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What is the basis for this warning? Is it the acidity of the juice or
something else? If it is the acidity, there are other juices that should
be mentioned > cranberry for one example.
At 10:47 AM 9/10/97 -0500, you wrote:
>PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
>Dear Fellows,
>
>Should drugs that have or are suspected of having possible clinically
>significant interaction with grapefruit juice, have warnings against it in
>patient=EDs inserts and/or doctor=EDs data sheets?
>
>I am asking this because of the replies to my question (ANCHODD and
>PharmCare) regarding the existence of such warnings. As you may have seen
>there are warnings for terfenadine in the UK, felodipine in Australia and
>indinavir and saquinavir as well.
>
>Both felodipine and terfenadine have proven interaction with grapefruit
>juice. On the other hand neither indinavir nor saquinavir have been shown
>to interact with grapefruit juice. Yet they both have the potential of such
>an interaction as they have low bioavailability and major CYP 3A4
metabolism.
>
>What about cyclosporin and nisoldipine, both having documented interactions
>with grapefruit juice?
>Should cisapride have a warning as well?
>
>Sincerely,
>Ofer Spiegelstein
>
>*********************************************************************
>Ofer Spiegelstein
>Department of Pharmacy
>The Hebrew University of Jerusalem
>P.O.Box 12065, Jerusalem 91120
>Israel
>ofersp.aaa.cc.huji.ac.il
>**********************************************************************
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Greetings, Ofer!
On Wed, 10 Sep 1997, Ofer Spiegelstein wrote:
> PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
> Dear Fellows,
>
> Should drugs that have or are suspected of having possible clinically
> significant interaction with grapefruit juice, have warnings against it in
> patient=CCs inserts and/or doctor=CCs data sheets?
Ideally, the answer would be yes. However, as I'm sure you're aware,
most office based physicians are not knowledgeable about food/drug
interactions. Thus, this task falls onto the pharmacist to inform the
patient. It only becomes a part of the package label if the country's
drug regulatory agency specifically asks for it, and that occurs,
unfortunately, after something bad has happened.
> Both felodipine and terfenadine have proven interaction with grapefruit
> juice. On the other hand neither indinavir nor saquinavir have been shown
> to interact with grapefruit juice. Yet they both have the potential of such
> an interaction as they have low bioavailability and major CYP 3A4
>metabolism.
In the US, these drugs' labels do not mention grapefruit juice as a
interacting agent. One could claim that the interaction with saquinavir
is beneficial because the bioavailability of saquinavir is so poor.
> What about cyclosporin and nisoldipine, both having documented interactions
> with grapefruit juice?
> Should cisapride have a warning as well?
In our hospital, we have a listing of food-drug interactions that
pharmacists inform the nurses/prescribers of when they are seen when
orders are written. It includes the above drugs, except nisoldipine only
because it is not on our formulary. At least an effort is made to avoid
the interaction when it is seen.
I hope this information proves useful.
With best regards,
Dr. Vince Pearson
Drug Information Pharmacist
The Johns Hopkins Hospital
Baltimore, Maryland USA
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The interaction of several drugs with grapefruit juice is thought to be due
to the presence of a bioflavonoid in the juice (most likely naringin which
is metabolized to naringenin in man) and inibition of in vivo cytochrome
P450 mediated drug oxidation, and is not related to the juices acidity.
However the exact nature of the interaction has not, to my knowledge, been
unequivocally demonstrated. Naringin is the major bioflavonoid in
grapefruit juice (in fact this is what gives the juice its bitter taste),
but is not found in many other juices such as orange juice. There are many
compounds for which an interaction with grapefruit juice has been
demonstrated (several 1,4 dihydropyridines including nifedipine,
felodipine, nisoldipine, and other drugs such as caffeine, coumarin,
terfenadine, midazolam, cyclosporine, and 17 beta-estradiol come to mind).
One important point about the nature of these interactions is the rather
large interindividual variability with respect to observed increases in
drug bioavailability and also the differences observed in the magnitude of
the grapefruit juice effect for different drugs. Hence, in my opinion the
magnitude (and variability) of the interaction should be evaluated for each
specific compound to determine if label warnings should be added to package
inserts or data sheets.
Sincerely,
John S. Grundy
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[Another popular topic - db]
From: "Tata, Prasad"
To: "'PharmPK.-at-.pharm.cpb.uokhsc.edu'"
Subject: Grapefruit juice-drug interaction warnings
Date: Thu, 11 Sep 1997 13:57:17 -0400
MIME-Version: 1.0
Grapefruit juice known to inhibit the metabolism of drugs that are
metabolized CYP-450 3A4 isozyme. Very popular example is
Terfenadine-Grapefruit interaction quoted in media as is your cough
medicine (Terfenadine) and your breakfast do not see eye to eye?
something like this.
Grapefruit known to ihibit the metabolism of cyclosporine.
The rationale for this type of drug interaction is believed to be
Syringinine a constituent of grapefruit juice? But there is no
conclusive proof Syringinine alone is responsible for this interaction.
Hope this clarifies.
Prasad Tata, Ph.D.
Division of Bioanalytical & Drug Metabolism
Otsuka America Pharmaceutical, Inc.
2440 Research Blvd.
Rockville. 20850
***
From: Jane.Duffy.-at-.adis.co.nz (Duffy, Jane)
To: PharmPK.-at-.pharm.cpb.uokhsc.edu (PharmPK),
vlewis.-a-.bite.db.uth.tmc.edu (Multiple recipients of PharmPK)
Mime-Version: 1.0
Date: Fri, 12 Sep 1997 09:01:56 +1200
Subject: Grapefruit juice-drug interaction warnings
For more details on grapefruit juice interactions see:
Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clinical
Pharmacokinetics 1997 August; 33 (2): 103-121
'The predominant mechanism for enhanced bioavailability is presumably the
inhibition of oxidative drug metabolism in the small intestine. The
consistent findings across studies of diverse cytochrome P450 (CYP) 3A
substrates support the mechanistic hypothesis that 1 or more grapefruit
juice components inhibit CYP3A enzymes in the gastrointestinal tract.'
>From abstract of the above article.
Hope this is informative.
Regards,
Jane Duffy
Publication Manager, Clinical Pharmacokinetics
Adis International
New Zealand
***
Date: Thu, 11 Sep 1997 14:28:58 -0700
From: bmurray.aaa.chsd.org (Bill Murray)
Reply-To: bmurray.-a-.chsd.org
Organization: Children's Hospital Pharmacy San Diego
MIME-Version: 1.0
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Grapefruit juice-drug interaction warnings
From what I understand, grapefruit juice (I don't know if a specific
chemical has been isolated) has been shown to inhibit the CYP1A2 enzyme
system. The acidity has nothing to do with these warnings.
Does anybody know the clinical significance of grapefruit juice
interactions? How much grapefruit juice needs to be ingested to see
this? How long does the interaction last, etc.? Any other drugs to be
worried about?
Bill Murray Pharm.D.
Children's Hospital San Diego
***
Date: Fri, 12 Sep 1997 08:06:13 +1200
From: Carl Kirkpatrick
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: Grapefruit juice-drug interaction warnings
Mime-Version: 1.0
Dear Dr Lewis,
you wrote,
>What is the basis for this warning? Is it the acidity of the juice or
>something else? If it is the acidity, there are other juices that should
>be mentioned > cranberry for one example.
Please see the commentary in Cinical Pharmacology and Therapeutics
Vol 61, 4:395:400 1997. This article by David J Spence discusses in
depth interactions with grapefruit juice.
It is nothing to do with the acidity of the juice. Grapefruit juice contains
naringenin which is the aglycone of naringen, a bioflavinoid. Naringenin
would appear to be in higher concentrations in grapefruit than other
citrus species, however this does need further investigation. It is
known that naringenin is a 3A4 inhibitor. It has also been suggested
that there may be a chemical in grapefruit which inhibits 1A2.
The inhibiting effect of grapefruit juice is remarkable, with increases in
AUC with drugs metabolised by 3A4 pathway ranging from 2 to 10 fold
This is particularly important for drugs such as terfenadine (causing QT
prolongation), cyclosporin , calcium channel blockers, cisapride,
HMGCoA reductase inhibitors, and midazolam.
Carl Kirkpatrick
Department of Clinical Pharmacology
Christchurch
New Zealand
***
X-Sender: sdyoo.-at-.yurim.skku.ac.kr (Unverified)
Mime-Version: 1.0
Date: Fri, 12 Sep 1997 11:35:33 +0900
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
From: Sun Dong Yoo
Subject: Grapefruit juice-drug interaction warnings
Re.: Grapefruit juice and drug interaction
Grapefruit juice is known to inhibit the CYP3A4 metabolism in small bowel
enterocyes but not in the liver or colon. This inhibition is primarily due
to naringen, naringenin and 6',7'-dihydroxybergamottin and possibly other
constituents contained in the juice. Even one drink or one grapefruit
within hours of ingestion may significantly increase the Cmax (up to 700%)
of drugs metabolized by CYP3A4 (e.g., terfenadine, nisoldipine,
cyclosphorine) and such increases may be of clinical significance. Orange
juice does not appear to possess such activity.
Lown K.S. et al., J. Clin. Invest. 99:2545-2553, 1997
Benton R.E. et al., Clin. Pharmacol. Ther. 59:383-388, 1995
Bailey D.G. et al., Clin. Pharmacol. Ther. 60:25-33, 1996
Edwards D.J. et al., Drug Metab. Dispos. 24:1287-1290, 1996
http://pharminfo.com/pubs/msb/gfj_effect.html#spence
***
Comments: Authenticated sender is
From: "Ralph Quadflieg"
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Date: Fri, 12 Sep 1997 15:13:26 +0000
Subject: Grapefruit juice-drug interaction warnings
X-Confirm-Reading-To: "Ralph Quadflieg"
X-pmrqc: 1
Priority: normal
> What is the basis for this warning? Is it the acidity of the juice or
> something else? If it is the acidity, there are other juices that should
> be mentioned > cranberry for one example.
Dear listmember,
grapefruit juice (the only citrus fruit juice) has an enzyme
inhibitory effect.
It is discussed that some of the flavonoid glycosides (narigin or the
aglycon naringenine) which are partly responsible for the bitter
taste of grapefruit juice, are the active compounds.
There are several in vitro results, that there is an
Cytochrome P450 IIIA4 inhibiting effect with these flavonoids,
but in vivo studies with the pure flavonoid are sparse and
without a clear outcome.
Additionally there are some more compounds wich occur in grapefruit
juice and not in orange juice (wich does not act as an enzyme
inhibitor). These compounds (coumarins and psoralens) also showed
enzyme inhibitory properties.
As far as I know there is nobody, who really knows what compound it
is, which inhibits the metabolism of drugs metabolized by
Cyt. P450 IIIA4.
I hope this information is helpful
Greetings from Bonn, Germany
Ralph Quadflieg, Pharm D
Department of Pharmaceutical Technology and Biopharmacy
Universtity of Bonn
An der Immenburg 4
D-53121 Bonn
Germany
Phone: ++49 228 73-5117
Fax: ++49 228 73-5268
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I want to add a new twist to the current knowledge on the inhibition of P450
3A4 isozyme
by constituents present in the grapefruit juice.
There is convincing data in the literature that grapefruit juice constituents
inhibit P450 3A4
metabolism in the gut but not liver. This findings provide a simple and
practical method of
distinguishing gut versus hepatic first-pass metabolism of highly cleared
drugs. All one would
have to do is to assess the degree of first-pass metabolism produced by
pretreatment with
ketoconazole (potent inhibitor of 3A4 in the liver and gut) and grapefruit
juice. The difference in
clearances between these two treatments could then be utilized in calculating
the
contribution of first-pass metabolism by gut. Optimal conditions for such a
study would naturally
would have to be worked out. There is no simple method currently to
distinguish
between gut versus hepatic first-pass metabolism without the use of
intravenous administration.
I would be most grateful for any comments and suggestions on my above
hypothesis.
Aziz Karim, Ph.D.
Aakari.-at-.msn.com
Chicago, Illinois, USA
Tel: (847) 982-4628
Fax: (847) 982-4734
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I disagree with the experimental method proposed by Dr. Karim for
determination of the contribution of the gut to the bioavailability of
compounds metabolized by CYP3A4. Ketoconazole would also alter the
systemic clearance of the compound you want to evaluate; hence, comparison
of oral clearances of a compound given with grapefruit juice or
ketoconazole would give inaccurate results for the contribution of the gut
to the bioavailability of a compound (i.e., when comparing bioavailability,
relative bioavailability calculations, one assumes that systemic clearance
remains constant). However, based on somewhat similar reasoning a simpler
experiment can be done. Just compare the relative oral bioavailability of
your compound adminstered without and with grapefruit juice (assuming that
grapefruit juice does not affect systemic clearance; this has been shown
with compounds such as cyclosporine and midazolam). This is analagous to
the ratio of F(without grapefruit juice) to F(with grapefruit juice) which
gives Fg (i.e., F=Fg*Fh; where F is oral bioavailability and Fg and Fh are
the fractions of the dose escaping destruction in the gut and liver,
respectively).
John S. Grundy, Ph.D.
jgrundy.at.lilly.com
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[A collection of replies - db]
From: Picogram.-at-.aol.com
Date: Mon, 15 Sep 1997 22:03:02 -0400 (EDT)
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: Grapefruit juice-drug interaction warnings
I am intrigued by Dr Karim's thinkings on grapefruit inhibiting only gut 3A
metabolism. This is certainly a departure from current ideas. Could someone
please provide a citation? I also wonder if anyone has given thought to
grapefruit's contribution to p-glycoprotein (MDR1) inhibition? If indeed, as
thought, PGP works in concert with 3A gut metabolism it makes sense to me
that there may be some inhibitors that effect either both or just one of the
two systems. By the same token, it also makes sense that there could well be
some agents which are substrates for only one of the two systems (i.e., PGP
but not 3A).
Certain enigmatic drug interactions occur which are not predicted by current,
state of the art, in vitro prediction models. As an example of this, I
invite everyone to look at the drug interaction section of the label from
HMR's fexofenadine HCl. I know of no data available in the literature to
explain these findings, and offer no speculation. I just think that it is
things like this that demonstrate weaknesses in our current mechanistic
paradigm of drug interactions.
I would really appreciate thoughts on this.
***
Date: Tue, 16 Sep 97 03:58:15 UT
From: "Aziz Karim"
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Grapefruit juice interaction
I appreciate the comments made by Dr Grundy. His comments still do not
contradict the interesting possibility that grapefruit juice can be used (even
without ketoconazole) for determining the extent of gut first-pass metabolism.
In my suggested design, grapefruit juice and ketoconazole wo uld not have been
given together but in a crossover fashion after a suitable washout period.
This would bring the clearance of the test drug back to the control level
similar to what we do in a comparative crossover bioavailability studies. This
of course assumes that the inhibitory activity of both ketoconazole and
grapefruit juice are reversible (not an unresonable assumption)
Aziz Karim, Ph.D.
***
Date: Tue, 16 Sep 1997 04:17:36 +0000 (GMT)
From: SKERJANEC ANDREJ
Subject: Grapefruit juice-drug interaction warnings
To: "PharmPK.at.pharm.cpb.uokhsc.edu"
Autoforwarded: false
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Hop-count: 1
Dr. Karim:
There are several well described experimental approaches to studying the
oral bioavailability of drugs. To accurately assess the contribution of
individual components such as the fraction of absorbed dose, gut and liver
extraction is no simple task. There is a series of excellent articles
published recently by Seattle group (Thummel) on midazolam and Benet's
work with cyclosporin. In my opinion, these articles are particularly
valuable since the assessments were conducted in humans. If more
physiological and direct approach is desired, animal models are the only
alternative. The group at the University of Alberta (led by Y.K. Tam) has
published a series of papers, describing instrumented conscious dog model
that provides a very powerfull tool to evaluate the first-pass effects in
a great detail.
I hope this helps and provides some guidance for your experimental design.
Andrej Skerjanec, Ph.D.
Lilly Laboratories for Clinical Research
askerjan.-at-.lilly.com
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There are 6 examples of grapefruit juice interaction noted in the current PDR:
PLENDIL (felodipine)
The bioavailability of PLENDIL is not influenced by the presence of food in
the gastrointestinal tract. In a study of six patients, the bioavailability of
felodipine was increased more than two-fold when taken with doubly
concentrated grapefruit juice, compared to when taken with water or orange
juice. A similar finding has been seen with some other dihydropyridine calcium
antagonists, but to a lesser extent than that seen with felodipine.
NEROAL Capsules (cyclosporine)
Patients should be given careful dosage instructions. Neoral(R) Oral Solution
(cyclosporine) oral solution for microemulsion) should be diluted, preferably
with orange or apple juice that is at room temperature. Grapefruit and
grapefruit juice affect metabolism of cyclosporine and should be avoided.
SULAR (nisoldipine)
Nisoldipine should not be administered with grapefruit juice as this has been
shown, in a study of 12 subjects, to interfere with nisoldipine metabolism,
resulting in a mean increase in Cmax of about 3-fold (ranging up to about
7-fold) and AUC of almost 2-fold (ranging up to about 5-fold). A similar
phenomenon has been seen with several other dihydropyridine calcium channel
blockers.
CRIXIVAN Capsules (indinavir)
Administration of a single 400-mg dose of indinavir with 8 oz. of grapefruit
juice resulted in a DECREASE in indinavir AUC (26% +/- 18%). Administration of
a single 400-mg dose of indinavir with 200 mg of quinidine sulfate resulted in
a 10% +/- 26% increase in indinavir AUC.
XANAX (alprazolam)
Available data from clinical studies of benzodiazepines other than alprazolam
suggest a possible drug interaction with alprazolam for the following:
diltiazem, isoniazid, macrolide antibiotics such as erythromycin and
clarithromycin, and grapefruit juice.
LEXXEL (felodipine)
As with other dihydropyridine calcium channel blockers, the bioavailability of
felodipine was increased when taken with grapefruit juice, compared to when
taken with water or orange juice.
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In reference to the above subject. I would like to add
" Drug Interactions with Grapefruit Juice"
Barbara Ameer and Randy A. Weintraub
Clin. Pharmacokinet. 1997 33, 103-121.
This seems to be a useful review
Another article I stumbled was
"The fate of Naringinin in humans: a key to grapefruit juice-drug
interactions"
Fuhr U and Kummert, A.
Clin Pharmacol. Ther. 1995, 58: 365-73.
Prasad Tata
>
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