Rapamycin and Grapefruit Juice

How much grapefruit juice can impact Rapamycin dose? I drink a sparkling water that says “less than 1 percent grapefruit juice” in a 20 ounce container. Could that little concentration impact things?

It seems way too low to worry about. It was an 8oz glass or grapefruit juice as I understand it. You’re drinking far less. Unlikely to have much of an effect.

Here was the dosing protocol with grapefruit juice and rapamycin:

For the sirolimus plus grapefruit juice study, sirolimus was administered alone in week 1 and with grapefruit juice starting in week 2, one day prior to sirolimus. Grapefruit juice (supplied by Florida Department of Citrus), 240 cc, was administered once daily without interruption. This dosing was based on research demonstrating that the half-life of intestinal enzyme inhibition of grapefruit juice is 12 hours(21) thus providing time for modulation prior to sirolimus dosing.

Many drugs contain warnings to avoid grapefruit juice or other members of the Rutaceae family, including Seville oranges and pummelo, but this is the first cancer study to harness this drug-food interaction.

Research discovered that grapefruit juice is a potent inhibitor of intestinal CYP3A4, CYP1A2, and CYP2A6 (27).
In fact, small bowel enterocyte CYP3A4 protein levels begin to decrease within hours of grapefruit juice administration and the effect is maximal if grapefruit juice is ingested simultaneously or within the previous four hours of drug administration.

Furthermore, the half-life of the effect is approximately 12 hours and enzyme levels are reduced by a mean of 62% even after 5 days of grapefruit juice consumption (21). The reduction in protein level is likely post-transcriptional requiring de novo CYP3A4 synthesis (27). Although the magnitude of the interaction is highly variable, it is reproducible within individuals and seems to be dependent on small bowel CYP3A4 content, i.e. persons with the highest intestinal CYP3A4 content have the largest reduction in enzyme levels and subsequently the greatest effect on drug metabolism (2730).

Interestingly, different grapefruit juice formulations appear to vary in inhibitory potency and therefore, in consultation with the Florida Department of Citrus, we employed a frozen concentrate product that was tested for furanocoumarin levels prior to delivery of each batch. This ensured consistency across cohorts and is something that must be kept in mind for future studies or applications. Of course, one advantage of grapefruit juice is that it is non-toxic without risk of overdose. Therefore, we have at our disposal an agent that can markedly increase drug bioavailability (in this study by approximately 350%) and, critically in the current environment, decrease prescription drug spending on many agents metabolized by P450 enzymes.

Background here:

Thank you for the bevy of info in your response. Extremely helpful.

1 Like

I found this study: Phase 1 Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients

I like this study because it looked at the effect of Grapefruit juice on maximum concentration and area-under-curve (AUC) for a once-weekly dose.

It found about a 2.5x increase in max concentration and a ~6x increase in AUC for a 15mg dose.

Grapefruit juice was administered daily at 240cc throughout.

My hypothesis is that Grapefruit juice 6 hours prior to dose, 24 hours, and 48 hours after would provide a good increase in Cmax and AUC without continuous juicing.

What do you think?

1 Like

Yes - I think your hypothesis is probably a reasonable one.

The biggest issue I have is that there seems to be some significant variation in the effectiveness of the grapefruit juice. So - I tend to think that actually eating a grapefruit is probably a better option for a few reasons:

  1. Grapefruit (the actual fruit) is perhaps more consistent with regard to reducing CYP3A4 protein levels. (just because in the study they found some juice had no effect… while I suspect that any fresh grapefruit is going to have some effect, and perhaps a smaller variability than the processed juice).
  2. Grapefruit kept in the fridge seems to keep better than processed grapefruit juice. When I was doing this protocol, I are only taking grapefruit once a week (or perhaps the day before and the day of taking the rapamycin) - and so I found that the typical grapefruit juice purchase ended up sitting in my fridge for many weeks because I was only drinking a glass for 1 or 2 days a week. In the end it was easier to buy a few grapefruit each week and keep those in the fridge. Also - it seems that grapefruit juice is becoming less popular and harder to find in stores these days.
  3. Generally, eating fruit is probably better (less of a glucose spike) than drinking just the juice.

WAIT, do you potentiate the rapamycin if you take grapefruit one day AND two days after administration (not just DURING administration?)

These studies from cancer and transplant patients are always a little difficult to interpret in the light of weekly or biweekly dosing schedules for anti-aging (vs. daily dosing for cancer and transplant patients).

You have to calculate the half-life of the rapamycin (which varies a lot by individual person - but which can range from 60 to 90 hours or so) and the half-life of enzyme inhibition of grapefruit juice, which seems to be around 12 hours.

In the study mentioned directly above they say:

Grapefruit juice (supplied by Florida Department of Citrus), 240 cc, was administered once daily without interruption. This dosing was based on research demonstrating that the half-life of intestinal enzyme inhibition of grapefruit juice is 12 hours(21) thus providing time for modulation prior to sirolimus dosing.

Given this data, when I was on the “grapefruit juice protocol” - I generally ate a grapefruit a few hours before taking rapamycin, then ate another the next morning.

Without any relevant studies in healthy people with weekly or every two week dosing of rapamycin, its hard to determine the optimal dosing strategy… I haven’t done the in-depth research on the pharmacokinetics of grapefruit juice vis a vis sirolimus. If you want to - this seems like a good starting point here:

Grapefruit juice drunk simultaneously with and 1, 4, 10 or 24 hours before the drug administration resulted in a 32-99% increase in mean Cmax values of felodipine, relative to concomitant water and felodipine intake. The effect on AUC was also significant when juice was taken up to 10 h before the drug. The effect of the interaction decreased with increasing time between juice and drug intake.

From the paper below:

This also looks relevant:

and

1 Like

Important to remember the the drug metabolizing enzymes are in two main places – intestines and liver. The intestinal enzymes are mainly affecting absorption, and these are what grapefruit juice inhibits. Inhibiting liver enzymes, on the other hand, would slow down metabolism of rapa and increase AUC.

So taking GF w/rapa once weekly should only increase absorption of that one dose. It should not affect the liver to any significant extent, and therefore wouldn’t increase AUC for the rest of the week (other than the increased AUC due to that early spike from increased absorption of the weekly dose).

3 Likes

Does it have to be Grapefruit juice, or would another citrus juice, such as Orange Juice, work at least to some degree?

2 Likes

Just an FYI on this thread - a doctor on Twitter (and I believe a rapamycin user) has been warning about Grapefruit juice and rapamycin (or, more broadly, the risk if someone is taking other medications too, while doing the “grapefruit / rapamycin protocol”

Here are the tweets:

Papers referenced:

“The ones who takes Rapamycin with GF juice are damaging their livers or renal system”

Well that’s all the proof I need. Are we sure he’s a real doctor?

2 Likes

Well… obviously an overgeneralization, but even Dr. Green and pretty much everyone on the University of Washington Rapamycin Study conference call side does not recommend the grapefruit juice protocol.

As soon as you start taking more than just rapamycin, things can get complex very quickly - worrying about half-lives of multiple drugs, phasing in the ones you don’t want affected by GFJ after you take the rapa with GFJ… and high penalty factor for making mistakes.

I think part of the motivation is that this is early days of the world of anti-aging medications, and one bad adverse result could really set back the entire field for a long time, so now more so than ever, the professionals would trade off a little “potential benefit” for safety and success in everyone. Of course, our risk/reward profiles may differ from that of the professionals.

2 Likes

In my view;

That is an option, not diagnostic proof.

1 Like

Lots of cognitive dissonance with respect to GFJ on this forum…

2 Likes

I don’t take GF w/rapa, but I’d consider it if I were strapped for cash and was sticking with very low doses. 2mg of rapa w/GF, even if it triples the effective dose to 6 or 7mg (which is likely a stretch unless you’re taking the special research-grade Florida GF that was used in the published study), why would it “kill the liver or kidneys” any more than taking a 6 or 7mg dose of straight rapa?

Maybe the doctor who posted the Twitter rant doesn’t understand that people who do this are only drinking the GF juice once weekly rather than every day, and/or maybe he doesn’t understand that this once weekly dose of GF appears to only affect intestinal rather than liver CYP 3A4 (thus only absorption not metabolism/excretion, see earlier thread).

That being said, it’s always easier to argue for caution rather than against it. One would definitely need to be aware of other drugs that one takes whose absorption would also be enhanced by the GF and could cause acute toxicity, for instance.

4 Likes

Since grapefruit and grapefruit juice has been on the store shelves all of my life and the FDA has not sounded any major alarms I think occasional grapefruit juice is no big deal. If you are taking a medicine that is potentially life harming if taken with grapefruit juice, a warning should be in the literature you receive with your medication or your doctor should have warned you.

2 Likes

Correct me if i am wrong about this. Two mg of rapa w/GF, triples the effective dose to 6 or 7mg. But in reality, we are just trying to extract as much as possible out of the 2mg. if you take 7mg without GF, you are actually getting 30% of it, that is 2.1mg. There is no danger of overdose because of GF.

Sorry, I’m not understanding what you mean here. The pharmacokinetic study with rapa and GF juice used serum rapamycin levels (post-absorption) to determine the increased absorption due to GF juice due to CYP 3A4 inhibition in the intestine. Is it possible you’re over-complicating it?