Drug interactions with grapefruit juice

Drug Interactions with Grapefruit JuiceExtent, Probable Mechanism and Clinical Relevance

Uwe FuhrInstitute for Pharmacology, Clinical Pharmacology, Universität zu Köln, Köln, Germany

ContentsSummary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2511. Observed Drug Interactions with Grapefruit Juice in Volunteers and in Patients . . . . . . . . . . 252

1.1 Drugs Subject to the Interaction and Extent of Effect . . . . . . . . . . . . . . . . . . . . . . . 2521.2 Change of Pharmacokinetic Variability by Grapefruit Juice . . . . . . . . . . . . . . . . . . . 2611.3 Grapefruit Juice Interactions during Long Term Intake . . . . . . . . . . . . . . . . . . . . . . 261

2. Proposed Mechanisms of Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2612.1 Gut Wall Cytochrome P450 CYP3A4 as the Main Target of Grapefruit Juice

Components In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2613. Characteristics of Grapefruit Juice Components Possibly Involved in the

Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2633.1 Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2643.2 Coumarin and Psoralen Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2663.3 Which Component is to Blame? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

4. How to Take Grapefruit Juice Interactions into Account in Drug Therapy . . . . . . . . . . . . . . 2674.1 Risks of Grapefruit Juice Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2674.2 Grapefruit Juice as a Drug-Sparing Agent? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

Summary Concomitant intake with grapefruit juice increases the concentrations of manydrugs in humans. The effect seems to be mediated mainly by suppression of thecytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in adiminished first pass metabolism with higher bioavailability and increased max-imal plasma concentrations of substrates of this enzyme. The effect was mostpronounced in drugs with a high first pass degradation and in many cases has theclear potential to reach clinical relevance, as shown by an occasional change indrug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquin-avir, the interaction was most marked with median increases of area under thecurve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (Cmax) values exceeding 70% of respective control periods.Less pronounced, but possibly relevant, concentration increases were found fornifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and ter-fenadine. This list is not complete because many drugs have not been studied yet.

The components of grapefruit juice which are the most probable causes of theinteraction are psoralen derivatives, but the flavonoid naringenin may also con-tribute. Concomitant grapefruit juice intake does not generally decrease the vari-ability of drug pharmacokinetic parameters. Therefore, it is recommended that

DRUG EXPERIENCE Drug Safety 1998 Apr; 18 (4): 251-2720114-5916/98/0004-0251/$11.00/0

© Adis International Limited. All rights reserved.

patients refrain from drinking grapefruit juice when they are taking a drug that isextensively metabolised, unless a lack of interaction has already been demon-strated for that drug. It is also recommended that drugs possibly interacting withgrapefruit juice should be appropriately labelled.

A place for grapefruit juice as a drug-sparing agent in treatment involvingexpensive medicine cannot be derived from the information currently availableon grapefruit juice interactions.

In an interaction study of felodipine with alco-hol (ethanol), where the study participants receivedgrapefruit juice to blind for the administrationof alcohol, Bailey and colleagues[1] observedthat felodipine concentrations were considerablyhigher than those reported previously for the doseof felodipine administered. Following from thischance finding, systematic studies of the effect ofgrapefruit juice coadministration have been carriedout for a wide range of drugs. The main finding hasbeen that grapefruit juice increases the bioavaila-bility of many drugs, but also it prolongs the meta-bolic elimination of a few drugs.[2,3] Mean changesin drug concentrations exceeded 30% in most stud-ies and surpassed 100% in several of them, sug-gesting that grapefruit juice drug interactions arenot negligible.

The objectives of this review are to summarisethe current knowledge of grapefruit juice interac-tions, to evaluate the risks they may cause, and todiscuss possible benefits and problems related tointentional inhibition of drug metabolism by thejuice from a fruit with the promising name Citrusparadisi or by its constituents.

1. Observed Drug Interactions with Grapefruit Juice in Volunteers and in Patients

1.1 Drugs Subject to the Interaction andExtent of Effect

The first studies of the effect of grapefruit juiceon drug metabolism were conducted with thedihydropyridine calcium antagonists. Once thepresumed main mechanism of action became ap-parent, i.e. inhibition of CYP3A mediated first passmetabolism (see section 2.1), cyclosporin and ter-fenadine were recognised as important targets for

the effects of grapefruit juice. Besides CYP3A sub-strates, several other drugs have also been tested.

For the purposes of this review, studies weremainly identified by a MEDLINE search using‘grapefruit’ as a keyword. Data from those studieswhere both drug and grapefruit juice administra-tion were described in detail are summarised in ta-bles I to V.[4-36] In all these studies, a cross-overdesign including a control period with concomitantadministration of water instead of grapefruit juicewas applied. With a few exceptions, the order ofperiods was also randomised. Blinding was obvi-ously not possible. However, statistical evaluationand description of the grapefruit juice effect wasnot uniform. Where available, mean and range orconfidence interval of the effect of grapefruit juicein the individual study was given, calculated as thepercentage change in the respective pharmacoki-netic parameter. For those studies where only meanvalues of parameters were published, the change ofthe mean values by grapefruit juice is listed in thetables. These 2 approaches are not equivalent butare closely related and are expected to provide sim-ilar estimates of the average effect.

1.1.1 FelodipineThe most studies have been conducted with the

dihydropyridine calcium antagonist felodipine (ta-ble I) and doses equivalent to 200 to 500ml singlestrength grapefruit juice have been administered.In the 9 comparative studies[4-9] where the drug wasgiven together with a single portion of grapefruitjuice, the mean increase in AUC ranged from 43 to234% of the control period, the median AUCgrowth was 125%. The mean increase in Cmax val-ues ranged from 70 to 225% (median 147%). Be-cause both AUC and Cmax were changed to a similarextent, concomitant intake of grapefruit juice with

252 Fuhr

© Adis International Limited. All rights reserved. Drug Safety 1998 Apr; 18 (4)

felodipine would be equivalent to a 2- to 3-foldincrease in the felodipine dose for most patientsrequiring the drug. The effect of grapefruit juice onthe time to reach maximum concentration follow-ing drug administration (tmax) was equivocal. Anincrease was also observed consistently for theconcentrations of the main metabolite of felodip-ine, i.e. dehydrofelodipine, although the extent ofthis increase was smaller than that for the parentcompound (see table I). The elimination half-lifeof felodipine was not changed by grapefruit juice.

A clear relationship between extent of the effectand felodipine dose was not observed. Althoughthe mean effect of double strength juice was higherthan that of the single strength juice in 1 studywhere 2 grapefruit juice doses were compared, sta-tistical significance was not reached.[4] In otherstudies, low grapefruit juice doses also exertedpronounced effects (table I). In 1 study with severaldays of grapefruit juice administration beforefelodipine intake, mean values of AUC and Cmaxwere increased by 211 and 335%, respectively.[7]

Thus, some grapefruit juice dose/effect relation-ship, which is possibly cumulative, may be pres-ent. However, other factors, such as compositionof the juice, are probably of similar importance.

Another important factor, that was addressed inthe study of Lundahl and colleagues,[6] appears tobe the timing of juice administration relative todrug intake. The effect on AUC and Cmax was mostpronounced when the grapefruit juice was givenwith the drug or 1 hour before felodipine adminis-tration, and steadily declined with an increasedtime lag. A minor, but significant, effect on felodip-ine Cmax was still present when felodipine wasgiven 24 hours after the glass of grapefruit juice(table I).

For those studies where grapefruit juice effectson felodipine pharmacodynamics were also moni-tored,[4,6,10] a pronounced increase in felodipineplasma concentrations was associated with an in-crease in the effects of felodipine on loweringblood pressure and/or increasing heart rate andthese effects occasionally reached statistical sig-nificance at some time points close to the tmax val-

ues for felodipine. This was shown in a small studyin hypertensive men[10] but was also seen inhealthy volunteers[4,6] in whom the pharmacody-namic effects of dihydropyridines usually are verylimited due to counter-regulation.[37] Grapefruitjuice, primarily at high doses, was also related toan increased incidence of adverse effects such asheadaches and flushing.[4,6,10] These findings con-firm what could be expected from the extent of thepharmacokinetic interaction. Thus, there is strongevidence that the interaction between felodipineand grapefruit juice has clinical relevance andneeds to be taken into account for individual treat-ment.

1.1.2 Calcium Antagonists other than FelodipineWith the exception of nifedipine[10,13,14] and

nitrendipine,[17,18] only 1 study was found for eachof amlodipine,[11] diltiazem,[12] nimodipine,[15]

nisoldipine[16] and verapamil[19] (table II). In thesestudies, grapefruit juice was found to change thepharmacokinetics of most of these calcium antag-onists. In all studies involving oral drug adminis-tration, a mean increase of AUC and Cmax wasfound, although this increase in some cases wasonly minor and failed to reach statistical signifi-cance (table II).

Taking into account that a single study providesonly limited information on the true mean extentof interaction (see section 1.1.1), it appears thatamlodipine[11] and diltiazem[12] are not subject to arelevant grapefruit juice interaction. In contrast,for all the other calcium antagonists tested, eitherAUC or Cmax (in most cases both) increased bymore than 50% (median of studies for the respec-tive drug) when given with grapefruit juice. Nodifference in grapefruit juice effects on the kineticsof parent drug and metabolite enantiomers wasfound following chiral drug measurements fornitrendipine[18] and verapamil (U. Fuhr et al., un-published observations).[19] As has been seen forfelodipine, there was no consistent change in tmaxor elimination half-life of parent drug and an in-crease in the concentrations of the metabolites wasobserved, but these increases did not reach those

Drug Interactions with Grapefruit Juice 253


254 Fuhr


Tabl

e I.

Effe

ct o

f gra

pefru

it ju

ice

on th

e ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

a s

ingl

e or

al d

ose

of fe

lodi

pine

Dos

e (m

g)Am

ount

of

GJ

(ml)a

Tim

e of

GJ

adm

inis

tratio

nbSt

udy

popu

latio

ncM

ean

chan

ge a

s %

of c

ontro

l (ra

nge)

Varia

tion

with

/with

out G

JdC

hang

e of

PD

with

GJ

Ref

.

AUC

Cm

axt m

axm

etab

olite

AUC

AUC

Cm

ax

520

00

9, m

ean

age

44y

+185

e14

7e62

+82e

0.87

0.80

HD

Es↑

with

GJ

4

540

00

9, m

ean

age

44y

+234

e+1

91e

54+1

09e

0.87

0.81

HD

Es a

nd A

Es↑

with

GJ

4

520

00

9, y

oung

+106

e (+

23to

+230

)+7

0e (+

27to

+210

)–1

9+3

0 (–

18

to +

63)

0.80

1.14

NA

5

10 S

R20

00

9, y

oung

+43e

+92e

–29

+25e

1.00

0.98

NS

6

10 S

R20

0–1

9, y

oung

+46e

+99e

−35

+33e

1.00

0.99

NS

6

10 S

R20

0–4

9, y

oung

+42e

+54e

−18

+20e

1.00

0.99

Effe

ct o

n BP

↑6

10 S

R20

0–1

09,

you

ng+2

5e+5

4e3

+15

1.00

0.99

NS

6

10 S

R20

0–2

49,

you

ng+1

3+3

2e0

+13

1.00

0.98

NS

6

1023

20

10, y

oung

+116

e+2

25e

NA

NA

0.33

e0.

30N

A7

10 S

R25

00

12, y

oung

+194

e (–

1 to

+550

)+1

43e

(+23

to+2

98)

−20

+44e

0.64

0.95

NA

8

20 S

R25

00f

12, y

oung

+125

e (+

3to

+369

)+1

70e

(+16

to+4

77)

−7+5

4e0.

950.

85N

A9

20 S

R25

00g

12, y

oung

+119

e+1

55e

−17

NA

1.28

1.57

NA

9

550

00

6, h

yper

tens

ive

+184

e (+

64to

+369

)+1

23e

+91e

+74e

0.75

0.67

Effe

ct o

n BP

↑10

1023

28

hour

lyh

10, y

oung

+211

e+3

35e

NA

NA

0.53

e0.

58e

NA

7

aFo

r dou

ble

stre

ngth

juic

e, v

olum

es a

dmin

iste

red

wer

e m

ultip

lied

by 2

.

bH

ours

rela

tive

to d

rug

adm

inis

tratio

n.

cAl

l hea

lthy,

non

smok

ing

men

unl

ess

othe

rwis

e st

ated

.

dVa

riatio

n fo

r eac

h pe

riod

was

cal

cula

ted

as s

tand

ard

devi

atio

n (S

D),

stan

dard

erro

r of t

he m

ean

(SEM

) or c

onfid

ence

inte

rval

(CI)

divi

ded

by th

e m

ean

or p

oint

est

imat

e, th

eva

lue

in th

e co

lum

n is

the

ratio

of t

his

varia

tion

betw

een

grap

efru

it ju

ice

and

cont

rol p

erio

d.

eSi

gnifi

cant

(p <

0.0

5) g

rape

fruit

juic

e ef

fect

s.

fFi

rst p

erio

d.

gSe

cond

per

iod.

hAd

min

iste

red

from

–12

0 ho

urs

to +

16 h

ours

.

Abbr

evia

tions

and

sym

bol:

AE =

adv

erse

effe

cts;

AU

C =

are

a un

der t

he p

lasm

a co

ncen

tratio

n ve

rsus

tim

e cu

rve

of th

e un

chan

ged

drug

; BP

= bl

ood

pres

sure

; Cm

ax =

max

imal

pla

sma

conc

entra

tion

of u

ncha

nged

dru

g; G

J =

grap

efru

it ju

ice;

HD

E =

haem

odyn

amic

effe

cts;

NA

= no

t ava

ilabl

e; N

S =

no s

igni

fican

t cha

nge;

PD

= p

harm

acod

ynam

ics;

SR

= s

low

rele

ase;

t max

= ti

me

at w

hich

Cm

ax o

ccur

red;

y =

yea

rs; ↑

= in

crea

sed.

Drug Interations with Grapefruit Juice 255

Tabl

e II.

Effe

ct o

f gra

pefru

it ju

ice

on th

e ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

sin

gle

oral

dos

es o

f cal

cium

ant

agon

ists

oth

er th

an fe

lodi

pine

Dru

gR

egim

enAm

ount

of

GJ

(ml)a

Tim

e of

GJ

adm

inis

tratio

nbSt

udy

popu

latio

ncM

ean

chan

ge a

s %

of c

ontro

l (ra

nge

unle

ss o

ther

wis

e st

ated

)Va

riatio

nw

ith/w

ithou

t GJd

Cha

nge

of P

Dw

ith G

JR

ef.

AUC

Cm

axt m

axm

etab

olite

AU

CAU

CC

max

Aml

1×

5mg

PO25

00

12, y

oung

+16e

(–20

to +

55)

+15e

(–21

to

+65)

+9N

A1.

111.

05N

o ef

fect

on

HD

11

Dil

1×

120m

g PO

200

0,+2

,+4,

+8 a

nd +

129,

you

ng+1

0+2

+4−5

0.71

1.35

No

effe

ct o

nH

D12

Nif

1×

10m

g PO

500

06,

hyp

erte

nsiv

e+3

4e (+

8 to

+69

)+1

7−1

0e+2

2e1.

220.

67BP

effe

ctun

chan

ged

10

Nif

1×

10m

g PO

400

–2 a

nd 0

8 (5

men

), yo

ung

+58e

+16

+97

+17

1.02

1.05

NA

13

Nif

1×

2.5m

g IV

400

–2 a

nd 0

8 (5

men

), yo

ung

+14

NA

NA

NA

1.14

NA

NA

13

Nif

SR1

× 20

mg

PO20

00,

+2,+

4,+8

and

+12

12, y

oung

+103

e (+

48 to

+26

5)+9

4e (–

23 to

+25

9)+7

3e+6

6e (−

30to

+236

)0.

850.

91N

A14

Nim

1×

30m

g PO

250

08

(4 s

mo)

, you

ng+5

1e (9

0% C

I+1

4 to

+10

0)+2

4 (9

0% C

I –2

4 to

+10

1)+6

7↑

in 2

prim

ary

met

abol

ites,

no

chan

ge in

a s

econ

-da

ry m

etab

olite

1.19

1.54

NA

15

Nis

SR1

× 20

mg

PO25

00

12, y

oung

+98e

(–19

to

+582

)+3

06e

(+7

to+7

36)

–53e

NA

1.52

1.00

Effe

ct o

n H

R↑

16

Nit

1×

10m

g PO

200

09,

you

ng+4

0e+4

0+7

70

0.96

NA

NA

17

Nit

1×

20m

g PO

150

–15,

–10

, –0.

25,

+5 a

nd +

109,

you

ng+1

06e

(95%

CI

+64

to +

158)

+99a

(95%

CI

+50

to +

164)

+27

+23

1.42

1.14

HD

and

AE

unch

ange

d18

Ver

SR12

0mg

PObi

d fo

r 7 d

ays

250

–48,

–45

, –40

,–3

6, –

24, –

21,

–16,

–12

, 0,

+3,+

8 an

d +1

2

24 (1

2 m

en; 6

sm

ofo

r eac

h ge

nder

),yo

ung

+42e

(90%

CI

+24

to +

65)

+61e

(90%

CI

+34

to +

92)

+0+2

80.

860.

82M

ax. m

ean

PR c

hang

e+6

mse

c (9

0%C

I 0 to

15.

5)

19

aFo

r dou

ble

stre

ngth

juic

e, v

olum

es a

dmin

iste

red

wer

e m

ultip

lied

by 2

.

bH

ours

rela

tive

to d

rug

adm

inis

tratio

n.

cAl

l hea

lthy,

non

smok

ing

men

unl

ess

othe

rwis

e st

ated

.

dVa

riatio

n fo

r eac

h pe

riod

was

cal

cula

ted

as s

tand

ard

devi

atio

n (S

D),

stan

dard

erro

r of t

he m

ean

(SEM

) or c

onfid

ence

inte

rval

(CI)

divi

ded

by th

e m

ean

or p

oint

est

imat

e, th

eva

lue

in th

e co

lum

n is

the

ratio

of t

his

varia

tion

betw

een

grap

efru

it ju

ice

and

cont

rol p

erio

d.

eSi

gnifi

cant

(p <

0.0

5) g

rape

fruit

juic

e ef

fect

s.

Abbr

evia

tions

and

sym

bol:

AE =

adv

erse

effe

cts;

Am

l = a

mlo

dipi

ne; A

UC

= a

rea

unde

r the

pla

sma

conc

entra

tion

vers

us ti

me

curv

e of

the

unch

ange

d dr

ug; b

id =

twic

e da

ily; B

P =

bloo

d pr

essu

re; C

max

= m

axim

al p

lasm

a co

ncen

tratio

n of

unc

hang

ed d

rug;

Dil

= di

ltiaz

em; G

J =

grap

efru

it ju

ice;

HD

= h

aem

odyn

amic

s; H

R =

hea

rt ra

te; I

V =

intra

veno

us; N

A =

not

avai

labl

e; N

if =

nife

dipi

ne; N

im =

nim

odip

ine;

Nis

= n

isol

dipi

ne; N

it =

nitre

ndip

ine;

PD

= p

harm

acod

ynam

ics;

PO

= o

ral;

PR =

PR

inte

rval

; sm

o =

ciga

rette

sm

oker

; SR

= s

low

rele

ase;

t max

= ti

me

at w

hich

Cm

ax o

ccur

red;

Ver

= v

erap

amil;

y =

yea

rs; ↑

= in

crea

sed.


levels seen with the respective parent drug (tableII).

It is not clear how the significant pharmacoki-netic changes in this group of drugs translate intoalterations in pharmacodynamics. A mean increaseof 34% in nifedipine AUC without a significantchange of Cmax was not related to a more pro-nounced haemodynamic effect in 6 men with hy-pertension.[10] Likewise, a doubling of both param-eters for nitrendipine when given with grapefruitjuice left haemodynamic effects and incidence ofadverse events unchanged.[18] In contrast, the in-crease in heart rate at 4 hours after administrationof nisoldipine was more pronounced when the drugwas given with grapefruit juice.[16] Long termcoadministration of grapefruit juice with steadystate verapamil was associated with a transient pro-longation of the ECG PR interval to more than 0.24sec in 4 volunteers, and the mean increase of 6 msecin the maximal difference of the PR interval be-tween grapefruit juice and control periods justfailed to reach statistical significance (U Fuhr et al.,unpublished observations).[19] Again, these stud-ies, with 1 exception, were conducted in healthyvolunteers where haemodynamic effects, at leastfor dihydropyridine calcium antagonists, are usu-ally less pronounced than in hypertensive pa-tients,[37] and drug effects were not monitored inmost cases. The lack of an apparent increase ofdrug effects by grapefruit juice in these studiesdoes not, therefore, preclude the fact that, in pa-tients with hypertension, a pronounced change indrug concentrations will be accompanied by an ac-cording change in drug effect.

1.1.3 CyclosporinParticular attention has been paid to the interac-

tion between cyclosporin and grapefruit juice, be-cause cyclosporin is metabolised by the same en-zymes as calcium antagonists (see section 2.1) andbecause of its narrow therapeutic range. For thisdrug, the majority of studies were conducted in pa-tients who were taking cyclosporin on a regularbasis (table III).[20-26]

The mean increase in the AUC for oral cyclo-sporin measured in the 12-hour dosage interval

ranged from 8 to 60% of the control period, themedian was 34%. Cmax mean values were increasedby between 10 and 43% (median 22%). The effecton tmax was again equivocal.

In the 3 studies where the concentrations ofcyclosporin metabolites were measured, a signifi-cant AUC increase was observed in 2 of them[25,26]

but not in the third[24] (table II). Since metaboliteconcentrations were obtained from the differencein cyclosporin concentrations, as measured using amethod specific for the parent drug and a nonspe-cific method which also includes cyclosporin me-tabolites, these indirect results must be regardedwith caution. However, it may be important toknow what the true effect of grapefruit juice oncyclosporin metabolites is, because these effectsmight be relevant for toxicity of the drug.[38]

A relationship between grapefruit juice admin-istration schemes and extent of effect on cyclo-sporin is not obvious (table III).

It is not probable that monitoring the effects ofcyclosporin will reveal tolerability changes, e.g. anincrease in serum creatinine level, upon short termconcentration increases. However, from the 2 stud-ies where effects were noted,[24,25] 1 patient expe-rienced adverse effects such as tremor, nausea,lightheadedness and nonspecific abdominal painthat occurred when taking grapefruit juice.[25]

Taking together all the results for cyclosporin,this interaction with grapefruit juice should not beignored in clinical practice (see section 4.2).

1.1.4 Terfenadine and AstemizoleThe antihistamines, terfenadine and astemizole,

are prodrugs that usually undergo extensive firstpass metabolism.[39] The parent compounds pro-long the QT interval, predisposing for ventriculararrhythmia. From instances of terfenadine over-dose, it is known that high plasma concentrationsof unchanged terfenadine may precipitate severe oreven fatal cardiac arrhythmia.[39] Accordingly, itappears that increased terfenadine concentrationsdue to interactions with drugs inhibiting CYP3A4such as ketoconazole or macrolide antibacterialsare associated with an increased risk for adversecardiac effects.[40-42] Serious concern has therefore

256 Fuhr


Tabl

e III

. Effe

ct o

f gra

pefru

it ju

ice

on th

e ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

cyc

losp

orin

Reg

imen

Amou

ntof

GJ

(ml)a

Tim

e of

GJ

adm

inis

tratio

nbSt

udy

popu

latio

ncM

ean

chan

ge a

s %

of c

ontro

l (ra

nge)

Varia

tion

with

/with

out G

JdC

hang

eof

PD

with

GJ

Ref

.

AUC

Cm

axt m

axm

etab

olite

AUC

AUC

Cm

ax

Med

ian

113m

g PO

bid

200

06

RTP

, mea

n 42

y+1

9e+2

7eN

AN

A0.

420.

94N

A20

Med

ian

175m

g PO

bid

232

010

RTP

, mea

n 44

y+2

4e (–

7 to

+93)

+4 (–

33

to 1

60)

+93e

NA

0.94

0.92

NA

21

1×

300m

g PO

250

014

(8 m

en) y

oung

+43e

+18e

+21

NA

1.05

1.21

NA

22

1×

7.5

mg/

kg b

w IV

250

0 an

d +2

10, y

oung

+7N

AN

AN

A0.

73N

AN

A23

1×

7.5

mg/

kg b

w P

O25

00

and

+210

, you

ng+6

0e+4

3e+3

1eN

A0.

810.

49N

A23

Med

ian

300m

g PO

od

150

3 ho

urly

f12

(8 m

en) R

TP+8

+22e

–23

–51.

010.

76N

o ef

fect

on A

Es24

Mea

n 1.

7 m

g/kg

bw

PO

bid

150

12 h

ourly

g9

(5 m

en) A

IP, m

ean

36y

+50e

(+9

to+1

25)

+42

(–44

to

+181

)N

AC+2

36e

(+19

to +

1770

)1.

011.

32AE

in 1

patie

ntw

ith G

J

25

Mea

n 1.

8 m

g/kg

bw

PO

bid

175

12 h

ourly

g10

(5 m

en) R

TP, m

ean

48y

+34e

+10

NAC

+55e

1.98

2.07

NA

26

aFo

r dou

ble

stre

ngth

juic

e, v

olum

es a

dmin

iste

red

wer

e m

ultip

lied

by 2

.

bH

ours

rela

tive

to d

rug

adm

inis

tratio

n.

cAl

l hea

lthy,

non

smok

ing

men

unl

ess

othe

r wis

e st

ated

.

dVa

riatio

n fo

r eac

h pe

riod

was

cal

cula

ted

as s

tand

ard

devi

atio

n (S

D),

stan

dard

erro

r of t

he m

ean

(SEM

) or c

onfid

ence

inte

rval

(CI)

divi

ded

by th

e m

ean

or p

oint

est

imat

e, th

eva

lue

in th

e co

lum

n is

the

ratio

of t

his

varia

tion

betw

een

grap

efru

it ju

ice

and

cont

rol p

erio

d.

eSi

gnifi

cant

(p <

0.0

5) g

rape

fruit

juic

e ef

fect

s.

fAd

min

iste

red

from

–7.

5 ho

urs

until

+22

.5 h

ours

.

gAd

min

iste

red

from

–14

4 ho

urs

until

0 h

ours

.

Abbr

evia

tions

:AE

= ad

vers

e ef

fect

s; A

IP =

aut

oim

mun

e pa

tient

s; A

UC

= a

rea

unde

r the

pla

sma

conc

entra

tion

vers

us ti

me

curv

e of

the

unch

ange

d dr

ug; b

id =

twic

e da

ily; b

w =

body

wei

ght;

Cm

ax =

max

imal

pla

sma

conc

entra

tion

of u

ncha

nged

dru

g; G

J =

grap

efru

it ju

ice;

IV =

intra

veno

us; N

A =

data

not

ava

ilabl

e; N

AC =

no

appa

rent

cha

nge;

od

= o

nce

daily

;PD

= p

harm

acod

ynam

ics;

PO

= o

ral;

RTP

= re

nal t

rans

plan

t pat

ient

s; t m

ax =

tim

e at

whi

ch C

max

occ

urre

d; y

= y

ears

.


Drug Interations with Grapefruit Juice 257

been expressed with respect to the interaction be-tween terfenadine and grapefruit juice, whichmight result in a relevant accumulation of thearrhythmogenic unchanged terfenadine in theplasma of individual patients.[43,44]

A number of recent studies of the effects ofgrapefruit juice on the pharmacokinetics and phar-macodynamics of terfenadine have been performed(table IV);[27-29] no such investigations have yetbeen published for astemizole.

In all the terfenadine studies, an increase in ter-fenadine and terfenadine carboxylate (fexofenad-ine) plasma concentrations was seen. The medianAUC gain for the metabolite was 28% (table IV).It is more difficult to assess to what extent grape-fruit juice elevates plasma concentrations of theparent drug, because usually concentrations of ter-fenadine when taken without an inhibitor are belowthe limit of detection of 5 μg/L.[27-29] The numberof samples with measurable terfenadine concentra-tions was higher in grapefruit juice periods for allstudies, clearly indicating the presence of an inter-action.

As observed with felodipine, the timing of juiceadministration relative to drug intake seems to beimportant. In 1 study,[29] concomitant intake ofdrug and juice caused a more pronounced interac-tion than grapefruit juice administration 2 hoursafter drug intake.

Heart rate corrected QT intervals (QTc) weremonitored in all studies. QTc interval was un-changed following single administration of grape-fruit juice and terfenadine,[27] whereas long termintake of terfenadine with grapefruit juice resultedin prolonged QTc intervals.[28,29] This pharmaco-dynamic consequence of grapefruit juice, however,was less pronounced than that produced bycoadministration of erythromycin or imidazole an-tifungal agents with terfenadine.[45,46] Whether thisuntoward effect is more severe in patients withchronic heart failure or other conditions where theQT interval is already prolonged remains to be in-vestigated. However, the possibility exists that thisinteraction has already caused fatal arrhythmia inone individual.[43] Furthermore, epidemiological

Landscape table

Table IV

258 Fuhr


Tabl

e IV

. Effe

ct o

f gra

pefru

it ju

ice

on th

e ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

ora

l ter

fena

dine

. Sin

ce te

rfena

dine

is a

pro

drug

, no

phar

mac

okin

etic

dat

a fo

r th

e pa

rent

subs

tanc

e ar

e av

aila

ble

Reg

imen

Amou

nt o

f GJ

(ml)a

Tim

e of

GJ

adm

inis

tratio

nbSt

udy

popu

latio

ncM

ean

Cm

axch

ange

(% o

fco

ntro

l)

Mea

n m

etab

olite

AUC

cha

nge

as %

of c

ontro

l (ra

nge)

Cha

nge

of P

D w

ith G

JR

ef.

1×

60m

g25

00

12, y

oung

↑ in

all

+43d

No

chan

ge in

QTc

inte

rval

27

1×

60m

g50

00

12, y

oung

↑ in

all

+33d

No

chan

ge in

QTc

inte

rval

27

60m

g bi

d fo

r ≈1

wee

k48

012

hou

rlye

6 (3

men

) hea

lthy

TPM

s↑

in a

ll+2

8d↑

QTc

inte

rval

28

60m

g bi

d fo

r 14

days

480

12 h

ourly

f6

volu

ntee

rs↑

in a

ll+5

5d (+

26 to

+11

2)Sm

all ↑

in Q

Tc in

terv

al29

60m

g bi

d fo

r 14

days

480

12 h

ourly

g6

volu

ntee

rs↑

in 2

+22d

(+11

to +

88)

No

chan

ge in

QTc

inte

rval

29

aFo

r dou

ble

stre

ngth

juic

e, v

olum

es a

dmin

iste

red

wer

e m

ultip

lied

by 2

.b

Hou

rs re

lativ

e to

dru

g ad

min

istra

tion.

cAl

l hea

lthy,

non

smok

ing

men

unl

ess

othe

rwis

e st

ated

.d

Sign

ifica

nt (p

< 0

.05)

gra

pefru

it ju

ice

effe

cts.

eAd

min

iste

red

from

–12

0 ho

urs

until

0 h

ours

.f

Adm

inis

tere

d fro

m –

144

hour

s un

til 0

hou

rs.

gAd

min

iste

red

from

–14

2 ho

urs

until

+2

hour

s.Ab

brev

iatio

ns a

nd s

ymbo

l: AU

C =

are

a un

der t

he p

lasm

a co

ncen

tratio

n ve

rsus

tim

e cu

rve

of th

e un

chan

ged

drug

; bid

= tw

ice

daily

; Cm

ax =

max

imal

pla

sma

conc

entra

tion

of u

ncha

nged

drug

; GJ

= gr

apef

ruit

juic

e; P

D =

pha

rmac

odyn

amic

s; Q

Tc =

QT

inte

rval

(cor

rect

ed fo

r hea

rt ra

te);

TPM

= te

rfena

dine

poo

r met

abol

iser

; y =

yea

rs; ↑

= in

crea

sed.


258 Fuhr

studies suggest that other antihistamines may alsoprolong the QT interval when taken with CYP3A4inhibitors.[42] Thus, although the true risk is diffi-cult to quantify, terfenadine and possibly other an-tihistamines should not be taken with grapefruitjuice.

1.1.5 Other Drugs

MethylxanthinesTheophylline and caffeine, both metabolised

primarily by the hepatic cytochrome P450 enzymeCYP1A2,[47] are 100% bioavailable. Therefore, adecrease in first pass metabolism is not possible.In one caffeine study with repeated grapefruit juiceadministration, caffeine clearance was decreasedby a mean of 23%, resulting in a correspondingAUC increase.[3] This result was in agreement within vitro inhibition experiments,[3] but was not con-firmed in 2 other studies with caffeine or theophyl-line, where grapefruit juice had no effect[30,31] (ta-ble V).

Steroid Hormone DerivativesData are available for 3 compounds (see table

V), which are characterised by a pronounced firstpass metabolism.[39] For the estradiol derivatives,the addition of grapefruit juice led to significantincreases in the parent drug concentrations[32] or itsmetabolite.[33] The studies were not designed tomonitor drug effects. The pharmacokinetic resultsof these studies, which are supported by in vitrodata[48,49] and by in vivo effects of grapefruit juiceon the oxidation of cortisol, an endogenous sub-strate for the cytochrome P450 enzyme 11β-hydroxysteroid dehydrogenase,[50] clearly showthat grapefruit juice has the potential to modifysteroid metabolism. The relevance of this findingis not clear, but it was speculated that grapefruitjuice may thus mediate a mineralocorticoid effectat high doses.[50]

BenzodiazepinesBoth oral midazolam and triazolam showed a

mean AUC increase with grapefruit juice of ap-proximately 50%, accompanied by significantlyelevated Cmax values (table V).[34,35] Eliminationhalf-life was unchanged, but tmax was also signifi-

cantly prolonged. In both studies, the typical CNSeffects of benzodiazepines were more pronouncedin the grapefruit juice period.[34,35] In contrast, an-other study found that the effects of single oraldoses of midazolam 10mg and triazolam 0.25mgwere essentially unchanged by concomitant grape-fruit juice administration.[51] However, the studydesign in this case precludes clear conclusions. Al-though additional investigations would be desir-able, it appears that the interaction between grape-fruit juice and midazolam or triazolam deservesmore public attention. One may speculate thatsome of the many road traffic accidents attributedto the use of benzodiazepines[52] could be due to amore pronounced effect of these agents when takenwith grapefruit juice.

Miscellaneous DrugsIn a study of the effect of grapefruit juice on the

pharmacokinetics and pharmacodynamics ofquinidine, tmax prolongation was the only effectseen.[36] No change was found for the QT interval.

A study of the effects of grapefruit juice onsaquinavir has been conducted (C. Möcklinghoff,et al., unpublished observation), and although thisstudy has not been published it has been madeavailable on the internet. In this study, grapefruitjuice caused a clear and dose-dependent increasein saquinavir AUC and Cmax (see table V). Al-though a decreased variability of pharmacokineticparameters of saquinavir was also reported withgrapefruit juice, the manufacturer does not recom-mend grapefruit juice as a means to improve thelow bioavailability of the drug.

Coumarin, a specific substrate for the cyto-chrome P450 isoform CYP2A6, showed a delayedrenal excretion of its main metabolite, i.e. 7-hydroxycoumarin, when administered with grape-fruit juice.[53,54]

Finally, in a case report, clomipramine anddesmethylclomipramine concentrations were higherwith concomitant grapefruit juice in 1 patient, re-sulting in clinical improvement, but not in a sec-ond.[55]



Tabl

e V.

Effe

ct o

f gra

pefru

it ju

ice

on th

e ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

oth

er d

rugs

Dru

gR

egim

enAm

ount

of G

J(m

l)a

Tim

e of

GJ

adm

ini-

stra

tionb

Stud

ypo

pula

tionc

Mea

n ch

ange

as

% o

f con

trol (

rang

e un

less

oth

erw

ise

stat

ed)

Varia

tion

with

/with

out

GJd

Cha

nge

of P

Dw

ith G

JR

ef.

AUC

Cm

axt m

axm

etab

olite

AUC

AUC

Cm

ax

Met

hylx

anth

ines

Caf

1×

165m

gPO

in c

offe

e30

0–0

.5,+

6,+1

2,+1

8,+2

4,+3

012

(4 m

en);

6sm

oker

s+2

8e (9

5% C

I+1

1 to

+46

)N

AN

AN

A1.

29N

AN

A3

Caf

1×

3.3

mg/

kg b

wPO

in c

offe

e

200

010

, you

ng+4

NA

NA

NA

1.36

NA

No

chan

ge

in H

D30

Caf

1×

3.3

mg/

kg b

wPO

in c

offe

e

200

–15,

–9,

–2,

0,+2

,+6

6, y

oung

+6N

AN

AN

A0.

61N

AN

o ch

ange

in

HD

30

Theo

1×

200m

gPO

100

0,+1

12, y

oung

+2 (9

0% C

I –5

to +

11)

–10

(90%

CI

–19

to 0

)N

ACN

A1.

001.

00N

A31

200

+4, +

8, +1

2, +1

612

, you

ngSt

eroi

d ho

rmon

e de

rivat

ives

Eth

1×

50μg

PO

100

–0.5

, 013

wom

en,

youn

g+2

8e (–

19to

+80

)+3

7 (–

36 to

+114

)N

ACN

A1.

021.

60N

A32

200

+3,+

6,+9

,+1

213

wom

en,

youn

g17

β-es

t1 ×

2m

g PO

200

08

OEW

+16

+31

–23

+27e

0.71

0.51

NA

33Pr

ed10

mg

od

stea

dy s

tate

150

3 ho

urly

f12

(8 m

en)

RTP

+50

+39

–29

−13

0.89

0.98

No

effe

ct o

nco

rtiso

l lev

el24

Ben

zodi

azep

ines

Mid

1×

15m

g PO

200

–1, –

0.25

8, y

oung

+52e

+56e

+79

+30e

0.79

1.34

Effe

ct o

n C

NS↑

34M

id1

× 5m

g IV

200

–1, –

0.25

8, y

oung

+4N

AN

A+7

0.90

NA

No

chan

ge34

Tri

1×

0.25

mg

PO25

00

10 (6

men

), yo

ung

+48e

+25e

+67

NA

0.67

0.53

Effe

ct o

n C

NS↑

35

Oth

ers

QS

1×

400m

gPO

232

012

vol

, yo

ung

+8–7

+106

−25e

1.27

1.17

No

diffe

renc

ein

QT

inte

rval

s36

Saq

1×

600m

gPO

150

0,+1

12 v

ol+3

9e (9

0% C

I +1

to +

91)

+63e

(90%

CI

+11

to +

138)

NA

NA

Varia

bilit

y ↓

Varia

bilit

y ↓

NA

unpu

bl.,

Möc

k-lin

ghof

f et a

l..Sa

q1

× 60

0mg

PO30

00,

+112

vol

+121

e (9

0% C

I+6

1 to

+20

3)+1

20e

(90%

CI

+50

to +

221)

NA

NA

Varia

bilit

y ↓

Varia

bilit

y ↓

NA

unpu

bl.,

Möc

k-lin

ghof

f et a

l..a

For d

oubl

e st

reng

th ju

ice,

vol

umes

adm

inis

tere

d w

ere

mul

tiplie

d by

2.

bH

ours

rela

tive

to d

rug

adm

inis

tratio

n.c

All h

ealth

y, n

onsm

okin

g m

en u

nles

s ot

herw

ise

stat

ed.

dva

riatio

n fo

r eac

h pe

riod

was

cal

cula

ted

as s

tand

ard

devi

atio

n (S

D),

stan

dard

erro

r of t

he m

ean

(SEM

) or c

onfid

ence

inte

rval

(CI)

divi

ded

by th

e m

ean

or p

oint

est

imat

e, th

eva

lue

in th

e co

lum

n is

the

ratio

of t

his

varia

tion

betw

een

grap

efru

it ju

ice

and

cont

rol p

erio

d.

eSi

gnifi

cant

(p <

0.0

5) g

rape

fruit

juic

e ef

fect

s.f

Adm

inis

tere

d fro

m –

7.5

hour

s un

til +

22.5

hou

rs.

Abbr

evia

tions

and

sym

bols

: 17β

-est

= 1

7β-e

stra

diol

; AU

C =

are

a un

der t

he p

lasm

a co

ncen

tratio

n ve

rsus

tim

e cu

rve

of th

e un

chan

ged

drug

; bw

= b

odyw

eigh

t; C

af =

caf

fein

e; C

max

= m

axim

al p

lasm

a co

ncen

tratio

n of

unc

hang

ed d

rug;

Eth

= e

thin

yles

tradi

ol; G

J =

grap

efru

it ju

ice;

HD

= h

aem

odyn

amic

s; IV

= in

trave

nous

; Mid

= m

idaz

olam

; NA

= da

ta n

ot a

vaila

ble;

NAC

= n

o ap

pare

nt c

hang

e; o

d =

once

dai

ly; O

EW =

ova

riect

omis

ed w

omen

; Pre

d =

pred

niso

ne; p

o =

oral

; QS

= qu

inid

ine

sulfa

te; R

TP =

rena

l tra

nspl

ant r

ecip

ient

s; S

aq =

saq

uina

vir;

Theo

= th

eoph

yllin

e; t m

ax =

tim

e at

whi

ch C

max

occ

urre

d; v

ol =

vol

unte

ers;

y =

yea

rs; T

ri =

triaz

olam

; ↑ =

incr

ease

d; ↓

= d

ecre

ased

.


260 Fuhr

1.2 Change of Pharmacokinetic Variabilityby Grapefruit Juice

Several authors have reported that grapefruitjuice not only increases drug concentrations butalso renders first pass metabolism more uniformbetween individual patients, with the most pro-nounced increases in AUC and/or Cmax occurringin those individuals who had the lowest values inthe control period (C. Möcklinghoff, et al., unpub-lished observation).[7,23] Of course, this effectwould be highly desirable because there is pro-nounced interindividual variation in gut wall firstpass metabolism[56] and this is a major factor inoverall variation of concentrations and response toparticular drugs.

If this is a general principle of grapefruit juiceinteractions, then one would expect that the inter-individual variability in pharmacokinetics woulddecrease when the drug is given with the juice. Toaddress this question, the relative variation in theseparameters was estimated (see tables I to V). Thisrelative variation was equal to the coefficient ofvariation in those studies where standard deviation(SD) or standard error of the mean (SEM) weregiven. The ratio between grapefruit juice and con-trol periods was used to compare between periods.A value above unity indicates that variation ishigher in the grapefruit juice period, whereas val-ues below unity suggest that grapefruit juice in-deed lowers variation. Across all drugs, the medianof this ratio is very close to unity (tables I to V).This evaluation clearly shows that there is no gen-eral difference in pharmacokinetic variability be-tween grapefruit juice and control periods and thatgrapefruit juice is not the ‘leveller of drug metabo-lism’ as proposed recently.[57]

1.3 Grapefruit Juice Interactions during inLong Term Intake

Another important question is whether the ex-tent of grapefruit juice interaction changes with theduration of juice intake, since for other CYP3A4inhibitors enzyme induction may attenuate the in-teraction.[7] It appears that this is not the case for

grapefruit juice interactions. In one study address-ing this question, an increase in the inhibitory ef-fect of grapefruit juice was observed, which maybe due to the mechanism of the interaction (seesection 2.1).[7] For those other substances wherestudies of long term and of single dose grapefruitjuice administration are available, i.e. cyclosporin(see table III)[24-26] and terfenadine (table IV),[28-29]

long term intake was not associated with a smallerdegree of interaction, when the lower doses usedin repeated administration were taken into consid-eration. If, however, it is confirmed that psoralensare responsible for grapefruit juice interac-tions,[58,59] their known potential to induce drugmetabolising enzymes[60-62] deserves further atten-tion.

2. Proposed Mechanisms of Interaction

2.1 Gut Wall Cytochrome P450 CYP3A4 asthe Main Target of Grapefruit JuiceComponents In Vivo

Most of the drugs subject to grapefruit juice in-teractions share a common property: dihydropyrid-ine calcium antagonists, verapamil, terfenadine,cyclosporin, ethinylestradiol, 17β-estradiol, pre-dnisone, midazolam, triazolam, quinidine andsaquinavir usually are subject to a relevant firstpass degradation, known to be mediated by cyto-chrome P4503A4/5 for most of these drugs andresulting in the formation of phase I metabo-lites.[39,63-69] From the results of an elegant studyby Kolars and colleagues,[70] it appears that the ma-jor site of this metabolism is the gut wall. Indeed,increased bioavailability in conjunction with un-changed elimination half-life, as seen for almost allof these drugs, supports the assumption that gutwall metabolism is decreased by grapefruit juicecomponents, whereas drug metabolism in the liveris essentially unchanged. Further support comesfrom 3 studies where the effects of grapefruit juiceon intravenous drug administration were comparedwith that on oral drug administration. For nifedi-pine[13] (see table II), cyclosporin[23] (see table III)and midazolam[34] (see table V), it was shown that



grapefruit juice had no effect on the pharmacoki-netics of these agents when they were administeredintravenously but clearly altered their pharmacoki-netics when they were administered orally.

Recent experimental data by Lown and col-leagues[7] directly confirm this hypothesis. In thispaper, it was shown that grapefruit juice adminis-tration results in a decrease of immunoreactiveCYP3A4 by a mean of 62% in the small intestine,without affecting small intestine CYP3A4 mRNAlevels, liver CYP3A4 activity, colon levels ofCYP3A5, or small bowel levels of P-glycoprotein.The authors concluded that ‘a mechanism for theeffect of grapefruit juice on oral felodipine kineticsis its selective downregulation of CYP3A4 in thesmall intestine’.[7] However, unchanged mRNAlevels suggest that grapefruit juice componentsmay have a more direct influence on the enzyme,such as mechanism-based inactivation. Assumingthat a constant fraction of active intestinalCYP3A4 is removed by grapefruit juice compo-nents, one would expect that those drugs that un-dergo a pronounced first pass metabolism are sub-ject to a higher grapefruit juice effect than drugswith only minor first pass biotransformation.

To test for this hypothesis, average effects ofshort term grapefruit juice intake on AUC (fig. 1)and Cmax (fig. 2) values of a drug were comparedwith its absolute bioavailability published in liter-ature. Using the Spearman’s rank correlation test(one-tailed), a significant decrease of the grapefruitjuice effect on AUC (n = 15 drugs; r = −0.788,p <0.001) and on Cmax (n = 14 drugs; r = −0.773,p <0.001) was indeed observed with increasingbioavailability. Thus, the expected relationshipwas confirmed despite the differences in study de-signs, despite different contributions of intestinaland hepatic metabolism to overall first pass bio-transformation of the individual drugs,[68] and de-spite the complexity of CYP3A4 mediated metabo-lism.[74]

What makes the interaction confined to thesmall intestine, in contrast to the effect of otherCYP3A4 inhibitors such as ketoconazole?[28] Thebest explanation available is that the compound(s)

causing a decrease of gut wall enzyme activity arealso subject to rapid inactivation at this very location.Current data for naringenin, showing extensivephase II metabolism, support this hypothesis[75,76]

(see section 3.1.2), whereas no information is yetavailable for grapefruit juice psoralens. In this con-text, an important question is why concentrationsof drug metabolites are also consistently increasedin those cases where the grapefruit juice interactionis present for the parent drug, although this increasedoes not reach the extent of that seen for the parentcompounds (see tables I to V). If the metabolic pat-tern is unchanged, one would expect delayed me-tabolite formation but the same AUC valuesbecause this parameter reflects the effective meta-bolite ‘dose’ which should be unchanged. I suggestone or several of the 3 following mechanisms or acombination thereof.

(i) It may well be that in the absence of grape-fruit juice, not only primary but also subsequentmetabolites are formed already during the first passmetabolism of a drug by CYP3A4. If this assump-tion is correct, the increase of primary metaboliteconcentrations by grapefruit juice componentsmay be due to inhibition of these secondary stepsas well as of the primary ones.

(ii) First pass metabolism could also be cir-cumvented for both primary and secondary meta-bolic steps by a possible additional action of grape-fruit juice components as a zonula occludens toxin,which would result in an increase of gut wall per-meability with substances bypassing drug metabo-lising enzymes.[77]

(iii) Grapefruit juice components may have theadditional potential to alter renal excretion of me-tabolites, since it has been shown that naringeninis able to change transport of xenobiotics acrossmembranes.[78]

The observation that drug metabolites are af-fected implicates that their action also needs to beconsidered in grapefruit juice interactions. Thismay be relevant for cyclosporin since a role of itsmetabolites in the precipitation of cyclosporin neu-rotoxicity has been suspected.[38]

262 Fuhr


3. Characteristics of Grapefruit JuiceComponents Possibly Involved in the Interaction

Several hundred chemical entities have beenidentified in grapefruit juice.[79] The compositionof the juice varies widely depending on the geneticbackground of the plant, environmental conditionsduring fruit growth, fruit maturity and fruit pro-cessing.[2,79] Most of the components are found notonly in grapefruit juice but also in other citrusfruits. However, the amounts of the individualchemical entities are quite different between spe-cies. Because drug interactions have been observedwith grapefruit juice from many different sources,

it appears that the substance(s) which are respon-sible for drug interactions are consistently presentin the juice. Whether the effect is unique to grape-fruit juice remains to be proven. In 2 studies, or-ange juice did not change felodipine[10] or cyclo-sporin[22] pharmacokinetics. However, due to thewidespread occurrence of components similar tothose supposed to cause the grapefruit juice inter-actions, one should not be surprised if more sys-tematic research into the effects of other fruitsyielded a large number of drug interactions.

Among the many typical components of grape-fruit juice, flavonoid and coumarin derivativeshave been suggested to contribute to grapefruitjuice drug interactions.

felodipine

nisoldipine

saquinavir

nitrendipine

nimodipine midazolamtriazolam

nifedipine

ethinylestradiolcyclosporin

diltiazem

amlodipine

quinidine caffeinetheophylline0

20

40

60

80

100

140

120

AU

C w

ith g

rape

fruit

juic

e (%

incr

ease

ove

r con

trol p

erio

d)

0 20 40 60 80 100 120Absolute bioavailability following oral administration (%)

Fig. 1. Relationship between the absolute bioavailability of drugs and the extent of increase in area under the curve (AUC) due tograpefruit juice interactions. Only drugs with reliable information on average bioavailability in the literature[39,71-73] and studies with lessthan 1 day of grapefruit juice administration prior to drug intake have been included. Grapefruit juice effects shown are median valuesof the mean effects seen in the studies with the respective drug (see tables I to V).



3.1 Flavonoids

3.1.1 Abundance of Flavonoids in Grapefruit JuiceIt appears that grapefruit juice is unique with

respect to high levels of naringenin (4′,5,7-trihydroxyflavanone) glycosides, mainly naringin(naringenin-7β-neohesperidoside) and narirutin(naringenin-7β-rutinosid) [see figure 3].[75,79]

Naringin concentrations in grapefruit juice arereported to range from 100 mg/L to 800 mg/L, butcan reach from 200 to 500 mg/L in most commer-cial grapefruit juice preparations.[34,75,80] The con-centrations of narirutin are reported to be between100 mg/L and 250 mg/L.[34,75,80] For naringin en-

antiomers, it is known that the ratio depends on thematurity of the fruit, with more (2S)-naringinfound in immature fruit.[2,79] High concentrationsof naringin are present in the albedo of the fruit;therefore, production procedures that optimisejuice yield will result in high levels of thisflavonoid.[81]

Further flavonoids found in grapefruit juice atlevels up to 70 mg/L include the hesperitin glyco-sides hesperidin and neohesperidin, the isokura-netin glycosides poncirin and isokuranetin-7β-rutenoside and other glycosides of flavanone,flavone and flavonol derivatives.[34,75,79,80]

nisoldipine

felodipine

nitrendipinesaquinavir

nimodipine

cyclosporin

diltiazem

midazolam

ethinylestradioltriazolam

nifedipineamlodipine

quinidine theophylline

0 20 40 60 80 100 120

0

50

100

150

200

250

300

Cm

ax w

ith g

rape

fruit

juic

e (%

incr

ease

ove

r con

trol p

erio

d)

Absolute bioavailability following oral administration (%)

Fig. 2. Relationship between the absolute bioavailability of drugs and the extent of increase in the maximum (peak) plasma drugconcentration after single-dose administration (Cmax) due to grapefruit juice interactions. Only drugs with reliable information onaverage bioavailability in the literature[39,71-73] and studies with less than 1 day of grapefruit juice administration prior to drug intakehave been included. Grapefruit juice effects shown are median values of the mean effects seen in the studies with the respectivedrug (see tables I to V).

264 Fuhr


3.1.2 Fate of Grapefruit Juice Flavonoids in theHuman BodyFlavonoid glycosides are polar compounds

which are poorly absorbed. No unchanged naringinwas found in plasma (S. Hensler and U. Fuhr, un-published observations) and in urine[75,76] follow-ing grapefruit juice or naringin ingestion. How-ever, a median of 5 to 7% of the naringin dose wasrecovered in urine as naringenin glucuronide,whereas renal excretion of unconjugated nar-ingenin reached only 0.05% of the naringin dosegiven.[75,76] Some individuals may excrete evenhigher levels of naringenin.[76] Therefore, the re-moval of the sugar moiety seems to be a prereq-uisite for the absorption of these compounds. Acleavage of glycosidic bonds has been proposed tooccur by hydrolysis in the acidic gastric environ-ment as well as by glucuronidases and glyco-sidases from gut bacteria.[75] Intestinal bacteriawere indeed able to metabolise naringin to nar-ingenin both in cattle and in humans under anaer-obic and aerobic conditions.[82,83] In contrast, therewas no evidence for naringenin formation by incu-bation of grapefruit juice or naringin with hydro-chloric acid (A. Ben Othman and U. Fuhr, unpub-lished observations). However, it is tempting tospeculate whether naringenin formation may alsobe mediated by hydrolases excreted from the pan-creas.

The observation that naringenin glucuronideswere detectable in plasma (S. Hensler and U. Fuhr,unpublished observations) and in high levels inurine[75,76] after grapefruit juice ingestion whereasfree naringenin was absent in plasma (S. Henslerand U. Fuhr, unpublished observations) and found

only at very low levels in urine[76] suggests thatnaringenin glucuronidation occurs during firstpass of the drug through the intestinal mucosaand/or the liver. Accordingly, naringenin was re-ported to be a high affinity substrate for aglucuronosyl transferase.[84] The fate of the re-maining glycoside is unknown, but it seems prob-able that the major fraction is excreted unchangedin the faeces (fig. 4).[75,76] The fate of other grape-fruit juice flavonoids in the human body may besimilar to that described for naringin.[75] A link be-tween those substances and grapefruit juice druginteractions, however, has not been established.

3.1.3 The Possible Role of Grapefruit JuiceFlavonoids in Drug InteractionsNaringenin, like many other flavonoids includ-

ing for example, quercetin, is a potent inhibitor ofcytochrome P450 enzymes in humans,[85] namelyof CYP3A4.[86] At a substrate concentration of 64μmol/L, naringenin inhibited midazolam hydrox-ylation with an IC50 value of approximately 120μmol/L.[87] Naringenin, but not naringin, was alsoable to inhibit verapamil metabolism[88] and had aclear inhibitory effect on CYP3A4 mediateddenitronifedipine degradation in human livermicrosomes (A. Ben Othman and U. Fuhr, unpub-lished observations). Accordingly, recent investi-gations of the inhibitory action of grapefruit juiceon CYP3A4 in human liver microsomes haveshown that this action is enhanced by incubationwith naringinase (A. Ben Othman and U. Fuhr, un-published observations).

However, several observations suggest that nar-ingin and its aglycone naringenin are not the majorinhibitory constituents of grapefruit juice. In 3studies, naringin, given as an ‘aqueous solu-tion’,[5,17] or in an ‘encapsulated’ preparation,[16] inthe same amounts as present in grapefruit juice,had no effect on nitrendipine,[17] felodipine[5] ornisoldipine[16] pharmacokinetics. Furthermore, theextent of inhibition of verapamil first pass metabo-lism was not correlated to naringenin glucuronideAUC in plasma or to urinary excretion of nar-ingenin or its glucuronides in urine, (S. Henslerand U. Fuhr, unpublished observations) which

R

OH

O

O

OH

Fig. 3. Chemical structure of naringin and naringenin. For nar-ingenin, R = OH; for naringin, R = β-neohesperidose.



were used as markers for individual naringenin ab-sorption in an interaction study between verapamiland grapefruit juice.[19] Finally, the grapefruit juiceinteraction was present equally for immediate-re-lease and for prolonged release drug preparations(see tables I to V). If naringenin formation fromnaringin by faecal bacteria is required for the inter-action, one would expect that the effect has a lagtime and also that grapefruit juice would changecolon rather than small intestine enzyme concen-trations. However, the results of a study by Lownand colleagues[7] clearly show that the small intes-tine is the site of interaction.

Besides inhibition of CYP3A4 mediated firstpass metabolism, it has been shown from in vitroexperiments using human liver microsomes thatCYP1A2 and CYP2A6 activities may also be de-creased by grapefruit juice flavonoids. Naringenin,but not naringin was a potent competitive inhibitorof CYP1A2 with inhibitor constants (Ki) of lessthan 50 μmol/L.[3] Coumarin hydroxylation wascompetitively inhibited by naringenin with a highmean Ki value of 690 μmol/L, indicating a poorinhibitory effect, whereas naringin again had noeffect.[89] However, the extent of the resulting in-teractions in vivo is minor or absent for caffeine andtheophylline (see table V), both of which are sub-ject to CYP1A2 mediated metabolism,[47] and is

not clearly defined for coumarin, which is aCYP2A6 substrate.[53,54]

3.2 Coumarin and Psoralen Derivatives

Many coumarin and psoralen (furocoumarin)derivatives have been found in grapefruit. The lo-cation of these substances is primarily in the peel,but concentrations of approximately 10 to 40 mg/Lare also found in the juice.[54,58,59,79,90-93] The fateof these moieties from grapefruit juice in the hu-man body is unknown. However, due to their highlipophilicity, one might expect that these com-pounds are readily absorbed from the gastrointes-tinal tract and extensively metabolised, as this isthe case for coumarin and psoralen drugs such aswarfarin, phenprocoumon and methoxsalen.[39]

In contradiction to the naringenin hypothesis,unprocessed grapefruit juice with no free nar-ingenin inhibits human CYP3A4 activity.[94] Themain inhibitory activity in native grapefruit juicewas mediated from lipophilic compounds extract-able by dichlormethane, (A. Ben Othman and U.Fuhr, unpublished observations)[94] or ethyl ace-tate.[95] In recent publications, such componentswith potent inhibitory action on rat or human liverCYP3A4 were identified as the psoralen derivative6′,7′-dihydroxybergamottin (fig. 5)[58] or as psor-alen dimers.[59] Other psoralens are known to bepotent inhibitors, but also inducers of several cyto-chrome P450 enzymes in laboratory animals and inhumans.[60-62,96-100] The mechanism of enzyme in-hibition by psoralens seems to be a reversible bind-ing to the substrate binding site,[101] in some casesfollowed by formation of active metabolites withirreversible inactivation of the enzyme.[100,102] Astudy addressing the mechanism of grapefruitpsoralen effects on human CYP3A4 activity invitro, which has very recently been published, hasfully confirmed this mechanism.[103]

3.3 Which Component is to Blame?

From the recent findings on the inhibitory activ-ity of nonflavonoid compounds, it is highly prob-able that psoralens, mainly 6′,7′-dihydroxy-bergamottin, in grapefruit juice are the components

Oral intake of grapefruit juice containing naringin

Microbial metabolism in the gut lumen

Naringenin

Median 5% of dose(range 3-55%)

Median 0.05% of dose(range 0.03-0.1%)

Gut wall metabolism

Naringenin glucuronide

Renal excretion

Urine

?

Faeces

Fig. 4. Presumed fate of naringin in the human body[75,76]

266 Fuhr


responsible for the drug interactions. However a,possibly minor, role of naringenin in grapefruitjuice interactions cannot be excluded. In contrast,it may well be that naringenin supports the inhibi-tory action of other juice components as naringinsupplementation of grapefruit juice reproduciblyincreased its effects in a pilot study,[104] or that amore complex synergy among grapefruit juicecomponents is involved.

4. How to Take Grapefruit JuiceInteractions into Account in Drug Therapy

4.1 Risks of Grapefruit Juice Interactions

Consumption of fruit and vegetables is gener-ally associated with beneficial health effects. Toname the most important ones, cardiovascular dis-eases and cancer are among the diseases possiblypreventable by this kind of food.[105,106] Flavo-noids and other grapefruit juice constituents maycontribute to this action.[107,108] Therefore, it is dif-ficult to create public awareness that grapefruitjuice also confers a health risk.

I have clearly emphasised in this review thatgrapefruit juice interactions are of potential clini-cal relevance in the individual patient for a widerange of drugs. Taking the mechanism of the inter-action into account, this is not surprising becauseCYP3A4 is a major drug metabolising enzyme.Other drugs not tested yet, but also subject toCYP3A4 mediated metabolism, include cholester-ine synthase inhibitors, macrolide antibacterials,antineoplastic agents such as cyclophosphamide,ifosfamide, taxoids, epipodophyllotoxins and

vinca alcaloids, cisapride, indinavir, finasteride,ganisetron and many more. Among others, all thesedrugs could potentially interact with grapefruitjuice.

It appears that the grapefruit juice interactionsare exclusively pharmacokinetic in nature. Thus,the risks related to grapefruit juice intake withdrugs are those seen with an overdose of the drugin question. Currently, there is no clear evidencethat the pattern of metabolites and thus the patternof adverse effects may change with grapefruit juiceat a clinically relevant range. To take this increasein concentrations in to account in drug therapy, Iagree with Lown and colleagues[7] that consistencyof intake of inhibitory substances could be the key.If a patient likes to take drug doses with grapefruitjuice, it would be desirable that she or he does sousing the same dose of the very same juice everyday. This however is not possible. Even a changein the brand or batch of grapefruit juice may influ-ence the grapefruit juice/drug interaction to an un-predictable extent since grapefruit juice is a naturalproduct with an unknown degree of variability incomposition. Standardisation of grapefruit juicewith respect to components causing the interactioncurrently is not feasible because the role of possi-ble candidates is not fully understood.

In addition to the variation in juice composition,one might speculate about the effects that a changein nutritional habits or initiation of antibacterialtherapy might have on the extent of the grapefruitjuice interaction, if indeed intestinal metabolism isnecessary to activate the ingredient(s) of grapefruitjuice.

With respect to interindividual differences indrug pharmacokinetics, grapefruit juice did not de-crease the variation between patients in AUC orCmax (see section 1.2 and tables I to V). Therefore,it appears that drug concentrations obtained by agiven dose are more difficult to predict if takenwith grapefruit juice. This increases the probabilityof inappropriate drug treatment. Avoiding the in-teraction by taking the drug after ingesting grape-fruit juice is not possible because of the long dura-tion of the effect.[6] Drug administration before

O−CH2CH=C−CH2−CH2−CH−C−CH3

O O O

−

CH3

− −−

CH3

OH OH

Fig. 5. Chemical structure of 6′, 7′-dihydroxybergamottin.



drinking grapefruit juice may attenuate the interac-tion but it was still present during long term druguse, presumably because the next dose was af-fected.[29]

Thus, as long as it appears that the extent ofthese interactions is unique for grapefruit juiceamong vegetables and fruits, it seems to be wise torefrain from grapefruit juice consumption whentaking drugs that are subject to a relevant metabo-lism and for which a lack of interaction by grape-fruit juice has not been shown.

When studies have shown that a particular druginteracts with grapefruit juice, most pharmaceuti-cal companies have reacted to the finding by in-cluding the information in the package insert of therespective drug and/or by other appropriate meas-ures and prohibiting concomitant intake of the drugwith grapefruit juice. This should be extended toall drugs that might interact based on their metabo-lism unless a lack of interaction has been proven.To improve public awareness, it might be helpfulto also place the warning in a more prominent lo-cation on the outside of the package. This could beachieved simply by use of a symbol such as acrossed out grapefruit.

4.2 Grapefruit Juice as a Drug-Sparing Agent?

The idea of using grapefruit intentionally as adrug-sparing and cost-reducing agent is a topic ofsome controversy.[2,22,76,109-111] Grapefruit juicecould be used as a drug-sparing agent in a settingsuch as cyclosporin treatment. In this situation,therapeutic drug monitoring takes place and thiswould enable the extent of interaction in the indi-vidual patient to be taken into account. However, aquestion of practical importance is whether thegrapefruit juice effect might increase the need fordose adjustments. This question is difficult to an-swer from experimental data because there are nostudies with repetitions of both the control and thegrapefruit juice period. In one felodipine study, arechallenge with grapefruit juice has been con-ducted under identical conditions and pharmacoki-netic parameters were similar for both grapefruit

juice periods.[9] The periods in this study, however,were only a few days apart.

There is no doubt that grapefruit juice haspotential as a drug-sparing agent. This has beendemonstrated for example in 2 case reports whereantihypertensive[112] or antipsoriasis therapy[113]

efficacy was improved by addition of grapefruitjuice. Indeed, some patients are known to takecyclosporin with grapefruit juice in order to savemoney by reducing doses, and a similar successfulapproach has been described with ketoconazole ordiltiazem without apparent serious adverse ef-fects.[22,23] However, the possibility of an increasedrisk of adverse effects, also associated with sub-sequent costs, may easily outweigh possible costsavings for cyclosporin that were estimated toreach approximately US$1500 per patient andyear.[23]

5. Conclusions

Concomitant intake with grapefruit juice has thepotential to increase the concentrations of manydrugs in humans and this effect is mediated mainlyby suppression of the cytochrome P450 enzymeCYP3A4 in the small intestine wall. The extent ofgrapefruit juice interactions is more pronouncedthan that of many well known drug-drug interac-tions. It is reasonable to assume that increased drugconcentrations may be associated with more pro-nounced drug effects, occasionally even causingtoxicity. The grapefruit interaction does not pro-duce a consistent decrease in the variability of drugpharmacokinetic parameters. Therefore, it is rec-ommended that patients refrain from ingestinggrapefruit juice when taking a drug that is exten-sively metabolised unless a lack of interaction hasbeen already been demonstrated for this particulardrug. It is also recommended that an appropriatelabelled warning should be added to the packagingto such drugs. At present, a place for grapefruitjuice as a drug-sparing agent in the treatment withexpensive medicine cannot be recognised.

268 Fuhr


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2. Bailey DG, Arnold JM, Spence JD. Grapefruit juice and drugs.How significant is the interaction? Clin Pharmacokinet 1994Feb; 26 (2): 91-8

3. Fuhr U, Klittich K, Staib AH. Inhibitory effect of grapefruitjuice and its bitter principal, naringenin, on CYP1A2 depend-ent metabolism of caffeine in man. Br J Clin Pharmacol 1993Apr; 35 (4): 431-6

4. Edgar B, Bailey D, Bergstrand R, et al. Acute effects of drinkinggrapefruit juice on the pharmacokinetics and dynamics offelodipine - and its potential clinical relevance. Eur J ClinPharmacol 1992; 42 (3): 313-7

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6. Lundahl J, Regardh CG, Edgar B, et al. Relationship betweentime of intake of grapefruit juice and its effect on pharmaco-kinetics and pharmacodynamics of felodipine in healthy sub-jects. Eur J Clin Pharmacol 1995; 49 (1-2): 61-7

7. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice in-creases felodipine oral availability in humans by decreasingintestinal CYP3A protein expression. J Clin Invest 1997 May15; 99 (10): 2545-53

8. Bailey DG, Bend JR, Arnold JM, et al. Erythromycin-felodipineinteraction: magnitude, mechanism, and comparison withgrapefruit juice. Clin Pharmacol Ther 1996 Jul; 60 (1): 25-33

9. Bailey DG, Arnold JM, Bend JR, et al. Grapefruit juice-felodip-ine interaction: reproducibility and characterization with theextended release drug formulation. Br J Clin Pharmacol 1995Aug; 40 (2): 135-40

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12. Sigusch H, Henschel L, Kraul H, et al. Lack of effect of grape-fruit juice on diltiazem bioavailability in normal subjects.Pharmazie 1994 Sep; 49 (9): 675-9

13. Rashid TJ, Martin U, Clarke H, et al. Factors affecting the ab-solute bioavailability of nifedipine. Br J Clin Pharmacol 1995Jul; 40 (1): 51-8

14. Sigusch H, Hippius M, Henschel L, et al. Influence of grapefruitjuice on the pharmacokinetics of a slow release nifedipineformulation. Pharmazie 1994 Jul; 49 (7): 522-4

15. Fuhr U, Maier A, Blume H, et al. Grapefruit juice increases oralnimodipine bioavailability [abstract]. Eur J Clin Pharmacol1994 Aug; 47 (1): A100

16. Bailey DG, Arnold JM, Strong HA, et al. Effect of grapefruitjuice and naringin on nisoldipine pharmacokinetics. ClinPharmacol Ther 1993 Dec; 54 (6): 589-94

17. Bailey DG, Munoz C, Arnold JM, et al. Grapefruit juice andnaringin interaction with nitrendipine. Clin Pharmacol Ther1992 Feb; 51 (2): 156

18. Soons PA, Vogels BA, Roosemalen MC, et al. Grapefruit juiceand cimetidine inhibit stereoselective metabolism of

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Correspondence and reprints: Professor Dr med Uwe Fuhr,Institut für Pharmakologie der Universität zu Köln,Klinische Pharmakologie, Gleueler Straße 24, 50931 Köln,Germany.E-mail: [email protected]

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