Terra Sigillata

Compounds in grapefruit juice inhibits an enzyme required for metabolism of nearly half of prescription drugs on the market. If you inhibit drug metabolism, would that allow you to take a lower (and cheaper) dose of one of those drugs, especially an expensive drug?

That is the proposition of a company called Bioavailability Systems, featured in today’s Wall Street Journal and alluded to on the WSJ Health Blog (yes, I cite the WSJ very often but only because they have some of the best medical and health reporting on topics well ahead of the MSM curve).

The intestines and the liver contain many drug metabolizing enzymes but the one in question here is a cytochrome P450 monooxygenase called CYP3A4. The enzyme works on drug molecules to slap on a water-soluble chemical group or remove water-insoluble groups. In most (but not all) cases, this action terminates the biological action of the drug.

In 1991, David Bailey and colleagues at the University of Western Ontario reported in The Lancet that grapefruit juice was found to increase blood levels of felodipine, a calcium channel-blocking antihypertensive drug. The precise reason was that grapefruit juice inhibited the CYP3A4 enzyme, an effect that was later ascribed to a group of compounds called furanocoumarins (bergamottin and 6′,7′-dihydroxybergamottin). So, taking felodipine while drinking grapefruit juice was essentially the same as taking a higher dose of the drug because its elimination from the body was slowed. Today’s WSJ article and blog post discuss the experimental and commercial approach to using CYP3A4 inhibitors as “dose boosters” to minimize the dose one needs to take of some very expensive drugs.

My educated prediction is that this approach might not work as well as expected and, worse, could prove to be quite dangerous.

As with herbal medicines, grapefruit juice content of furanocoumarins varies from different suppliers or different lots at different times of the year. So, it is difficult to predict what dose of grapefruit juice to use to increase drug levels to a specific target level. Companies like Bioavailability Systems propose to get around this issue by making a standardized pill that contains known amounts of inhibitor.

Another concern is that large interindividual differences exist in CYP3A4 activity. That is, a dose of grapefruit juice or some inhibitor pill might block half of my CYP3A4 while totally knocking out yours. For a drug like felodipine, this effect might double my blood concentrations but may cause yours to increase 10-fold.

And this is where I am most concerned. Some CYP3A4 substrates have a very narrow window between their therapeutic concentrations and their toxic concentrations. Fiddling with CYP3A4 may lead to unpredictable increases in drug concentrations to a point that mimics getting an overdose of drug.

The rationale given for using grapefruit juice or a commercial inhibitor pill is that it will allow patients to reduce their doses of expensive, oral drugs and save money. Well, I can guarantee that companies like Bioavailability Systems won’t be offering their pill for free, especially since they have isolated unique, patented CYP3A4 inhibitors. And we’ve already discussed that using grapefruit juice is fraught with difficulties in determining the proper dose.

However, I hate to be a naysayer without actually seeing a few well-designed experiments done. Researchers at the University of Chicago are leading a clinical trial to learn if grapefruit juice can be used safely to increase blood levels (and reduce the dose needed) of the expensive immunosuppressive drug, rapamycin.

Of course, I want to be sure this disclaimer and caution is clear to readers, as written in the WSJ:

Don’t Try This at Home
Experts also warn that people should not try boosting on their own to make an expensive medication last longer or make their medicines more effective. Only a clinical trial can show whether the approach is helpful for an individual drug, they say. And it is impossible to know who will respond too strongly or not at all to the grapefruit effect. In people who take multiple drugs, the approach could backfire by interfering with the effects of other medicines that are already working well without boosting.

Comments

#1 Drugmonkey
November 27, 2007

you buzzkill, you.

now caffeine that has a nice big therapeutic index. mmmmm. morning grapefruit juice to boost the coffee high….
#2 chezjake
November 27, 2007

It’s perhaps wise to mention that probably the most widely prescribed class of drugs that show increased serum levels after consuming grapefruit are the statin type anticholesterol drugs.

That said, it would be nice to know how long the effects of a portion of grapefruit on CYP3A4 last. Since the statins are usually taken on a once a day dosage schedule, it would be helpful to know if it’s actually safe to have grapefruit for breakfast if you are not taking your statin until dinnertime or bedtime. I really miss having fresh grapefruit every once in a while.
#3 Ian Musgrave
November 27, 2007

This is a great commentary and will go straight to my students.

Of course, people who take drugs combined with designer CY3A4 inhibitors will have to be warned not to drink grapefruit juice.

That worked so well with terfenadine.
#4 N.B.
November 27, 2007

I think I’ve seen this mentioned as a “potential money saving method” on local news programs before. I was completely and totally horrified.

DrugMonkey’s post is laugh-worthy. Some of my fellow students had the same reaction when we were talking about drugs affected by CYP3A4 inhibition/induction…
#5 Abel Pharmboy
November 27, 2007

Mega-bummer, DrugMonkey – but I also hate to be a buzzkill on the caffeine thing as well. Turns out that caffeine is N-demethylated by CYP1A2; while grapefruit juice does also inhibit 1A2 (because of naringin and not the bergamottin compounds), it’s not deemed significant enough to increase caffeine’s effect. However, caffeine is well-absorbed through the skin and we could put Starbucks out of business with caffeine transdermal patches – a great adjunct while you or BikeMonkey are out on your long bike treks.

chezjake, good point because increased statin levels could increase risk of muscle pain or the rare rhabdomyolysis. I’m not a doc (nor even a practicing pharmacist) but I think the recommendation might be to drink grapefruit juice in the morning and take the statin at night? Comments?

Prof Musgrave, you pharmacology oracle, yes, you bring up the point about the old Seldane prodrug (terfenadine) that had cardiotoxic effects with another CYP3A4 inhibitor (erythromycin). Torsade de pointes, right? I recall that newer non-sedating H₁-antagonists have to be tested for QT prolongation in both the prodrug and active metabolite forms. Frankly, I think that I must come to Adelaide in person to lecture; perhaps a Friday Fermentable live-blogging session from the Barossa Valley?

N.B., yes, I had seen news coverage of this before but never for a company that was making a proprietary CYP3A4 dosage form for this explicit purpose. In fact, the first time I learned about this strategy was in a newspaper column by Joe and Terry Graedon of NPR’s People’s Pharmacy show – the Q&A from Sept 2004 should still be here.
#6 N.B.
November 27, 2007

I’ve heard mixed things on the grapefruit juice issue with statins. However, according to Pharmacist’s Letter, it takes up to 3 days for CYP enzymes to return to normal after consuming just an eight ounce glass of juice or one grapefruit. The consensus in the profession as I understand it is to cut the stuff out of your diet altogether.
#7 bcpmoon
November 28, 2007

Another concern is that large interindividual differences exist in CYP3A4 activity.

If this difference makes grapefruit as booster dangerous, isn`t that also true without juice? Wouldn`t those differences in enzyme activity have to be taken into account when the right dose of the drug is determined for each individual patient and wouldn`t this dose-finding simply (?) have to be repeated if furanocoumarins were used?
#8 Abel Pharmboy
November 28, 2007

N.B., indeed, if the drug you’re taking is highly affected by grapefruit juice 3A4 inhibition, it’s probably easier to take the stuff out of your diet. However, the Florida Dept of Citrus isn’t too keen on that and the day may come when they begin to sell furanocoumarin-depleted grapefruit juice.

To look more closely at individual drugs and the magnitude of the grapefruit juice effect, the Univ of Florida Center for Food-Drug Interaction Research and Education maintains a searchable database. Mind you, their advisory board contains two members of the Florida Dept of Citrus.

bcpmoon raises a very important point. For drugs with a narrow therapeutic index, like many immunosuppressants, each patient is titrated to therapeutic blood levels. This is obviously not common with drugs that have a much wider therapeutic window but dose-range finding is done empirically by monitoring some endpoint (blood pressure, cholesterol levels, etc.)
#9 Zachary Tong
November 28, 2007

It is common drug lore that drinking grapefruit juice with mushrooms (the psychedelic variety) increases potency and duration. I’ve always been curious if this was true or just some drug superstition, looks like hippies might have known for a while what mainstream is just catching onto.
#10 Abel Pharmboy
November 28, 2007

Zachary, the published literature to date suggests that this drug lore is not based on data.

I assume from your comment that we are talking about psilocybin (from Psilocybe cubensis), the primary psychoactive compound in the mushroom. Its metabolic pathway involves dephosphorylation to psilocin, the metabolite responsible for much of the mushroom’s hallucinogenic effect. This step involves phosphatases, not any CYP.

The next step is an inactivation step involving deamination of psilocin. Most published work indicates this step is catalyzed by monoamine oxidase-A (MAO-A). Blocking this step would increase the concentrations and duration of psilocin action. Psilocin can also be inactivated by glucuronidation (enzymatic attachment of a sugar molecule), but glucuronidation seems to only be minimally inhibited by one grapefruit juice constituent, bergamottin, at relevant concentrations.

However, there is no evidence that grapefruit juice components inhibit either MAO enzyme. Some deamination reactions of tryptamines (like psilocybin & psilocin) could be accomplished by CYP2D6, but the consensus is the CYP2D6 is also not inhibited by grapefruit juice components. So, any step that would increase psilocin levels does not seem to be influenced by grapefruit juice (at least not yet).

There are, of course, several related compounds in Psilocybe but their structures look to me like they would also be MAO substrates, not CYP substrates.

So, the only way that grapefruit juice would increase the potency and duration of Psilocybe-induced hallucinations is
1) grapefruit juice were shown to inhibit MAO-A, or,
2) psilocin deamination were catalyzed by CYP3A4.

At present, the data do not support either of these two scenarios. If anyone out there has data that contradict my present understanding, please write a comment.

Thanks for the question, though. It is certainly worthy of a separate post.

(Usual disclaimers apply that this blog in no way recommends the use of illegal substances nor are we absolutely certain the grapefruit juice has no interaction with hallucinogenic compounds.)
#11 none
November 28, 2007

Well, I knew kids that used grapefruit juice to lower their doses of DXM (dextromethorphan). And what you said in your blog about CYPs having narrow windows is quite right. A kid who would usually take the same dose as the others and drank the same amount of GF juice (approx. same body weight) then overdosed(i.e. very very strong experience). A too small sample, I know, but it kind of points in that direction.

Sorry for the anonymity.
#12 Abel Pharmboy
November 28, 2007

Anon/none: no need to apologize for the anonymity; sounds like a friend had a very bad experience. Yes, indeed, DXM is metabolized by CYP3A4, the enzyme that is so strongly inhibited by GF juice components. Adolescents should be strongly discouraged from screwing around like this.
#13 Dan
November 29, 2007

The DXM alone would explain people thinking psilocybin is grapefruit-enhanced. Drug information has a tendency to slide between different drugs in the same class. The DXM kids are often also the psilocybin kids, and a mix-up between the two over successive retellings could start the ball going nicely.
#14 jen_m
November 29, 2007

Not that I condone such choices or anything, but I recall in my college days (late 80s/early 90s) that there were warnings about psilocybins and MAOIs, and psilocybins and tyramine-containing substances, and that slid over to the then-common MDMA and its relatives. (MDMA is metabolized by COMT and CYP2D6, mostly. So I guess grapefruit juice might be a problem, but aged cheese not so much.)
#15 Vince Noir
November 29, 2007

I hate to be the one to bring this up, but I know an opiate addicted person who used grapefruit juice to increase to duration of his highs. One fellow told me he would drink nearly a bottle of the stuff several hours before taking the drug. If it worked, that could certainly save money!

As a plan for taking less prescription medication? Absolute garbage! The first thing you (should) learn about drug metabolism is that it is extraordinarily complex and unpredictable, both within an individual and within the population. I could see this being a disaster.
#16 MattXIV
November 29, 2007

While certainly nothing to mess around with, I think it would be possible to use CYP3A4 inhibitors to make drugs with narrow therapeutic indices or drugs that rapidly break down safer by slowing the breakdown, so that effective levels in the bloodstream over the same length of time can be obtained with a smaller peak concentration. A sustained-release inhibitor could serve as a substitute for sustained-release formulations for drugs which aren’t ammenable to them. The doses of other effected drugs would have to be kept in mind too, so it’s not an idea substitute, but it may be more useful in this regard than as a simple money saver.
#17 Anon
November 29, 2007

So, not to beat a dead horse, but the concensus is that care should be taken with MDMA? What about MDA?
#18 Dan
November 29, 2007

MDA is chemically very close to MDMA. It’s … MDMA’s mellower half-brother. Generally speaking, anything that applies to MDMA probably applies to MDA.
#19 Becca
November 29, 2007

Does anyone know if glucuronidation is *activated* by any components of grapefruit juice?
Glucuronidation detoxifies almost all substrates, but not morphine… perhaps the opiate-grapefruit juice connection is not through CYPs but UGTs?
#20 Stan
February 12, 2008

I have been using grapefruit juice in combination with “medical marajuana” for some time now the effect is a longer high without having to smoke as much. Nicotine is also affected by grapefruit juice and drinking it thirty minutes before smoking could mean the user can smoke less ciggarettes thus possibly reducing cancer risk and still obtain the same high. To address Zachary grapefruit is not a potent drug booster of the mushrooms which contain psilocybin. The metabolism of psilocybin seems to be more effected by CNS stimulants and SSRI’s than grapefruit juice. It should be noted though that risks of serotonin syndrome are associated with taking drugs that affect the serotenergic system in multiple ways and thus using psilocybin with any other serotonergic effecting drugs should be avoided.
#21 DrugMonkey
February 12, 2008

“there were warnings about psilocybins and MAOIs, and psilocybins and tyramine-containing substances, and that slid over to the then-common MDMA and its relatives. (MDMA is metabolized by COMT and CYP2D6, mostly.”

to clarify jen_m’s point a bit. While MDMA may be metabolized mostly by other mechanisms, the neurotransmitter serotonin is metabolized by one of the Monoamine Oxidases (MAO-A). MDMA, of course, both releases and blocks the re-uptake (into the neuron that just released it) of serotonin. Inhibiting MAO-A would tend to further potentiate the MDMA signal , so to speak.

“So, not to beat a dead horse, but the concensus is that care should be taken with MDMA? What about MDA?”

yes, care should be taken with most any exogenous drug. In the case of MDMA and MDA there are very specific and well-established reasons to do so. Acute mortality being the worst of course but also lasting dysregulation of brain neurotransmission. Is this really not commonly understood?

“MDA is chemically very close to MDMA. It’s … MDMA’s mellower half-brother. Generally speaking, anything that applies to MDMA probably applies to MDA.”

I dunno where you come up with “mellower” and these compounds do have significant differences. But yes, they do share the potential for unregulated hyperthermia and death. With most comparisons between drugs, you want to be very careful that you have some appreciation of the full dose-response function before you attempt comparisons. For any given outcome (subjective “high”, cardiac or respiratory effects, thermoregulatory effects, locomotor stimulation, etc) you are going to have a relationship with the dose administered (well actually the dose that makes it to the relevant receptor population). These relationships may not be entirely consistent across outcome measures. So to ask, “Is DrugX “safer” or “mellower” than DrugY, you need to know something about dose and how this relates to a given outcome measure.