I think we’re looking at CYP3A4 inhibition as a feature, not a bug–given how expensive rapamycin is, it’s useful to have a tool that effectively increases the dose. But I agree that it becomes more tricky to evaluate dose, time to washout and trough levels when you throw in more variables. Which is why taking this approach might make a two-week cycle safer.
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It seems that a person with some reasonable math skills and some time, patience and curiosity to create an algorithm to calculate this for people…
What I’m envisioning is an algorithm that takes the CYP3A4 effect of any of the compounds / medications you are taking given the state of the science today. I do wonder if the effect of multiple types of these compounds is simply additive, or more complex…
(e.g. a person enters or checks all the medications and supplements is taking)
The algorithm takes the known increase / decrease effect of all the supplements / compounds and medications that you are taking and gives you a net effective bioavailability score/ dose (range) for all your current medications based in the aforementioned information.
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I would pay for such an app.
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The problem is that CYP enzyme inhibition isn’t just on/off but rather is a matter of degree. For instance, a supplement/drug may inhibit CYP 3A4 in vitro but may have no effect or a small/medium/large effect in vivo, or in animals vs humans. Also, there’s the matter of intestinal CYP inhibition (affects absorption only, in the case of grapefruit juice+rapamycin) vs liver inhibition (which would also slow down metabolism/elimination of the rapa, as in ketoconazole, for instance). It gets incredibly complicated when throwing in multiple supplements with little or no human pharmacokinetic data into the mix. I think such data would need to exist first before anyone could write a program/app to make use of it, if that makes sense.
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LOL, I wonder if this is the reason why in the ITP studies, metformin+rapa did better than metformin or rapa (from previous studies).
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would these work with animal bioavailability? I.E. if I were to give my dog sardines and rapamycin together?
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Yes, most likely. The biology of dogs is very similar to humans. I do exactly that.
I stopped taking rapamycin with food after reading this article:
“Sirolimus was absorbed more slowly when administered after a high-fat meal than when administered after fasting, as shown by statistically significant reductions in peak concentration (Cmax) and the ratio of Cmax to the area under the curve (AUC), and lengthening of the time to peak concentration.”
I believe Drs. Blagosklonny and Kaeberlein have stated that Cmax of rapamycin appears to be more important (from a longevity perspective) than AUC.
Also, according to this article, the Cmax of rapamycin is increased to a lesser degree than AUC by co-administration with grapefruit juice (see Table 3):
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Funny, I did the opposite after reading the same article!
“The oral availability of sirolimus was increased to a modest extent (35%) and in a uniform manner when administered with a high-fat meal”
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I have not been able to find the full text: what is the reduction of peak?
I take rapa with morning coffee (which includes some fat in the creamer and some extra MCT oil, but no food) in order to help maximize Cmax, with running assumption that this is more important than overall AUC (I guess time and more studies will show if this is true). The liquid fat helps with rapa absorption while hopefully not slowing down the overall speed of absorption, as would be the case with a meal of solid food, fiber, etc. If taking with GF juice, it might also be helpful to mix in some rapidly-absorbed MCT oil as well (again I’m assuming MCT helps with rapa absorption, no studies showing this).
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That sounds like a reasonable approach! Are you avoiding the grapefruit juice protocol for any particular reason?
I’m not sure of this… I think people may talk about “higher levels” of rapamycin as a general term to cover higher levels of exposure to rapamycin, and not necessarily the absolute peak blood levels (cmax)… I’ll bounce this issue off Matt kaeberlein next time I talk to him and if anyone here is talking with Dr. Green or Blagosklonny in the next while, please ask them on their thoughts on this…
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for now, a reasonable approach might be to alternate weeks of a high fat breakfast or fasting.
I’m not doing grapefruit for the time being because I have a prescription for sirolimus and currently have the luxury of just taking the full dosage of what I’m prescribed. Also, since they used a special form of high-coumarin GF juice for the published studies w/rapamycin, there’s some question of how much “normal” GF increases absorption and I’d rather take that variability of out the equation.
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Please do! I’ve read multiple posts (notably without literature references) claiming that Blago/Green currently believe Cmax needs to be above a certain threshold for rapa to get into the hypothalamus, which may in turn be important for optimal anti-aging benefits of rapa, and that the higher Cmax is the reasoning behind doing a higher dose every 10 or 14 days rather than a lower dose once weekly.
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An interesting paper for anyone who is thinking about using Grapefruit Juice or one of the drugs that increases CYP3A4 inhibition - to help you get a better understanding of the timing issues:
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It seems that the inhibition of CYP3A4 lasts some time. Last cycle I ate a couple of grapefruits for desert on Sat night and then had the rapamycin Sunday morning with coffee + 33% heavy cream, and no other food for 24 hours. I think I’ll follow this approach for at least a few cycles.
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Grapefruit juice can block the action of intestinal CYP3A4 , so instead of being metabolized, more of the drug enters the blood and stays in the body longer. The result: too much drug in your body.
https://www.fda.gov/consumers/consumer-updates/grapefruit-juice-and-some-drugs-dont-mix
What about CBD which also block CYP3A4?
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