The importance of "washout" time for Rapamycin dosing?

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).

Or eating the grapefruit in whole slices along with rapa would be fine too, fiber and all (even reducing the sugar spike)

I will add there is a ton of confusion here regarding grapefruit juice.

Liver CYP3A4 is NOT affected at the levels tested.

“Hence, it has been concluded that only intestinal CYP3A4 is inhibited by grapefruit juice, while liver resident CYP3A4 enzymes are not affected. This conclusion is further supported by the finding that the interaction with grapefruit juice markedly elevated the area under the plasma concentration–time curve (AUC), while no significant change has been observed in elimination half-life or systemic clearance (Bailey et al, 1991).”

https://www.nature.com/articles/1601736

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Maybe mechanistically, you may indeed by right…but NOT clinically. Without a doubt, GFJ delivers a huge AUC boost. Basically, it delivers a bigger bolus systemically, but elimination and half life are unabated, this makes intuitive sense pharmacologically.

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I’m not sure what you’re pointing to.

If only intestinal CYP is inhibited at those levels tested (higher amounts of GFJ could change things, but I’m just referring to typical amounts in studies - not chugging 20 glasses of concentrate in one sitting), serum concentration of the drug would be higher and AUC higher. What I said is what you’re pointing to later on in your response, so I don’t get what you mean by “mechanistically not clinically”.

Sorry, did you mean the confusion revolves around the biological location of the impact of GFJ…it’s really the intestine, not the liver? I am agreeing. I don’t think anyone taking GFJ to spike rapamycin cares, btw.

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Yeah, I meant a lot of the earlier responses mentioning this all the way down, by a supposed pharmacist working with renal transplant patients.

Beware of misinformation. I’ve seen way too many mistakes made by plenty of people in healthcare.

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