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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CBD inhibits CYP3A4 and CYP2D6 , and can increase levels of drugs metabolized by these isoenzymes.
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The plot thickens! Looks like taking sirolimus with high-fat food has opposite effects on the Cmax, depending on whether you’re taking the Oral Solution or Tablets.
"Food effects: In 22 healthy volunteers receiving Rapamune Oral Solution, a high-fat meal (861.8 kcal,
54.9% kcal from fat) altered the bioavailability characteristics of sirolimus. Compared with fasting, a
34% decrease in the peak blood sirolimus concentration (Cmax), a 3.5-fold increase in the time-to-peak concentration (tmax), and a 35% increase in total exposure (AUC) was observed.
After administration of Rapamune Tablets and a high-fat meal in 24 healthy volunteers, Cmax, tmax, and AUC showed increases of 65%, 32%, and 23%, respectively."
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Wow, thanks for posting that Brandy. I never even realized that the first study you posted in the thread (the one I’ve been basing my regimen on, which showed food lowered CMax) also used a rapamycin solution, which clearly has opposing CMax parameters with/without food compared to the tablets. Since I take tablets, it sounds like taking them with fatty meal is the way to go in order to increase CMax (perhaps my high fat coffee is doing the same thing, but it hasn’t been tested).
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Have you found any studies on the half life of grapefruit’s CYP3A4 inhibition? I’m looking for the curve to figure out more specifically what the impact is for use with rapamycin and best timing for the grapefruit prior to the rapamycin.
I did find this resource - still looking for something better though:
The half life of the effect of grapefruit juice appears to be around 12 hours and therefore, it is advisable to discontinue grapefruit juice 72 hours prior to starting any drug with potential interactions. 8,9
Due to the prolonged effect of CYP3A4 inhibition which may last up to 24 hours, it is not possible to avoid these interactions by separating the times of drug and grapefruit juice consumption.8,9
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Here are the two sources cited in the above paper on the timing / half-life of grapefruit juice on medications:
Full Paper from Sci-Hub.se: Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects
Full Paper from Sci-Hub.se: Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects
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It seems like the Felodipine study (mentioned above) is designed closest to what we are trying to do. In this study they tested taking grapefruit juice a specific number of hours prior (for example 1, 4, 10 or 24 hours before) the dosing of the medication, and then tracked AUC and Cmax.
It seems that the highest (from our perspective with rapamycin - the “best” response) was taking the medication 1 hour after the grapefruit juice (1 hour is identified as “G1” in the table, but 4 hours, “G4” is pretty close too - so you have a wide “window” - as can be seen in this table below:
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Note - I have seen people who are trying to design dosing protocols around using rapamycin / grapefruit juice, while still using a statin medication. You definitely don’t want to take them on the same day due to the potential to “overdose” on the statin.
It seems like a reasonable strategy (and obviously, discuss this with your doctor as we are not medical professionals here) in this situation may be to skip taking the statin on the day you take the rapamycin, and instead take the statin a day or two after the day you take the grapefruit juice / rapamycin. This rationale is based on what this study showed:
Conclusions: When simvastatin is taken 24 hours after ingestion of “high-dose” grapefruit juice, the effect of grapefruit juice on the AUC of simvastatin is only about 10% of the effect observed during concomitant intake of grapefruit juice and simvastatin. The interaction potential of even high amounts of grapefruit juice with CYP3A4 substrates dissipates within 3 to 7 days after ingestion of the last dose of grapefruit juice.
Source:
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It seems from this study I mentioned here - that a better approach might be to just eat the grapefruit 1 hour before you take the rapamycin - or do you have some other information I’m missing?
For maximizing the effective dose, I agree one hour before is probably optimal. The only reason I do it the night before is because grapefruit also gives me a glucose spike and I try to fast the day I take rapamycin, except for a little bit of fat (usually in the form of heavy cream in my coffee). That’s significantly less effective for CYP3A4 inhibition, but not useless. It’s a trade-off.
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Glad to help, Davin8r!
My current biweekly protocol is 6mg sirolimus (3 x 2mg tablets) with one whole grapefruit 12 hrs prior to dosing, and another grapefruit 1 hr prior (as well as 500 mg metformin and ~1/4 teaspoon of black pepper for potentially more CYP3A4 enzyme inhibition). I take the sirolimus tablets with two small avocados (as a source of fat) in an attempt to further boost the rapamycin Cmax and AUC. My weight is 57 kg.
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I’m currently having 8-10oz grapefruit a couple hours prior to weekly 4mg rapamycin and a fatty snack like nuts. It’s the only grapefruit I have during the week. I will be going to 5mg next week, and then getting my peak measured the following week.
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Looking forward to the hearing results of your upcoming lab test, EnrQay! Are you planning on doing several blood draws in order to try to catch the actual peak level?
The time-to-peak (Tmax) for sirolimus tablets was increased by 32% when taking it with a high-fat meal (see my post above). The Tmax also can vary somewhat depending on whether you’re taking 1 mg, 2 mg, or 5 mg tablets of sirolimus.
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Piperine …a bit in this thread about this…This is interesting in regard to increasing bioavailability. Not specific to rapa but seems pretty universal in its effect on other drugs/supplements.
Cannot tell for sure if my extrapolations are accurate…but from looking at enhancements of this in general, looks like 50% boost. So like with most other enhancers, kind of a shot in the dark. be good to have people go into this and see what they come up with.
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Found this graph that illustrates the impact of grapefruit juice (or grapefruit, if you’re like me and just eating the entire fruit) on the drug levels in your body, compared to taking the medicine with water.
This is for Lovastatin, but I suspect the curve is similar for rapamycin and other drugs (at least in hours of effect, if not magnitude of effect). So, just be aware of this timescale and dosing impact generally for rapamycin and many other drugs.
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