily for 2 days(solid triangles), or with 200 mL water 24 hours (solid diamonds), 3
days (open triangles), or 7 days (solid stars) after last dose of grapefruit juice. Error bars were omitted for clarity. (Reproduce from, Lilja
JJ, et al: Clin Pharmacol Ther 2000; 68, 384–390, Copyright 6 (2000),with permission from Mosby, Elsevier Ltd.)

quantity (300 mL). Such decreases in the absorption of
fexofenadine are caused also by an intake of orange
juice or apple juice (Fig. 7).19 Results similar to those of
fexofenadine have been obtained in the concomitantintake of celiprolol, a b-blocker, with GFJ.20
One of the mechanism of these decreases is estimated to be inhibition of some organic anion transporting polypeptide (OATP-A, -B, -C, etc.) in intestinal
epithelial or hepatic cells by a common component infruit juices, because fexofenadine and celiprolol are
substrates of some OATP and not of CYP3A4, but bothdrugs are substrates of MDR1.19–21 Moreover, somemedicines are considered to be substrates of bothCYP3A4 or MDR1 and OATPs, in which case predic-

142
Table 2
iment

Ohnishi N and Yokoyama T: Interactions between drugs and supplements
Pharmacokinetic Parameters of Nisoldipine in Each Exper-

ControlG0

AUC(0-y)78.1 321(106 % of
dose  h/mL)
Dose (mg)10.0
5.0
AUC(0-y)7.81 16.0(mg  h/mL)
CLoral (L/h)
1281
312
CL iv (L/h)
49.9
49.9
CLH; int (L/h)
144
144
34.8
34.8
Fliver (%)
F and F 0 (%)
3.9
16.0
FGI (%)
11.2
46.0
427
63.2
CLGI; int (L/h)
e
1.00
0.148
t max (h)
1.50
1.69
t (h)
–
1.688
Ratio of AUC
1.00
4.11

G14
181

G38
132

G72
107

G96
108

5.0
9.04

5.0
6.59

5.0
5.33

5.0
5.39

553
49.9
144
34.8
9.03
26.0
154
0.360
1.00
169
2.32

758
49.9
144
34.8
6.59
18.9
231
0.541
1.50
194
1.69

939
49.9
144
34.8
5.32
15.3
299
0.699
0.875
217
1.36

928
49.9
144
34.8
5.38
15.5
295
0.690
1.19
241
1.38

0

F is availability after intake of grapefruit juice; e is the ratio of active
CYP3A4 to total CYP3A4. AUC and oral clearance (CLoral ) were
calculated. Control nisoldipine bioavailability (F) was 3.9%, 38 thenintravenous clearance (CL iv ) was calculated. Intrinsic hepatic clearance (CLH; int ) and hepatic bioavailability (Fliver ) were calculated fromthe CL iv and QH ¼ 76:62 L/h. 36 F was calculated from CLoral andCL iv , gastrointestinal bioavailability (FGI ) was calculated form F
and Fliver , then the intrinsic gastrointestinal clearance (CLGI; int ) was
calculated from QGI ¼ 53:9 L/h. 36 t max (h) is the time of maximum
plasma concentration, and t (h) is t max þ (time after grapefruit juice
ingestion). (Reproduce from, Takanaga H, et al: Clin Pharmacol Ther
2000; 67, 201–214, Copyright 6 (2000), with permission from Mosby,
Elsevier Ltd.)tion of interactions is very difﬁcult. It should be notedthat GFJ also inhibits MDR1.
From these observations, GFJ induces opposite interactions depending on the type of medicine, so thateven greater caution than has been exercised is required. Especially, it is necessary to instruct patients
who are taking medicines that are metabolized by
CYP3A4 or those absorbed through the intestines via
OATP (fexofenadine and celiprolol) to avoid the intake
of GFJ. Among the many HMG-CoA reductase inhibitors, the bioavailability of pitavastatin, which is nota substrate of either CYP3A4 or MDR1 is completely
unaffected by the concomitant intake of GFJ,22 unlike simvastatin, atorvastatin, or lovastatin. Therefore,
pharmacokinetic interactions are expected to be veryrare with pitavastatin, and the agent is considered to behighly useful in the treatment of hyperlipidemia.
Noted Interactions between Medicines and Functional
Foods (Herbs, Vitamins, Minerals, Amino Acids orCatecholamines) and Their Management
Problematic interactions of various health foods(herbs, vitamins, minerals, amino acids, or catecholamines) other than SJW and GFJ with medicines andtheir management are described.6,23 Medicines withwhich concomitant use of vitamins and minerals is recommended because of possible vitamin or mineral deﬁciency on long-term administration are also touchedon brieﬂy.
Interactions with herbs

Fig. 7 Mean plasma fexofenadine concentration-time proﬁles for
persons (n ¼ 10) orally administered fexofenadine (120 mg) with 300
ml water, grapefruit juice at 25% of regular strength (25% GFJ),
grapefruit juice (GFJ), orange juice (OJ), or apple juice (AJ) followed
by 150 ml of the same ﬂuid every 0.5 to 3 hours (total volume, 1.2 L).
(Reproduce from, Dresser GK, et al: Clin Pharmacol Ther 2002; 71,
11–20, Copyright 6 (2002), with permission from Mosby, Elsevier
Ltd.)

Since the number of herb-related health foods haverecently increased, needs for them have grown, andthey are likely to contain components with strong inductor or inhibitor activities against functional proteinsin the body (enzymes and transporters), utmost caution
is necessary concerning herb-drug interactions. Also, as
multiple herbs are often blended in recent products,
careful reading of package inserts is needed. Unfortunately, herbs are a category that most lack scientiﬁc
evidence because of their uniqueness, e.g. (1) they are
mixtures of many components, (2) they are a kindof prodrugs (many of their components are absorbed
after they are transformed by the intestinal ﬂora), (3)many of their active components are unknown, and (4)the contents of active components in herbs are variable. Here, typical examples of herb-drug interactions
reported to date are shown in Table 3.6,23
Interactions with vitamins
Most of the vitamins have been used as medicines,
and information about most interactions between herbs

Keio J Med 2004; 53 (3): 137–150
Table 3143

Representative Interactions between Medicines and Herbs6,23

Food

Drug

Side-effect

Package insert

Management

Fig

methoxsalen

phototoxity

Precaution in combination

Avoid the intake of a lot of ﬁg

Ginkgo biloba leaf

warfarin

Intracerebral hemorrhage

Not mentioned

Avoid concomitant use

aspirinSpontaneous hyphema

Plantain, seedlithiumcarbonate

Decreases in plasma drug concentrations

Avoid simultaneous use

Tamarindaspirin

Increases in plasma drug concentrations

Avoid concomitant use

Chlorella

warfarin

Increased platelet aggregation

Precaution in combination

Red wine

ciclosporin

Decreases in plasma drug concentrations

Not mentioned

Garlicwarfarin

Possible increased risk of bleedingsaquinavir

Decreases in plasma drug concentrations

Possible increased risk of bleeding
Ginseng
Avoid simultaneous use
Avoid concomitant use
Precaution in combinationand vitamins has become available with clariﬁcation of
their mechanisms. Table 4 summarizes part of them.23

foods with high L-tryptophan contents should be
avoided to prevent serotonin syndrome.

Interactions with minerals

Interactions that cause vitamin or mineral deﬁciency

As shown in Table 5, many of the interactions
between medicines and minerals occur as they form
poorly soluble complexes such as chelates in the digestive tract, causing a decrease in their absorption.23
Therefore, they are often manageable by avoiding theirsimultaneous intake such as by taking one at an appropriate interval after the intake of the other.

Caution is needed in long-term administration of
medicines or simultaneous intake of vitamins or minerals with drugs, because it may cause vitamin or mineraldeﬁciency (Table 7). In such cases, vitamins or minerals
should be supplemented to prevent their deﬁciency or
to treat existing symptoms of their deﬁciency.
Basic Studies on Pharmacokinetic Interactions
between Medicines and Functional Foods

Interactions with amino acids or catecholamines
Table 6 shows examples of interactions between
amino acids or catecholamines and medicines, and their
management. The concomitant use of SSRI and SNRI,
which are attracting attention as antidepressants, with
Table 4

Ginkgo biloba leaf extract
In our country, the market size of Ginkgo biloba leaf
extract (GBE) is estimated to be 11 billion yen (2001),

Representative Interactions between Medicines and Vitamins23

Food
Vitamin A

Drugpaclitaxel

Side-effectReduced function in bonemarrow

Package insert

Management

Precaution in combination

Reduce the drug dose or
lengthen the dosing interval
during concomitant use
Avoid concomitant use

etretinate

Hypervitaminosis

Contraindication in combination

acetazoramide

Renal or urinary calculus

Contraindication in combination

deferoxamine

Reduced function in heart

Precaution in combination

Be careful of reduced functionin heart during concomitant use

warfarin

Increased platelet aggregation

Not mentioned

Avoid concomitant use

Vitamin D

alfacalcidol

Hypercalcemia

Precaution in combination

Desirable to avoid concomitant use

Vitamin E

warfarin

Possible increased risk of bleeding

Not mentioned

Avoid concomitant use

Folic acidphenytoin

Convulsions

Vitamin C

Desirable to avoid concomitant use

144

Ohnishi N and Yokoyama T: Interactions between drugs and supplements
Representative Interactions between Medicines and Minerals23

Table 5Food

Drug

Side-effect

Package insert

Ca

digoxin

Digitalis toxityFe

cefdinir
penicillamine

Ca,
Fe,
Mg,
Al,
Zn,
etc.

tetracyclines
new quinolones
sodium risedronate hydrate,
alendronate sodium hydrare

Decreases ingastrointestional
drug absorption
Decreases in drugconcentrations

Table 6

Representative Interactions between Medicines and Amino Acids or Catecholamines23

Food

Precaution in combination

Management

Avoid simultaneous use(Keep a dosing interval for 2–3 h)

Avoid simultaneous use of all foods except water(Take drugs before the ingestion of breakfast at
rising, and avoid all foods except water at least
30 min after drug intake)DrugSide-effectL-tryptophan (serotonin precursor)

ﬂuvoxamine

serotonin syndrome

Yogurt (tyramine)isoniazidparoxetine

Category
OTC
drug

Ethicaldrug

Package insert

Management

Not mentioned

Desirable to avoid concomitant use

Precaution in combination
hypertension, etc.

and it is among very popular items of health foods.
Therefore, the possibility of concomitant use of
GBE with various medicines is very high. The calcium
blocker diltiazem (DTZ) is a typical highly extracted
drug and has been shown to be metabolized into Ndemethyldiltiazem (MA), an active metabolite, by
CYP3A in humans and rats.24–26 Similarly to DTZ,
nifedipine (NFP) has also been shown to be metabolized primarily by CYP3A and to have a very low bioavailability.27,28 Therefore, we selected DTZ and NFP
as model substrates of CYP3A and studied the effectsof concomitant administration of GBE on the absorption or metabolism of these drugs in rats.

Table 7

Avoid the intake of a lot of CaFirst, we evaluated the effect of the addition of GBE
on the DTZ N-demethylation reaction (CYP3A activity) using intestinal and hepatic microsomes derived
from rats or humans. GBE inhibited the CYP3A activity in a manner dependent on the concentration (50%
inhibition concentration: about 50 mg/mL in the rat
intestine, about 182 mg/mL in the rat liver, 159 mg/mL in
the human liver).29 In NFP, the 50% inhibition concentrations in the rat intestine and liver were about 33
and 107 mg/mL, respectively.30 Moreover, evaluations
using rat intestinal or hepatic microsomes indicatedthat the mechanism of at least part of this inhibition
was mechanism-based inhibition (Fig. 8).29 Also, theRepresentative Interactions That Vitamins or Minerals is Possible to be Decreased by Taking Medicines
Drug (Brand name)Food

Side-effect, etc.

aspirin(Bufferin1)

folic acidElevated excretion in folicacid due to displacement
between folic acid and aspirin,
deﬁciency of folic acidfamotidine(Gaster1 10)
omeprazole

Food-derived
VB12 , folic acid, Fe
Food-derived VB12

Reduced gastrointestinal absorptionin each nutritional supplement due
to the decrease in gastric acids,
deﬁciency of each nutritional supplement

colestyramine

VA, VD, VE, VK,
folic acid

Reduced gastrointestinal absorptionin each nutritional supplement due
to adsorption to drug, deﬁciency ofeach nutritional supplement

Package insert

Management

Not mentioned

Desirable to takeeach supplement

Important basic
precautions

Avoid simultaneoususe (Keep a dosinginterval for 4–6 h)Keio J Med 2004; 53 (3): 137–150

145

a)

100

150

a)

MA formation rate(% of control)

MA formation rate(% of control)

N.S.

75
50
25

0
Preincubation GBE (200 µg/ml)
NADPH
Incubation
GBE (200 µg/ml)
NADPH
DTZ (25 µM)

–
+
–
+
+

–
+
+
+
+

+
+
+
+
+

+
–
+
+
+

Fig. 8 Effects of the Preincubation under Various Conditions on
the Formation of MA from DTZ by Rat Liver Microsomes.29 Eachcolumn represents the mean G S.E. of 3 rats. a) and b) p < 0:05 andp < 0:01, respectively (repeated measures ANOVA and Fisher’s
PLSD test). After preincubation for 10 min, the incubations were
performed in an NADPH-generating system containing microsomes(150 mg) and DTZ (25 mM) without or with GBE (200 mg/ml) at 37 C
for 3 min. (Reproduce from, Ohnishi N et al: Biol Pharm Bull 2003;
26, 1315–1320, Copyright 6 (2003), with permission from The Pharmaceutical Society of Japan)

CYP3A activity in intestinal and hepatic microsomes
was temporarily reduced after a single oral administration of GBE (20 mg/kg) in rats. Furthermore, this decrease corresponded with the decrease in the total CYP
content. The cytochrome b5 content in hepatic microscomes showed no change (Fig. 9).29
Next, we evaluated the effects of the concomitant use
of GBE on the pharmacokinetics of DTZ in rats after
intravenous administration and observed signiﬁcantdecrease in the elimination rate constant (l) and signiﬁcant prolongation of the mean residence time (MRT)of DTZ by the concomitant use. Also, the peak plasma
MA concentration was signiﬁcantly lower in concomitant use of GBE than in the control. We also evaluatedwhether the concomitant use with GBE affects thepharmacokinetics of DTZ after oral administrationand showed signiﬁcant increases in the area under theplasma concentration-time curve (AUC) and bioavailability (F) of DTZ by the concomitant administration(Fig. 10 and Table 8).
These results indicate that GBE concomitantly
administered with DTZ inhibits the metabolism of
DTZ at least partly by inhibiting intestinal and hepatic
CYP3A and increases the plasma DTZ concentration.
Although the metabolic clearance of DTZ is markedly greater in rats than in humans, the bioavailability
after its oral administration is low in both species.
The drug is also known to be metabolized primarily by
CYP3A and esterases by nearly the same route in both

(A)

125
100
75
50

b) c) a)

25
0
0

150
Cytochrome content(% of control)

b)

125

(B)

125
100
75
50
25

a)

0

0 6 12 18 24
6 12 18 24
Time after administration (h)Fig. 9 Effects of Single Oral Pretreatment with GBE on the Formation of MA from DTZ (A) and Cytochrome Content (B) in Rat
Small Intestine and Liver Microsomes.29 Each point represents themean G S.E. of 3–6 rats. a) and b) p < 0:05 and p < 0:01 vs. eachpoint at 0 h for small intestine, respectively, and c) p < 0:05 vs. thepoint at 0 h for liver (non-repeated measures ANOVA and Fisher’s
PLSD test). The GBE suspension (20 mg/kg) was administered orally
to unanesthetized rats, and then the small intestine and liver were
excised at indicated time points. (A) The reactions were performed inan NADPH-generating system containing small intestine or liver
microsomes (300 or 150 mg) and DTZ (25 mM) at 37 C for 5 or 3 min,respectively. c, small intestine (MA formation); g, liver (MA formation); s, small intestine (CYP content); C, liver (CYP content);o, liver (cytochrome b5 content). (Reproduce from, Ohnishi N, et al:
Biol Pharm Bull 2003; 26, 1315–1320, Copyright 6 (2003), with permission from The Pharmaceutical Society of Japan)

species.24,25 Therefore, the above results are considered be useful basic information for the evaluationof pharmacokinetic interactions of GBE with highly
extracted drugs including DTZ, which are substrates of
CYP3A.
We, therefore, carried out a study of interactions
between GBE and NFP on simultaneous administrationin 8 healthy adult males. The results suggested the possible occurrence of pharmacokinetic interactions also inhumans despite individual variation.31 A report of thisstudy is under review for publication.
Agaricus blazei Murill extract
When we performed an in vivo study similar to thatof GBE in rats, the absorption of DTZ was delayed byconcomitant administration of Agaricus blazei Murill(ABM) extract (200 mg/kg: about 10 times a standarddose) contrary to GBE (Fig. 11A).32 There were no
signiﬁcant differences in plasma MA concentrations andits pharmacokinetic parameters among the three groups(Fig. 11B).
Propolis extract
Simultaneous administration of propolis extract (20mg/kg: about 10 times a standard dose) with DTZ

Ohnishi N and Yokoyama T: Interactions between drugs and supplements

Concentration (µg/ml)

146

10

(A) DTZ

10

1

increased the absorption of DTZ in rats, but the increase was not signiﬁcant.32(B) MA

Pomegranate juice

1

0.1

0.1

0.01
0 0.5

0.01
1 1.5 2
0 0.5 1 1.5
Time after administration (h)2Fig. 10 Effects of Single Oral Pretreatment with GBE on the Plasma
DTZ and MA Concentrations after Oral Administration of DTZ to
Rats.29 Each point represents the mean G S.E. of 5 or 6 rats. The vehicle (control) or GBE suspension (20 mg/kg) was administered orally
to unanesthetized rats, and then the DTZ solution (30 mg/kg) was
administered orally 1 h later. c, control (DTZ); g, GBE (DTZ); s,
control (MA); C, GBE (MA). (Reproduce from, Ohnishi N, et al:
Biol Pharm Bull 2003; 26, 1315–1320, Copyright 6 (2003), with permission from The Pharmaceutical Society of Japan)

Table 8 Effects of Single Oral Pretreatment with GBE on the Pharmacokinetic Parameters of DTZ and MA after Oral Administrationof DTZ to Rats29
Parameter

C max (mg/ml)
Tmax (h)l (/h)
t1=2ðlÞ (h)AUC 0-y(mgh/ml)
MRT (h)
F (%)

DTZ

MA

Control

GBE

Control

GBE

0.55 G 0.06
0.12 G 0.02
0.96 G 0.08
0.75 G 0.06
0.30 G 0.04

0.92 G 0.19
0.13 G 0.02
1.11 G 0.09
0.65 G 0.05
0.67 G 0.14a)

1.11 G 0.21
0.12 G 0.02
0.61 G 0.06
1.20 G 0.15
1.03 G 0.18

2.24 G 0.66
0.14 G 0.02
0.68 G 0.10
1.28 G 0.35
2.63 G 0.80

0.90 G 0.07
2.0 G 0.3

1.02 G 0.13
4.6 G 0.9a)

1.57 G 0.16


1.77 G 0.48
Each value represents the mean G S.E. of 5 or 6 rats. a) p < 0:05 vs.
each control value (unpaired Student’s t-test). The vehicle (control) or
GBE suspension (20 mg/kg) was administered orally to unanesthetized rats, and then the DTZ solution (30 mg/kg) was administered orally 1 h later. The peak plasma concentration (Cmax) and thetime to reach Cmax (Tmax) of DTZ and MA were determined fromthe actual data obtained after intravenous or oral administration. The
terminal elimination rate constant (l) was calculated by ﬁtting individual data for three terminal points of the plasma concentration
proﬁle with a log-linear regression equation using the least-squares
method. The corresponding elimination half-life (t1=2ðlÞ ) was calculated by dividing ln 2 by l. The areas under the plasma concentrationtime curves from zero to inﬁnity (AUC 0-y ) for DTZ and MA were
calculated by means of the trapezoidal rule with extrapolation to inﬁnity with l. The mean residence time from zero to inﬁnity (MRT) forDTZ and MA was estimated by moment analysis.24 The absolutebioavailability of DTZ after oral administration (F) was estimated asfollows: (AUCp.o.  Di.v.)/(AUCi.v. (DTZ alone)  Dp.o.)  100.
(Reproduce from, Ohnishi N, et al: Biol Pharm Bull 2003; 26, 1315–
1320, Copyright 6 (2003), with permission from The PharmaceuticalSociety of Japan)

Pomegranate extract is a health food popular primarily among women for the alleviation of menopausal syndrome, because its seeds contain a factor
resembling the female hormone, estrogen. When DTZ
was orally administered to rats after the administrationof pomegranate juice (5 mL/kg; 3-fold concentrate:
about 10 times the conventional dose), little change
was observed in the pharmacokinetics of DTA or its
metabolites.33
The above results are useful basic information for
the evaluation of pharmacokinetic interactions of these4 health foods with liver-blood-ﬂow-dependent drugs,
which are CYP3A substrates, in humans.
Problems with Health Foods and Measures for
Their Management
Distressing health damage caused by health foods
for dieting that contained thyroid powder or N-nitrosofenﬂuramine (a possible carcinogen that accumulates in
the liver) occurred in our country from the middle of2000 to the fall of 2002. This incidence seems to be anatural consequence of the circumstances. As the
products were popular dieting items among healthfoods, the number of victims amounted to 833 (including 4 deaths) (as of October 30, 2002).
In addition, in August, 2003, there were emergency
admissions of people who took health foods (such as
Tojigen), which were alleged to be effective for thetreatment of diabetes mellitus, due to hypoglycemia,
because they contained the oral hypoglycemic drug
glibenclamide. The occurrence of health damages ofthis kind seems endless. Various problems emerge
from these instances. I will summarize such problems and present measures that are being taken by theadministration.
Quality of health foods
No strict GMP (Good Manufacturing Practice) has
been established by the legislation for health foods as
has been for medicines. Moreover, the system to prevent entry of non-approved medicines, or components
the use of which in health foods is not approved by the
Pharmaceutical Affairs Law (Food-Drug Discrimination: amended in April, 2001), is not functioning adequately. For these reasons, the quality and safety of allhealth foods are not guaranteed.
In summer, 2002, the Japan Health Food & Nutrition
Food Association (JHFA) independently drafted andKeio J Med 2004; 53 (3): 137–150

147(A) DTZ(B) MA
3

Plasma concentration(µg/mL)

1

2.5
0.75
2
1.5

0.5

1
0.25
0.5
0

0
0

0.5

1

1.5

2

0

0.5

1

1.5

2

Time after administration (h)Fig. 11 Effects of Simultaneous Oral Administration of ABM Extract on the Plasma Concentrations of DTZ (A) and MA (B) after Oral
Administration of DTZ to Rats.32 Each point represents the mean G S.E. of 5–8 rats. The DTZ solution (30 mg/2.5/kg) was administeredsimultaneously with water (control, 2.5 mL/kg) or ABM extract (40 or 200 mg/2.5 mL/kg) to unanesthetized rats. c, control (DTZ); g, 40 mg/
kg ABM (DTZ); g, 200 mg/kg ABM (DTZ); s, control (MA); C, 40 mg/kg ABM (MA); C, 200 mg/kg ABM (MA). (Reproduce from,
Ohnishi N, et al: FFI J Jpn 2003; 208, 353–360, Copyright 6 (2003), with permission from FFI Journal)

announced the ‘‘Supplementary Health Foods GMP’’to ensure the quality and safety of health supplements
and to pave the way to further development of theindustry. Relevant legislative actions are urgently
needed.
Safety of health foods
The tolerable daily intakes based on scientiﬁc evidence have been decided for only a handful of items(e.g. foods for speciﬁc health uses and nutrition functional foods) among health foods for their safe use.
Presently, the National Institute of Health Sciences isconducting chronic toxicity studies of some food items.
Effectiveness of health foods
The effectiveness of health foods remains to beevaluated. It is no exaggeration to say that reliable data
concerning the effectiveness are available only for
health functional foods among health foods. Believing
whatever mass media and advertisements say is very
dangerous.
Quality of information about health foods and systems
for its distribution
Necessary and proper information about matterssuch as the effectiveness of health foods, adverse
reactions, and interactions between medicines andhealth foods to be provided to consumers is markedly
deﬁcient compared with information about medicines(Table 9). Therefore, their collection, sorting, assessment, accumulation, and use are important problems
for the future. To cope with this need, the National
Institute of Health and Nutrition started to operate the‘‘Health Foods Safety Information Network (http://
humpty.nih.go.jp/food/)’’ in March, 2003, and collectionof data and construction of a database are in progress.
The Ministry of Health, Labor and Welfare is also
working to develop a similar system, and I am looking
forward to their completion.
Distribution of health foods
The health foods that were identiﬁed as the cause of
the above health damage were primarily purchased byindividual import, but it was later revealed that they
were also sold by domestic agents over the Internet, by
mail-order systems, and at retail stores. To prevent such
incidents, the ability of consumers to critically selectgoods must be improved.
To summarize the above 5 points, the formulationand enforcement of a ‘‘Food Health Protection Law’’(tentative naming), which systematically regulates
health foods, are urgently needed to prevent recurrenceof similar incidents. Presently, the Ministry of Health,
Labor and Welfare is evaluating such a law at the
Evaluation Committee of Systems Related to Health
Foods and other organizations. Also, the Fundamental

148
Table 9Ohnishi N and Yokoyama T: Interactions between drugs and supplements
Comparison of Information Provided as Package Inserts between Medicines and Health Foods (multiple vitamin preparations)

Description (Excerpt)

OTC drug

Nutrition functional food

Health food(Dietary supplement)

Brand nameShin-Popon1-S

Multiple Vitamin

Multiple Vitamin

Components

10 vitamins and others

13 vitamins

10 vitamins

Indications or functions

Nutritional supplementation,
weak constitution, nourishingand strengthening of the body

Vitamin C is a nutrient that supports
the health of the skin and mucosa

Not mentioned

Dosage regimen or
recommended dose

2 tablets at a time, once a day(Vitamin A: 2000 units)

1 tablet/day(Vitamin A: 1800 units)

2 tablets/day(Vitamin A: 1800 units)

Contraindica-tions

Pregnant women within 3 monthsof pregnancy and women who
expect pregnancy must consult apharmacist, etc. before they starttaking this drug

Pregnant or breast-feeding womenmust consult a physician before
they start taking this productNot mentioned

Interaction, duplicatedadministration

who are being treated by physiciansmust consult with themThose who are being medicated ortreated on the outpatient basis must
consult with their physicians

Adverse reactions

If nausea, vomiting, diarrhea, anditching appear, stop taking the drug
and consult a physician

If any physical abnormality is felt,
stop taking the product

Overdosing

Not mentioned

Intake of the product in large quantities
does not contribute to the healingof the disease or promotion of the health

Period of use

Consult a pharmacist or physician
if no improvement is observed
after taking the drug for about 1 month

Not mentioned

OthersYellowing of urine is no problem(Vitamin B2 )Law of Food Safety was established in May, 2003 although the law is not focused on health foods. In August, 2003, the Amended Health Promotion Law was
enforced, and legislative control of announcements andadvertisements that induce excessive expectations anddisclosure of commercial names of the health foods thathave caused serious health damages has been introduced. Thus, consumer-protection systems are being
improved though slowly.
Conclusion
Diverse health foods are distributed in our country
as well as in the United States and Europe. Also, alongwith the policies to reduce government control and thereview of food-drug discrimination currently advancedby the administration, the numbers of health foods andtheir categories are expected to increase further. The
occurrence of interstitial pneumonia due to concomitant use of sho-saiko-to and interferon-a, interaction
between drugs including calcium blockers and GFJ, andthe above pharmacokinetic interactions between medi-cines and SJW, which became topics in the late 1990’s,
are only the tip of the iceberg, and the advent of thesecond and third SJW is considered to be highly likely.
Therefore, in addition to scientiﬁc demonstrationof functions and safety of health foods themselves,
how quickly to accumulate and utilize information
based on scientiﬁc evidence concerning interactions
between medicines and health foods, which is particularly deﬁcient, is expected to be a key to the ‘‘properuse of health foods’’. Moreover, the author believes
that pharmacists are the most appropriate humanresources that can play this role (advisory staff) (Table
10). Pharmacists are considered to be responsible forprotecting people from the risk of health foods as wellas medicines by appropriately distributing such information to a wide range of people via hospital pharmacies, community pharmacies, and drugstores. I would
like to close this article by showing 6 points to beobserved not only by medical professionals to do theirduties but also patients and consumers in general toprotect themselves from health damages associatedwith health foods in Table 11.

Keio J Med 2004; 53 (3): 137–150
Table 10 Basic Concepts of Training of the Advisory Staff Concerning the Use of Functional Foods
Deﬁnition of theadvisory staff

Individuals who can provide appropriate
information concerning functional foods toconsumers and whom consumers feel closeand easy to talk to.

Persons who
implement training

Private bodies appropriate in organizationand management

Intended trainees

Management nutritionists, pharmacists,public health nurses, doctors, otherspecialists

Knowledge to beacquired by theadvisory staff(1) Proper methods for use or intake(2) Differences from medicines(3) Interactions among foods andbetween medicines and foods(4) Emphasis on health and nutrition innotes and descriptions(5) Basic knowledge for understandingof scientiﬁc evidence(6) Knowledge about foods and foodadditives(7) Knowledge about health andnutrition(8) Related laws
(9) Viewpoints and protection of
consumers(10) Market and overseas information

Excerpts from Shokuhatsu No. 0221002, Ministry of Health, Laborand Welfare (February 21, 2002).

Table 11 Six Items That Medical Professionals, Patients, and Consumers Must Observe for the Prevention of Health Damages Due to
Health Foods
1. To eliminate products that are, or are suspected to be,unapproved or unauthorized medicines!
1) Doesn’t the product contain raw materials of medicines?
2) Isn’t the product prepared in the form of an ampoule,
sublingual tablet, etc.?
3) Doesn’t the product claim to have indications?
4) Isn’t dosage regimen resembling that of a medicine
mentioned?
2. To judge whether the health food is really necessary for thepatient!
3. To have medical professionals to become familiar with differences
between medicines and health foods and also to have patients
understand them.
4. If the patient’s condition permits, to recommend general
medicines, functional foods, and supplements (JHFA) in thisorder (if there are products with the same active components).
5. To monitor health foods that patients report are very effectivewith particular attention.
6. To try to minimize the possibility of interactions between
medicines and health foods and duplicated intake of the sameactive components.

149

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