Psychopharm Notes-- Grapefruit + meds

I remember a couple of a years ago when my pdoc warned me about my intake of grapefruit products in combination with Xanax.

Turns out that there is a list of meds that grapefruit can interfere with-- I think it interacts with an enzyme in the intenstine. It can increase the levels of med in the bloodstream, taking it from a therapeutic doseage to just over-- thus, toxic.

I imagine this fact is little known-- my previous pdoc was the only one who ever mentioned it to me-- and he only specified it in regards to Xanax... I didn't know it could interact with other meds until I looked it up myself.

Yes it can as it has an ingredient that competes for the liver enzyme needed to metabolize certain meds. However, unless you have severe liver disease, it would take about 15 grapefruits right before your med to have any real effect. Certain foods can do this too, like BBQ'd or grilled meat, but I have never seen this clinically be a problem. It is interesting in a biochemistry kind of way though. Look of CYP450/psych meds.

The enzyme in question, called CYP3A4, is at least partially responsible for the degradation and elimination of many different drugs. Grapefruit juice inhibits it, leading to delayed clearance (enhanced blood concentrations) of drugs metabolized by it. St. John's wort has the opposite effect; by enhancing clearance, substrate drugs become less effective.

Here is a partial list of drugs affected by grapefruit at 3A4: Acetaminophen, Alfentanil, Alprazolam, Amiodarone, Amitriptyline, Amiodipine, Anastrozole, Astemizole, Atovastatin, Bepridil, Buspirone, Busulfan, Cafergot, Caffeine, Cannabinoids, Carbamazepine, Cerivastatin, Chlorpheniramine, Chlorpromazine, Cimetidine, Cisapride, Clarithromycin, Clindamycin, Clomipramine, Clonazepam, Cocaine, Codeine, Cortsol, Cyclonenzaprine, Cyclophosphamide, Cyclosporin, Dapsone, Delavirdine, Dexamethazone, Dextromethorphan, Diazepam, Diltiazem, Disopyramide, Dolasetron, Donepezil, Doxorubicin, Enalapril, Ergot Alkaloids, Erythromycin, Estrogens(oral), Ethinyl-Estradiol, Ethosuximide, Etoposide, Felodipine, Fentanyl, Fexofenadine, Finasteride, Fluconazole, Flutamide, Gleevac, Glyburide, Granisetron, Haloperidol, Hydrocodone, Hydrocortisone, Ifosfamide, Imipramine, Indinavir, Irinotecan, Isotretinoin(retinoids), Isradipine, Itraconazole, Ketoconazole, Lansoprazole, Lidocaine, Loratadine, Losartan, Lovastatin, Methadone, Miconazole, Midazolam, Mirtazapine, Nateglinide, Navalbine, Nefazodone, Nelfinavir, Nevirapine, Nicardipine, Nifedipine, Nimodipine, Nisoldpine, Nitrendipine, Ondansetron, Oral-contraceptives, Paclitaxel, Pimozide, Pravastatin, Prednisone, Progesterone, Propafenone, Quinidine, Quinine, R-Warfarin, Rapamycin, Rifabutin, Rifampin, Ritonavir, Salmeterol, Saquinavir, Sertraline, Sildenafil, Sirolimus, Simvastatin, Sufentanil, Tacrolimus, Tamoxifen, Taxol, Temazepam, Teniposide, Terfenadine, Testosterone, Theophylline, Tiagabine, Trazodone, Triazolam, Troleandomycin, Verapamil, Vinblastin, Vinca alkaloids, Vincristin, Zaleplon, Zileutin

Grapefruit also affects CYP1A2, and thus reduces clearance of the following: Acetaminophen, Amitriptyline, Caffeine, Clomipramine, Clozapine, Cyclobenzamine, Desipiramine, Diazepam, Ethinyl Estradiol, Fluvoxamine, Haloperidol, Imipramine, Isotretinoin (retinoids), Maxiletine, Methadone, Mirtazapine, Naproxen, Nortriptyline, Olanzapine, Ondansetron, Phenacetin, Propafenone, Propranolol, R-Warfarin, Riluzole, Ritonavir, Ropivacaine, Tacrine, Tamoxifen, Theophylline, Verapamil, Warfarin, Zileuton, Zolmitriptan

Drug lists are from http://www.edhayes.com/CYP450-4.html They should not be considered to be complete lists.

If you habitually consume grapefruit or its juice, and you're on a stable dose of a drug, you have nothing to worry about. Your dose of drug has been titrated during a period of stable inhibition. Problems could arise, though, if you use grapefruit products irregularly. Serum drug concentrations could change quite significantly between periods of use and abstention.

Lar

My mom takes Lipitor, and on the safety data sheet, it mentions not to take with grapefruit juice.
She thinks that means she shouldn't drink the stuff, was it wrong for me to tell her it's okay if not near the time she takes the med? She takes the med in the PM before going to bed, but if she has grapefruit in the AM hours is it safe then?

Does the general rule of grapefruit affecting contraceptive efficacy still apply even if you are taking the Pill at a 'stable' dose and also having grapefruit regularly?

My pill is Yasmin.

I think it was on my Lamictal insert not to drink grapefruit juice.--Suzy

She shouldn't drink it at all. The duration of the grapefruit inhibition of 3A4 is roughly 3 days. Of course, the dose of grapefruit juice, and the manner in which it is prepared (home-made is safer than commercial), etc. etc. influence things, also. Because there are toxic consequences from statin overdose, the prohibition is quite reasonable. Not all statin drugs are affected to the same extent, so you can't generalize......but Lipitor is definitely affected by grapefruit.

Lar

It'll be affected, yes. The question is, by how much? As far as I can tell, the influence of grapefruit on the two active ingredients would be quite modest.....perhaps a 30% increase in blood concentration of the estradiol, and about 20% for the drospirenone. The risk, if any, would come from stopping the grapefruit. Breakthrough bleeding would be a sign that hormone levels had fallen into the "risky" zone.

Lar

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psisci said:
Yes it can as it has an ingredient that competes for the liver enzyme needed to metabolize certain meds. However, unless you have severe liver disease, it would take about 15 grapefruits right before your med to have any real effect.

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I'm a little concerned about blanket statements such as this one. There are far too many variables than to generalize in this way. For some drugs, the grapefruit effect is quite dramatic. The statin drug Simvastatin demonstrated an AUC (total drug exposure) increase of 1250%, with Cmax (peak blood concentration) increased 1104%. Buspar (buspirone) showed ncreased Cmax of about 4-fold, and increased AUC 9-fold. Luvox (fluvoxamine) more than doubled, whereas Zoloft (sertraline) and Tegretol (carbamazepine) increased by about 50%. There is a real risk of over-sedation from most benzodiazepine drugs. Someone accustomed to taking a benzo before getting into their car could be seriously impaired by washing it down with grapefruit juice.

The studies which provided the numbers I reference above used doses of between 200 mL and 1200 mL grapefruit juice per day. Even at the maximum tested, that's less than 15 fruits. And the inhibition zone that matters most is not in the liver; it is in the intestinal wall. Bioavailability of the drugs is what is most affected (intestine), not half-life (liver).

Lar

I am not sure where these numbers came from, but in all my pharmacology training, every study that has been reviewed has show miniscule elevations for psych meds with normal grapefruit ingestion. I have never met a pharmacologist or psychiatrist who worries about grapefruit. I guess I would only worry about this if someone started a new med that was heavy on 3A4, and the person was just starting a grapefruit diet. The problem with stable kinetics and dynamics studies of any sort is that they are invitro and do not account for the incredible dynamics of a living system. Someone who eats grapefruit for breakfast daily will have upregulated prodiction of the needed enzymes, which will increase clearance of grapefruit and allow for equilibrium if another med or substance needs those enzymes.

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psisci said:
I am not sure where these numbers came from, but in all my pharmacology training, every study that has been reviewed has show miniscule elevations for psych meds with normal grapefruit ingestion.

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Simvastatin:
http://www.ncbi.nlm.nih.gov/entrez/q..._uids=11061578
http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=9834039
The second abstract shows massive inter-individual variability in Cmax increase: mean about 9-fold (range, 5.1-fold to 31.4-fold; P < .01).

Buspirone:
http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=9871430
Again, large variability: "Grapefruit juice increased the mean peak plasma concentration of buspirone 4.3-fold (range, 2-fold to 15.6-fold; P < .01) and the mean area under the plasma buspirone concentration-time curve 9.2-fold (range, 3-fold to 20.4-fold; P < .01)."

Fluvoxamine:
J Clin Psychopharmacol. 2003 Aug;23(4):422-4. (I used a secondary citation of this original, abstract not available)

Sertraline:
http://www.ncbi.nlm.nih.gov/entrez/q..._uids=10890261

Carbamazepine:
http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=9757152

Diazepam (Valium):
http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=9625273
"The mean AUC(0-24) of diazepam was increased 3.2-fold (P < 0.001) and Cmax was increased 1.5-fold (P < 0.05) by the grapefruit juice." ....after a single glass of grapefruit juice (250 mL = approx. 8 oz.).

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I have never met a pharmacologist or psychiatrist who worries about grapefruit.

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That scares me. 50% of all meds are metabolized, at least in part, by 3A4.

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I guess I would only worry about this if someone started a new med that was heavy on 3A4, and the person was just starting a grapefruit diet. The problem with stable kinetics and dynamics studies of any sort is that they are invitro and do not account for the incredible dynamics of a living system.

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I only quoted in vivo (human) work.

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Someone who eats grapefruit for breakfast daily will have upregulated prodiction of the needed enzymes, which will increase clearance of grapefruit and allow for equilibrium if another med or substance needs those enzymes.

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None of the work that I studied showed any evidence of induction of intestinal 3A4 over time. Liver induction is about clearance. This issue is about bioavailability. Luminal 3A4 is the concern.

Lar

I'm amazed that yet another debate has occurred on the support forums.

The grapefruit effect was accidently discovered about ten years ago... and while there are pharmacists that caution against drinking or eating it while on various medications, I am led to believe it's because of the haphazardness of the patient himself and not the real worry over the interactions. By this I mean that since everyone is different, and some might have some affect, it's because they can't remember what they ate or drank when in determining when they take their meds.imo

I do think I read that Dr Wylie was discussing PSYCH meds, and I'll go with him on this.

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Larry_Hoover said:
The enzyme in question, called CYP3A4, is at least partially responsible for the degradation and elimination of many different drugs. Grapefruit juice inhibits it, leading to delayed clearance (enhanced blood concentrations) of drugs metabolized by it. St. John's wort has the opposite effect; by enhancing clearance, substrate drugs become less effective.

Here is a partial list of drugs affected by grapefruit at 3A4: Acetaminophen, Alfentanil, Alprazolam, Amiodarone, Amitriptyline, Amiodipine, Anastrozole, Astemizole, Atovastatin, Bepridil, Buspirone, Busulfan, Cafergot, Caffeine, Cannabinoids, Carbamazepine, Cerivastatin, Chlorpheniramine, Chlorpromazine, Cimetidine, Cisapride, Clarithromycin, Clindamycin, Clomipramine, Clonazepam, Cocaine, Codeine, Cortsol, Cyclonenzaprine, Cyclophosphamide, Cyclosporin, Dapsone, Delavirdine, Dexamethazone, Dextromethorphan, Diazepam, Diltiazem, Disopyramide, Dolasetron, Donepezil, Doxorubicin, Enalapril, Ergot Alkaloids, Erythromycin, Estrogens(oral), Ethinyl-Estradiol, Ethosuximide, Etoposide, Felodipine, Fentanyl, Fexofenadine, Finasteride, Fluconazole, Flutamide, Gleevac, Glyburide, Granisetron, Haloperidol, Hydrocodone, Hydrocortisone, Ifosfamide, Imipramine, Indinavir, Irinotecan, Isotretinoin(retinoids), Isradipine, Itraconazole, Ketoconazole, Lansoprazole, Lidocaine, Loratadine, Losartan, Lovastatin, Methadone, Miconazole, Midazolam, Mirtazapine, Nateglinide, Navalbine, Nefazodone, Nelfinavir, Nevirapine, Nicardipine, Nifedipine, Nimodipine, Nisoldpine, Nitrendipine, Ondansetron, Oral-contraceptives, Paclitaxel, Pimozide, Pravastatin, Prednisone, Progesterone, Propafenone, Quinidine, Quinine, R-Warfarin, Rapamycin, Rifabutin, Rifampin, Ritonavir, Salmeterol, Saquinavir, Sertraline, Sildenafil, Sirolimus, Simvastatin, Sufentanil, Tacrolimus, Tamoxifen, Taxol, Temazepam, Teniposide, Terfenadine, Testosterone, Theophylline, Tiagabine, Trazodone, Triazolam, Troleandomycin, Verapamil, Vinblastin, Vinca alkaloids, Vincristin, Zaleplon, Zileutin

Grapefruit also affects CYP1A2, and thus reduces clearance of the following: Acetaminophen, Amitriptyline, Caffeine, Clomipramine, Clozapine, Cyclobenzamine, Desipiramine, Diazepam, Ethinyl Estradiol, Fluvoxamine, Haloperidol, Imipramine, Isotretinoin (retinoids), Maxiletine, Methadone, Mirtazapine, Naproxen, Nortriptyline, Olanzapine, Ondansetron, Phenacetin, Propafenone, Propranolol, R-Warfarin, Riluzole, Ritonavir, Ropivacaine, Tacrine, Tamoxifen, Theophylline, Verapamil, Warfarin, Zileuton, Zolmitriptan

Drug lists are from http://www.edhayes.com/CYP450-4.html They should not be considered to be complete lists.

If you habitually consume grapefruit or its juice, and you're on a stable dose of a drug, you have nothing to worry about. Your dose of drug has been titrated during a period of stable inhibition. Problems could arise, though, if you use grapefruit products irregularly. Serum drug concentrations could change quite significantly between periods of use and abstention.

Lar

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Surely there are some psyc meds in here _Sky?



My question was simply as an aside as I assumed the chemical process would be similar. Sorry for the distraction.

I guess it's just jump on professionals week??

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Surely there are some psyc meds in here _Sky?

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From the list I posted, here are the psych drugs (that I recognize) affected by grapefruit at 3A4: Alprazolam, Amitriptyline, Buspirone, Carbamazepine, Chlorpromazine, Clomipramine, Clonazepam, Diazepam, Diltiazem, Haloperidol, Imipramine, Mirtazapine, Nefazodone, Sertraline, Temazepam, Tiagabine, Trazodone, Triazolam, Verapamil.

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My question was simply as an aside as I assumed the chemical process would be similar. Sorry for the distraction.

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Surely, it is the same issue. I used both psych and non-psych drugs to demonstrate just how powerful this effect can be. I reiterate that my concern was the general dismissal of this issue as being relevant to psych meds. The reference I used for Valium shows more than tripling of the the blood concentration from a single glass of grapefruit juice. 5 to 9-fold increase for Buspar. These are effects of which we are aware. The list I provided is not complete, by any stretch of the imagination.

Lar

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_Sky said:
I guess it's just jump on professionals week??

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What do you mean?

This has been a debate between two of the experts on the site.

If you are grumpy over someone asking a question on a female contraceptive just because it seemed to be a pertinent place to do so - rather than clogging up the forum with another post - because it is not a PSYCH med ... then I feel that is a bit poo.

I only asked because presumably the action of grapefruit is similar on both.

I don't see any professionals getting jumped on, apart from maybe some sparky pharmacological debate between our resident experts.

peace.

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_Sky said:
I guess it's just jump on professionals week??

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I'm a toxicologist (disabled). I'm trying to be informative.

Lar

thanks larry.

I am always willing to learn. I meant in viro, not because they were not in humans, but that they were static studies that do not take into account the way biochemistry changes to adapt over time. I am not arguing that grapefruit has no effect on medication absorbsion and metabolism, but that it is rarely clinically relevant. I have been working with meds and patients for over 10 years and have never seen or heard of a problem.

As a Dr of tox you should speak up alot more often about drugs etc..... I have science training, but am not a scientist. I know the difference as my wife is a PhD biochemist, and can't figure out what med to take when she gets the flu. I bring a strong clinician perspective about meds, and we could use a strong science perspective as well. Whatta ya think?

Thank you.....I honestly would like to contribute more, but my health precludes it. There have certainly been threads I thought about posting to, but I couldn't rise above lurker mode.

Lar

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Larry_Hoover said:
Thank you.....I honestly would like to contribute more, but my health precludes it. There have certainly been threads I thought about posting to, but I couldn't rise above lurker mode.

Lar

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*hugs*

your contributions have ALWAYS been valued so much in the past ... post when you feel able to though au?

xx

am on Wellbutrin SR and Seroquel need I be aware?

Larry, I agree with DSF on this.

In fact info that you and/or psisci can provide here is quite an asset. Larry, I have always appreciated what you contribute here and admire your experise.
Thanks

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darkeyes said:
Larry, I agree with DSF on this.

In fact info that you and/or psisci can provide here is quite an asset. Larry, I have always appreciated what you contribute here and admire your experise.
Thanks

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Yea ... I almost regard it as 'independent' information that is well above the level most GPs are able to advise.

I recall asking someone on here (maybe you, maybe psisci) something about how ADs were supposed to work, as according to a gp.

I got a 'Who told you that? It is BS' response.

(in essence).

Reading up a bit ... it kinda was simplified I guess ... or maybe just a part of it.

How else would I have got that info?

I may hate meds / drs but I am kinda a 'ok do whatever just to get out of there' type - I'll believe anything, especially if it seems well intentioned.

So I suppose ... to be able to ask over an internet forum ... and received the knowledge of the two of you (and there's someone else too isn't there? name escapes) ... is very privileged, even if it is only to challenge what one is told IRL and provide some food for thought.

kia ora (thank you)

edited for extremely bad spelling :>