Rapamycin and Grapefruit Juice

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

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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.

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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.

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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.

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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?

The doctor I exchanged some emails with, who was an author of the GFJ/Sirolimus/cancer paper, a practicing oncologist, said he would not use it as a prophylactic. Imagine a conventional doctor.

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Did you get any info from him on the efficacy of different types of grapefruit juice (frozen, pasteurized, fresh, etc.) or use of the physical fruit, in terms of CYP3A4?

This seems to be the big issue with this strategy - obviously fresh juice and fruit are probably ok, but the other versions I’m not sure, and also wonder about the variation between different types/ colors / species of grapefruit…

for example, these statements, by Randall on his rapamycin grapefruit juice protocol:

Did you get any good info on this?

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Sorry, not part of the reason for inquiring with him.

Agreed, that’s a problem with reproducibility using grapefruit for enyzme inhibition. We have no way to monitor other than Sirolimus in blood, unless you have a completely reliable source, and dose on a very regimented schedule.

There are several molecules in GFJ that inhibit the enzyme

White vs Red Grapefruit
https://sci-hub.se/https://doi.org/10.1691/ph.2008.8550

And of course, there is the timing issue.

Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects

My current source is so cheap, I’ve been toying with dropping GFJ, and just doing straight Rapamycin, better control of my dose/response experiments.

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Did you stop this protocol?

I have not seen much correlation in my results between taking or not taking grapefruit juice.
If I take a high pulse dose as Dr. B seems to believe in, the only ill effect I experienced was with taking 20 mg, of rapamycin with grapefruit juice and experiencing mild diarrhea for the next two or three days. I backed off and had no other side effects except rapamycin keeps increasing my lipid levels.
Why I like bi-weekly dosing, I am not saying its better
I feel much better subjectively with the high, bi-weekly pulse dosing.
Weekly dosing with 5 to 10 mg with olive or other oils always left me feeling a little down and weaker at the gym for most of the week. Bi-weekly high dose pulse dosing sometimes even produces mild euphoria for the next day or two. I have not seen this reported elsewhere, so maybe it’s just me.
The correlation I am very sure of is, that higher doses mean higher lipid levels.

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MAC is right unless you are able to take your set amount of rapamycin and set amount of GFJ and how long to a blood draw with a LabCorp blood test - you won’t know your cmax dosage.

On Monday at 7am I took four 2mg rapamycin pills (so 8mg) and 8 ounces of grapefruit juice. Had my blood drawn at 10 am - exactly 3-hours after ingestion of pills and GFJ. why 3 hours?? Everything on this site seems to point to 2.5 to 3 hours is peak blood absorption - cmax. I will have my results on Monday and share. At least you will see my N=1 results from this dosage and time frame.

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“MAC is right unless you are able to take your set amount of rapamycin and set amount of GFJ and how long to a blood draw with a LabCorp blood test - you won’t know your cmax dosage.”

So, what? Nobody knows the proper dosage or routine. Unless you are a researcher, why would you care? I took rapamycin at higher and higher dosages until I reached a point where I started having a little diarrhea then backed off. I am not just following Dr. B’s advice.
Everything I have read about max dosage is, that the limit has not been defined. Rapamycin extends life in rats and mice in a dose-dependent manner, higher dose = longer life. The safest path in my opinion is for younger people to take a low dose regularly because you are going to be taking it for a long time. The longer the time rapamycin is taken also equates to a longer life. You are still pretty young compared to me. Just take a regular dose that you think is good for you. Unless something happens you will be taking it for decades to come. (And long after the thrill of taking rapamycin is gone :laughing:)
Don’t worry about testing other than your routine blood markers like LDL and try to keep them in the normal range

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Like your spunk.

I have been on 6mg 1.5 years with great results. Now looking to taking a 20 mg weely dose using GFJ…8mg pill and GFJ. Been doing that 2 months… certainly get the diarrhea for a few days at that dose. Getting it figured out and under control tho.

Then with higher dose of 20mg…checking my Glycans in 6 months and DNA methylation… to see how it compares to past year’s tests.

As to LDL-C in my case is 167 .Ummm… 130 is high normal.
My coronary calcium score from CT scan… is zero… nada… technician says my heart is younger than 35 years. So for me LDL-C isn’t an issue. Curious to see my latest LDL-C score on Monday. Been high since I started getting it tested at 40 years. More soon.

As good a place as any for my “Friday Rant” This is my chosen manifesto and until someone proves otherwise, the path I choose to follow.

Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening.

“If used properly, rapamycin is not much more dangerous than ordinary aspirin.”
I totally disagree with this. Aspirin is much more likely to kill you than rapamycin

“rapamycin’s LD50, a measure of drug lethality, could not be determined because it is higher than 2500 mg/kg.” (Which in my case would amount to 17,500, 1mg tablets.)

"At low doses [8,9,86], or when administered as a single high dose [103], no side effects have been detected so far in the elderly. (Well, they didn’t try 20 mg with grapefruit juice.)

Please if in doubt follow the many references Dr. [Mikhail]V. Blagosklonny provides at the bottom of the article.

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@agetron @desertshores

The reason for my recommendation to do a Sirolimus blood test:

  1. Are you even taking rapamycin/Sirolimus?

  2. There is HUGE inter-person variability. Two people taking the same dose can have massively different pharmacokinetics/absorption. “The inter subject variability in clearance (CLpo) was large
    and was suggested to partially result from an elevenfold variation in the intestinal content of CYP3A4 enzymes that have been observed among individuals based on small intestinal biopsies

  3. Are you dosing sufficient to even get a good enough trough level to be a meaningful signal? Say at least 3-5 ng/L, lower band limit? (Conventional therapeutic dosing control is 5-15 ng/L trough). All the transplant/cancer data in humans…trough is correlated with AUC, which if we’re trying to slow down cancer pathways (ie mice translation), is likely very important therapeutic monitoring requirement. “RAPA, at trough concentrations as low as 0.5 mg/L, prolonged graft survival compared to controls. However, long-term graft survival was only achieved in
    animals having mean trough concentrations of 9.3 +/- 5.4 mg/L” (1)

(1) Sci-Hub | Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update. Clinical Biochemistry, 31(5), 345–351 | 10.1016/s0009-9120(98)00048-4

I have no idea what should be the longevity dosing protocol re Siromilus pharmacokinetic signal.

One of the only guiding principles is from Dr B “take as much as you can tolerate”, with my caveat, with likely a MIN trough level.

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“One of the only guiding principles is from Dr B “take as much as you can tolerate”
That’s my mantra.
I have titrated up to the point of undesirable side effects then backed down.
The complete clearing of my actinic keratoses and the “essential” age-related tremors, plus my general sense of well-being is enough to convince me I am getting a therapeutic dose.
There is enough evidence that the two-week dosing protocol is enough to ensure that I don’t depress my immune system.

I have no problem if someone wants to take the test per se, but I don’t think it is meaningful except under the supervision of a qualified doctor who can interpret the results in relation to the person taking it.
Locally only Lab Corp is giving the test and is completely unreliable on the time you are seen, so no chance about peak dose info and I personally don’t care about trough dose info on the bi-weekly protocol.
And yes, I am sure I am getting sirolimus. Many of us are using the Zydus brand from the same source in India and some have taken blood tests to insure the efficacy of the product.

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What did you think of Rapacon? What was the reason for the switch? I ask because I just ordered 100 pills from Jagdish and ordered a couple tests from life extension and wondered whether I should use that on the test or the stuff I get from Wal Mart. I don’t even know what they use.

As I posted earlier, I had no problem with Rapacon. I took it for several months before I switched to Zydus. Two outdated tests show Rapacon had slightly less rapamycin per tablet ~1 or 2%, not enough to worry about. The Zydus tablets have slightly fewer filler materials. Again nothing I would worry about.

See tests on Zydus and Rapacon here: Rapamycin / Sirolimus from India, Lab Test Report on Quality / Purity

Jagdish supplies either brand. The cost of rapamycin from India is so extraordinarily cheap when compared to Pfizer or compounding pharmacies that I didn’t mind paying a little more for the Zydus tablets.

BTW, I was paying Jagdish with bank transfers from Wise.com, but they say they no longer support transfers to the Niba Healthcare account.
May I ask how you paid Jagdish?

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My rapamycin/sirolimus physician prescription is the real deal from Accredo Pharmacy - 30 pills 2mg each – delivered by mail on schedule every month.

Still… I think it is a good idea for a LabCorp test to absolutely know I am getting good Rapa.

I can actually control my blood draw appointment - my total work up 4-5 vials of blood every 3-4 months (paid by my insurance), getting a true blood draw at 3 hours by just taking my rapamycin in advance of my scheduled appointment.

I changed my normal schedule of taking my Rapa before bed to get a c-max reading blood draw – just for this blood test. Then back to my old schedule.

As MAC says - I have no idea what should be the longevity dosing protocol re Sirolimus pharmacokinetic signal.

At 6mg for 1 1/2 years I have seen great improvement - skin, memory, swallowing, resistance to allergies, general great health. My biological glycans are 37 years. DNA Methylation 51 years.

Over the last 6 months been doing 8mg/ 10 mg a few months and last 3 months with GFJ boost approx. 20mg. With this dosage can I hold at my biological age for 37 and 51 years a bit?? Or even push biology back a few more years? Will know in 6 months at this dose.

I am looking at trying to hit about a 20mg + dosage per week to see how my biological age testing looks in 6 months and see if no negative effect on diminished muscle tone/strength. The current 8mg Rapa pills with 8 ounces of GFJ has produced mild diarrhea a few days. Taking Pepto Bismol pills 24 hours post Rapa medication should remedy this in the future. I should have the LabCorp Sirolimus level results on Monday to know how much of a boost my 8mg gets with GFJ.

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Wow, 20mg+ per week with GFJ? That certainly beats the max bi-weekly dose I used.
Let us know how that goes. With that dose, I would have constant diarrhea.
I wonder if the body would adapt to the high doses and if diarrhea would go away.
As far as I know, you will be the max dose pioneer in this forum.
Good luck we will be watching.