I wish I could help you with this one, but I am unsure how an NO enhancer will affect the bioavailability of Rapamycin. I think the key to the GFJ and fat (as well as Metformin) is that these either disable the enzyme that breaks down Rapamycin (GFJ + Metformin) or coats and shields the Rapamycin from the enzymes (fat).
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I am not thinking as much on absorption as on the systemic distribution in the body, after the rapamycin is absorbed. I’ll see how it goes.
Maybe increased NO will improve the bloodflow, and then also improve the systemic distribution of the rapamycin. And then more rapamycin will reach more tissues/cells.
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I like it. Better blood flow and lower (but not too low) BP has to be good for the body. As for increasing the benefits of rapamycin, I don’t know. Use nitrate test strips (saliva) to find out if your beets are able to help you with NO. It’s an oral microbiome thing.
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@DeStrider FYI, I just did an interview with Daniel Tawfik (and Dr Cohen), Founder of Healthspan. They do not think use of GFJ is smart. It is too unpredictable on top of a speculative drug. Dr Cohen also does not think use of a fatty meal is optimal due to the blunting of the rapa peak. I am rethinking my approach.
I’ll publish this episode in the next week or two.
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I appreciate your concern, but GFJ is the only way I can reasonably get the quantity of Rapamycin I would like. I can’t imagine taking 21 pills every two weeks. There will always be some variability, so I have accepted it.
Curious as to why the fatty meal is not recommended? How does it blunt the Rapa peak?
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Fat slows absorption but increases bioavailability. Dr Cohen says the peak is the key. I speculate that the AUC is what gets me in trouble with mTORC 2. I will stop using a fatty meal from now on. I’m still thinking about GFJ as that is a money saver, but I have backed off the dose already.
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What data did he give to support the claim that the peak is the key? Especially for humans, which is the study population we should all care the most about. I ask this because it’s directly contradicted by the Mannick study where they dosed a rapalog 3 different ways for elderly patients prior to influenza vaccination. The 20 mg/week dose was no more effective than 5 mg/week, but the higher dose was associated with greater side effects.
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He provided no data. As far as contradicting mannick data: she studied immune system response in elderly people to a vaccine after a short duration rapa usage. Dr Cohen was talking about general healthspan improvement. Is that the same thing? I don’t know. Also, the Healthspan company recommends 5-6mg per week, not 20mg. The concern expressed was that using a fatty meal to improve bioavailability was lowering the peak from a normal dose. He didn’t say the biggest dose possible was best. I think he was saying too low of a peak isn’t ideal. But I tend to agree that a bigger dose, too often, without breaks is not the way to go until more is known.
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Unfortunately, I don’t think we really have a ton of data to support this. I suspect its Dr. Cohen’s best guess based on the data he’s seen. But given the lack of data/studies on this topic, the uncertainty level has to be quite high.
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Agreed. A lot of uncertainty regarding rapamycin.
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I’ve been giving this a lot of thought… GFJ causes CYP3A4 enzyme inhibition, the effect of drinking a single glass of grapefruit juice can last for more than 3 days. So, while it seems great that GFJ gives us a 3.5X boost in peak. I also think it’s quite possible that the prolonged CYP3A4 inhibition from the GFJ might cause that peak to be much more prolonged over the next 3+ days rather than the sharp fall we ordinarily expect to see. Thoughts?
The only benefit I see at taking rapa with gfj is to save money. And, as long as I can get rapa from India it’s fairly inexpensive anyway. I’m not sure it’s worth the unknowns.
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I thought the only effect GFJ had was increase bioavailability, and that can’t be a bad thing if you lower the dose.
" I also think it’s quite possible that the prolonged CYP3A4 inhibition from the GFJ might cause that peak to be much more prolonged over the next 3+ days rather than the sharp fall we ordinarily expect to see".
Could this be a good thing, as opposed to being bad thing?
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I might not have worded it very well. I was hypothesizing that GFJ might not only increase peak but might also increase half life for the first 3 days because of CYP3A4 inhibition. But, disregard my hypothesis. I just looked it up. It appears that GFJ usually increases bioavailability and peak but not half-life. I say usually because I don’t know if this has been studied for rapamycin specifically.
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I think the best answer is I don’t know what is best for anyone including myself . Saving money is good but might not be worth the risk (if you perceive a risk as I do). I’m still sorting out my thoughts but so far I think that if I want to continue using GFJ, I should move to a 2 week cycle (or maybe weekly with 3 weeks on and 1 week off) to make sure I get to zero rapamycin. In addition, I don’t have any reason to think that flattening (and extending) the rapamycin curve is better even though it might also be a (smaller) money saver. As I tongue my latest mouth ulcer I’m leaning toward a 3/1 weekly cycle.
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I’m assuming you’d want to get to zero to allow for Mtorc2 activation? But I thought that at relatively low levels (maybe not even that low) of RAPA in blood Mtorc2 seemed to activate just fine? Any other reason you want to get to zero?
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Just trying to balance the risk vs reward. I don’t want rapa to accumulate, and I don’t have to give up much (if any) upside to be certain.
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There is quite alot of research on CYP3A4 and but I can’t say that I have seen any good review.
It is difficult to draw conclusions but hopefully members of this forum can contribute with more knowledge.
Since I try to inhibit CD38 with Apigenin, the effect that apigenin might have on CYP3A4 makes me wonderiwhat effect it has on rapamycin metabolism in vivo.
there are quite a few substances that can inhibit CYP3A4. Milk thistle, bergamottin, And some say quercetin and curcumin can inhibit and other papers point at Curcumin as an activator of CYP3A4. Thymoquinone the bioactive substance in black seed (Nigella sativa) plant is an inhibitor. And apigenin and chrysin is mentioned as inhibitors. Irreversible inhibitors, meaning that they inhibit CYP3A4 even after they are cleared from the human body. With a reversible inhibitor, the inhibition stops/can be stopped when the inhibitor is cleared from the system.
Irreversible interactions are important since irreversible inhibition cannot be overcome by discontinuation of the inhibitor and the enzyme is inactivated and time is needed for a new enzyme to be re-expressed. As the half-life of cytochromes P450 is between 24 and 72 h, regeneration of enzyme activity can take up to two weeks, preventing successful therapy. This is especially of importance in cases where the medicinal drug is exclusively metabolized by the inhibited enzyme .
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I think this makes total sense. But, I think there is a big difference between a fatty meal and a tablespoon of olive oil. If you take a drug with a meal (especially a large meal) it’s going to dissolve and get mixed around in the meal and most likely get absorbed/digested over the 1-2 hours it takes for your stomach to empty. Whereas taking it with a very small fatty meal such as a can of sardines, as I’ve heard @RapAdmin doing, or even better yet an empty stomach with the exception of a tablespoon of olive oil I think would be ideal. There would be so very little in the stomach to compete for rapid absorption. Just my thoughts
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Just searching around to see if I can find evidence of what you are suggesting…
I came across this:
Notes for Professionals: Food may affect the exposure to sirolimus. As compared with the fasted state, administration of sirolimus oral solution with a high-fat meal decreased the peak blood concentration of sirolimus by 34% , increased the Tmax 3.5-fold, and increased the AUC by 35%.
Source: Drug Monitoring of Sirolimus and Everolimus, Victor Armstrong, Frank Streit
https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1439-0477.2003.03040.x
But nobody seems to have done any studies on dosing with minimal amounts of fat or olive oil, that I can find.
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