Apparently Dr. Green is recommending 5 half-lives for rapamycin dosing intervals:
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So that’s 13 days for rapa. Is he recommending that across the board for everyone, or just the folks taking higher doses?
I’ve read somewhere figures pointing to over 300%-350% increase in absorption.
And the protocol I follow with grape fruit juice - seems to be Dr. Green’s - is a 300/400ml. vase in empty stomach in the morning and after one fasting hour my 6 mg. rapa biweekly dose, so inhibiting action on CYP 450 3A4 enzyme seems to be at its peak. Just my two cents.
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Great thread with references. ONE ‘dose’ of GF juice prior to your rapa makes sense (and cents). Note the effect on statins however. I would not do the GF juice if you are taking ANY other medication that interacts. It’s always a warning label on your pill bottle. What a great group this is.
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Please explain. Five 1-mg pills should contain the maximum rapamycin of 5 mg at the most. Because poor bioavailability and CYPxx enzyme, our gut may absorb only 2 mg. How can grapefruit juice boost the rapamycin absorption to 300% to the equivalent of 15 mg? There are no 15 mg worth of rapamycin molecules around.
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In this quote “The biweekly dose is 30mg sirolimus without grapefruit juice. Every 6 week dosing of 90mg was 30mg sirolimus dosed with grapefruit juice”, Dr. Thimineur seems to imply his 90 mg dose are converted from 30 mg with GFJ. In fact, there are no 90 mg equivalent of Rapamycin molecule in the body.
I haven’t study pharmacokinetics, so this is just my rough understanding
Assume the rapamycin bioavailability is 14%
Also assume grapefruit can truely boost rapamycin bioavailability 300%
Consider the following scenario:
(1). If you take 5mg => then only 5mg * 14% = 0.7mg is absorbed
(2). If you take 5mg + grapefruit => then 5mg * 14% * 300% = 2.1mg is absorbed
(3). If you take 15mg => then only 15mg * 14% = 2.1mg is absorbed
(4). If you take 15mg + grapefruit => then 5mg * 14% * 300% = 6.3mg is absorbed
Compare the (2) and (3)
We can conclude that (5mg rapamycin + grapefruit) = 2.1mg is absorbed = 15mg rapamycin
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thanks, then when we calculate half live elimination of rapa, we should be using the absorbed rapamycin concentrations. Rapamycin tablet bioavailability is 27%, 35% if taken with a high fat diet, the 6mg scenario without GF, we only get 2.1 mg to begin with. Is that right?
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Regarding the question of “washout”…it depends how you define the term. In my mind, rapamycin therapy results in plasma levels of rapamycin that would visually look similar to a sine-wave with repeating peaks and valleys. The peaks are equal to the maximum level of partial mTOR inhibition which corresponds with maximum level of autophagy activation. So…the “washout” period is when most of the rapamycin has been metabolized and eliminated, which corresponds with normal mTOR activation. But…we are so new in this field, we as yet don’t know what the optimal peak plasma level is…or how long one should maintain elevated mTOR inhibition…and how long (how many days) should it be from one peak plasma rapamycin level to the next peak. I’m sure that biochemical individuality will result is different doses and time periods for different people. It’s the NEW FRONTIER of Life Extension. Exciting times indeed. Ross
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Hi, from what I’ve learned reading about ketoconazole as a compound increasing rapa absorption - from your link -, it exerts its action mainly at hepatic level, where it is metabolized. Grape fruit acts in our bowel and ketoconazole in the liver, in a synergistic manner somehow.
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Interesting… does that suggest that they could be used in combination for even higher multiples of rapa absorption?
The problem with using ketoconazole is that we’d have to know how long it inhibits CYP 3A4 in liver after a single dose. If the inhibition lasts for multiple days or longer, it’s going decrease elimination kinetics and lengthen the period needed for adequate washout between doses.
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RapAdmin, its what it looks like but I can’t tell to what extent. This study abstract may shed some light on the matter.
Yeah, it looks like they used daily dosing of both the ketoconazole and the rapa in this study. We’d need to see a study that shows how long ketoconazole suppresses cytochrome p450 3A4 after a single dose, and how much the net increase in blood rapa levels are after a single dose. Since we have that data for grapefruit but not for ketoconazole, it seems safer (in more ways than one) to just use GF, otherwise you’re shooting in the dark when it comes to estimating net dosage equivalence.
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This is the issue - all these studies are dosing rapamycin daily, because thats what they do in transplant and cancer applications…
so the information is a start for us, but really we need new studies that dose both rapamycin and the other compound (keoconazole, grapefruit juice etc) in different manners (e.g. 1 time weekly) that are more like how we are using rapamycin…
we have some data for GFJ, but I still wonder how much variation there is from both the fruit (e.g. dosing once), and from the different types/brands/etc of juice.
I was thinking that ketoconazole is more reliable because the effect is likely to be the same every time and very consistent, whereas GFJ you really have no idea , but as you point out there are other issues with the lack of knowledge we have around ketoconazole…
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From my humble point of view, I only need to trust THE fruit, no types/brands/etc., the real thing. You never know whether pasteurization or any other heat treatment to kill bacteria may reduce its necessary effects on CYP 450 3A4 enzyme. One and a half fruit juice from the extractor, plus the remains of the unfortunate grape fruit in the machine, gives you more than 300ml. That easy. A bit too bitter? Some few drops of artificial sweetener and you are done. And I guess it works because my blood works are very, very close to optimal for my age, 63.
Btw interestingly, this study from the year 2000 using various single doses in healthy men, showed a half life of 82 +/- 12 hours (i.e. 70-94 hours). Isn’t that longer than the value we’ve been using?
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This study says that diltiazem (a CYP3A4 inhibitor) in volunteers taking oral simvastatin significantly increased simvastatin Cmax 3.6-fold, AUC 5-fold, and half-life 2.3-fold (no change in simvastatin tmax) . So are all CYP3A4 inhibitors supposed to increase half-life? or grape juice is special and does not? Simvastatin - an overview | ScienceDirect Topics
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Grapefruit juice increases absorption of rapamycin by inhibiting CYP3A4 in the intestine but apparently minimal if any effect on liver CYP3A4, at least when used as with current dosing protocols (there’s more detail and references in another thread).