Although I agree with @Olafurpall that the change in the amount absorbed will not itself change the half life, I think it is possible to extend the half life by knocking out enzymes in the liver.
However, this is not something I would try to do as I aim to keep Rapamycin effectively inactive for most of the time.
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I agree. For most purposes, trying to increase the half-life would be a bad idea. It’s already long enough for the type of intermittent inhibition that is likely best for longevity.
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GFJ adds a lot of variability to the pharmacokinetics of rapamycin (and other drugs).
Here are some quotes from papers on pubmed about that:
and from Phase 1 Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients
With GFJ, the AUC is 3x to 5x greater and the half-life is 1.3x to 2x longer which is quite a lot.
In summary GFJ increases Cmax, AUC and half-life with a lot of variability on the individual and GF used. BTW Max is irrelevant but not the others.
People using GFJ should really measure their own blood concentration at 48 and 72h to assess the level and half-life.
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I don’t think it’s true that GFJ will increase the half-life of rapamycin significantly. The quote above that grapefruit juice inhibits CYP3A4 and to a lesser extend hepatic CYP3A4 is from PMID: 37111635. To put that quote into more context, here is a quote with more text from that study:
“Pharmacokinetics of imatinib 400 mg QD compared to imatinib 400 mg QD boosted with grapefruit juice were not significantly different. A possible explanation is that this is due to the fact grapefruit juice predominantly inhibits intestinal CYP3A4 and to a lesser extent hepatic CYP3A4. Imatinib bioavailability is almost 100%, thus only inhibiting the intestinal CYP3A4 has little effect. The study was prematurely terminated because no significant effect of grapefruit juice on imatinib exposure was observed.”
The study they refer to above where the pharmacokinetics of imatinib was not influenced by rapamycin is this study: Can grapefruit juice decrease the cost of imatinib for the treatment of chronic myelogenous leukemia? - PubMed
That study shows that GFJ does not change the through level of imatinib, which suggests it does not inhibit CYP3A4 in the liver to a degree high enough to have significant effects on the half-life of the drug. Imatinib is a drug that is metabolized in the liver by enzymes such as CYP3A4 so if GFJ were significantly influencing CYP3A4 in the liver, you would have expected to see it change the pharmacokinetics of imatinib, but that did not happen.
In conclusion, I don’t think GFJ has strong enough effects on CYP3A4 in the liver to significantly increase the half-life of rapamycin.
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The half-life for rapamycin with and without GFJ is explicitly given in table 3 of the paper I linked.
For 15mg ramamycin: No GFJ: 36h, with GFJ: 46h
For 20mg ramamycin: No GFJ: 26h, with GFJ: 53h
For 25mg ramamycin: No GFJ: 30h, with GFJ: 40h
Half-life is last column below
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Is this based on your modeling or on studies done on living creatures?
My question as well. We are discussing an empirical question the answer to which is satisfied by an appropriate design (including appropriate sample parameters), methodology, and execution. It seems too important to leave to deconstructing chemistry or to extrapolating from animals.
It’s in all the rapamycin pharmacokinetics papers on humans, notably the one on fatty meal absorption.
The peak is just the competition between rapa going into blood from GI and rapa going out of blood to organs.
If you have a super fast absorption then 100% of the rapa is in the blood as nothing has started to go into the organs so you have the highest peak possible.
If you have a slow absorption, then rapa will go to the organs before the whole dose is in the blood so the full blood concentration will never be 100% and the peak will be lower.
If you slow down the absorption you end up with more rapa into the organs.
When rapa is in the blood it is >95% into red blood cells and <5% into plasma which is not that useful for longevity given that the average lifespan of an RBC is about 120 days.
As you can see below, if you reduce the absorption speed with a fatty meal, you reduce the blood peak by approximatively 2 but you end up with 2x more rapa in the system.
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Thanks. That’s interesting. “In the system” means in blood and in organs? Why does a higher blood peak (of rapa) result in faster clearance? (I’d guess clearance only is measured in blood so Rapa might only seem to clear faster with faster absorption). Why does a higher blood peak result in more rapa lost to red blood cells? If slower absorption means a higher AUC what keeps the rapa out of the red blood cells when absorbed more slowly but at a higher volume?
And today we learned here that the use of GFJ slows clearance AND increases absorption. So maybe GFJ can substitute for food but also get a bigger multiplier (if that is desired).
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Yes, both.
The clearance is due to rapa being metabolized by enzymes and that’s proportional to the concentration unless you are limited by the enzymes (which is the case BTW when GFJ neutralizes those enzymes).
It’s very dependent on the individuals. For instance my half-life is 82h which means I should not do weekly dosing but every 2 weeks at most. If I double it with GFJ I should wait 4 weeks or so between doses.
That said fast metabolizers will get rid of rapa very fast so for them GFJ might be good.
As always in biology it depends a lot on individual variations.
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PBJ
#31
Given the long half life, fasted looks more attractive to me, but I could be wrong.
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There are three kinds if CYP3A4 inhibitors. And all if them can effect the AUC. Reversible, irreversible and Pseudo-Irreversible inhibitors.
The inhibition of a substance that is a reversible inhibitor stops when the CYP3A4 no longer is exposed to the substance.
When the CYP3A4 is exposed to irreversible inhibitor, the inhibition is permenant and the metabolism of the drug is markedly reduced until a new CYP3A4 enzym is formed.
A pseudo-irreversible inhibitor blocks CYP3A4 like a irreversible inhibitor, but can be replaced with a substance that with a stronger affinity.
I know that a few persons on this forum has used ritonavir to boost AUC.
I find this paper about ritonavir and its effect on the metabolism of sirolimus and everolimus interesting.
We had a discussion about this in a few older threads.
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I find this discussion about whether GFJ extends the half-life of rapamycin
“Much ado about nothing”.
Thanks for the info. This study suggests that rapamycin may have an effect on the half-life but I think the effect is smaller than it seems.
While the numbers above indicate that GFJ has a moderate effect on the half-life of rapamycin, I think the difference is smaller than it seems. The sample size in this study is very small and the “No GFJ” numbers above are unusually low, which is likely a coincidence. If we instead take the average half-life of all the control subjects in this study, then we get an average half-life of roughly 40 hours. Using that as control the difference between GFJ and no GFJ becomes much smaller. That suggests to me that GFJ might increase the half-life, but the increase is likely to be small.
Another thing to consider is that they took GFJ every day in this study. That will keep the CYP3A4 inhibited constantly. If a person instead takes GFJ once with rapamycin and then doesn’t take it for a week or two, then the CYP3A4 inhibitory effects of GFJ will decline fast in a matter of 2-3 days, so the half-life will probably be back to normal in 2-3 days.
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I start eating grapefruit 12 hours before, and then have another grapefruit around 4-5 hours before and then again at 1 hour before my rapa dose. Yesterday I did this and then rode my bike for 1.5 hours and then slept like the dead.
I spend enough on grapefruit that I’m not saving money on rapa but I also get a hunger free 24 hour fast.
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Herm
#36
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Its a really good find as to a paper, but does seem to be a bit all over the place on the effects of CYP3A4 inhibition. I would think if someone was drinking GFJ every day that would have more of an effect on Half Life, but some half lives are in fact shorter with keto.
Still a really useful find.
I am now in my second week after 16mg of Rapamycin with a grapefruit. I think my sleep has been disrupted by a bit when sober, but I have been overdrinking even for me and that has quite a few effects of its own.
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I am surprised and confused by this statement in the posted paper.
“ 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).”
Everything else I read in the paper suggested that grapefruit took time to have an effect which was long lasting. This statement says taking GFJ with rapa has the (same) maximal effect.
Its long lasting in the digestive system, but what effect it has in the liver is unclear.
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