#1

**Peak Values and Half-Life Measurements results in Half-Life of 6-8 hrs

Thank you! I joined this group in January and learned a lot, especially the importance of measuring blood levels. Here is my data for information and comments. As you will see I have a problem with my rapa being metabolized too fast, and I hope for helpful comments.

I started with 7 mg without GPJ. I initially measured the levels approx. 2 hrs after ingestion to allow for full absorption and 24 and 48 hours thereafter. To exclude measuring errors, I had initially two different labs doing the measurement, the differences were insignificant. Having done this twice I got two very different peak levels of 33.1 and 16.3 ug/l respectively. A half-life of 12 hrs approx. was determined using a best fit exponential, and the calculated residual after 7 days was less than 0.001 mg. I decided to go 14 mg to have more initial exposure, and to investigate the peak level. I did this twice with 3 measurements each. The curves for the two measurements (best fit quadratic) and a curve for the results averaged are in the following plot. t=0 is the time of ingestion.

Pik 3 Curves 14 mg Feb March 2025.docx
MISSING GRAPH I COULD NOT DRAG AND DROP out of ignorance

A peak value of 66.7 ug/l =100 and 2.4 hrs as t= 0 was assumed as standard for further calculations. A best fit exponential on all measurements with an intake of 14 mg (normalized to the standard peak values) was run to determine the half-life:

Peak Values and Half Life.docx
MISSING GRAPH I COULD NOT DRAG AND DROP out of ignorance

Taking into account the calculations of individual and not combined measurement, there is scatter, and the half-time range is 6 - 8 hrs, which is starkly shorter than the generally accepted values of 50-60 hrs. However, this is very plausible, as rapamycin is metabolized through CYP450 3A4 and my pharmacogenetic profile indicates I am a rapid metabolizer of 3A4 (as well as others). We (myself and my pharmacological savy MD’s) expected a somewhat shorter value than the standard, but this seemed incredible which is why I took several measures.

Conclusion : the positives are: I have a nice peak even without GPJ and I have not to worry about the residual value after 7 days; my problem is that I may have too little AUC in the first 24 hrs. Hence I am considering taking a CYP3A4 Inhibitor during the first 24 hours to keep the Rapa level up. GPJ is not the solution as it only increases absorption in the intestine and the peak value, but is not an inhibitor in the liver, I am investigating this, but I look forward to helpful comments.

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#2

I would go with and irreversible inhibitor like grapefruit juice. GFJ gives youirreversible inhibition of the CYP3A4 enzyme. It takes a few days until the body produces new enzymes. That would prolong the AUC a few days.

Could combine with an inhibitor that works on CYP3A4 in the liver. Many inhibitors work on both sites. Milk tistle comes to mind as a dose dependant inhibitor in the liver.

#3

Your model looks totally off. You need to use a 2 compartment model (3 with GI intake). Here is a post on how to fit the correct model:

BTW at that time I was taking Berberine which inhibits CYP3A4: Repeated administration of berberine inhibits cytochromes P450 in humans - PMC
I think that’s why my rapamycin half life was 83h as shown here:

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#4

Why do you think this? I would have thought the only effect was more rapa got past digestion and into the bloodstream to be cleared as per normal. I don’t think I want a longer half-life but it would be good to know what is happening.

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#5

I was thinking of the general knowledge we have about the effects we get from GFJ on drug meabolism. Grapefruit juice significantly increases the area under the curve (AUC) for many drugs metabolized by the intestinal enzyme CYP3A4, enhancing their bioavailability. This effect stems from irreversible inhibition of intestinal CYP3A4, which reduces first-pass metabolism. Key examples include:

Statins:

Lovastatin**: 15-fold AUC increase with grapefruit juice consumption16
Atorvastatin 2.5-fold increase in AUC for atorvastatin acid4
3.3-fold increase for atorvastatin lactone4
Simvastatin: Over 10-fold AUC increase with repeated high-quantity consumption

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#6

Yes…It would increase the AUC by increasing the starting amount but not by increasing the half-life (which is what I thought you meant). Nevermind.

#7

Yes I was unclear in my writing. My thought was that if we can inhibit CYPA4 in the lver? Then we can prolong the AUC even more. Milk tistle came to my mind and also others substances. .

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#8

Thank you, your model is comprehensive. I did not develop a full modeI, i just calculated the half time from amount of the measured peak (time=0 and not from the ingestion time. Unfortunately my graphic did not show. I used drag and drop and copy/paste but could not insert it. How do you insert pictures ?

#9

I thought GPJ inhibits only in the intestine (hence higher peak), but not in the liver (hence no effect on half time). Am I wrong ?

#10

I would want a longer half life because mine as measured from the decay from the peak is 6-8 hrs because I am a fast metabolizer of 3A4. My peak is excellent but my AUC is too low. So I need something to increase the half life for 24 hours, after that my fast metabolizing is good

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#11

GFJ mostly inhibits CYP3A4 in the intestine. But to some degree in the liver. I recommend using some AI engine before adjusting your approach, I have found (using AI models) that GFJ in larger amounts also inhibits CYP3A4 to some degree in the liver. But some say that milk thistle and other supplements might be better if one tries to inhibit CYP3A4 in the liver.

"Intestinal vs. Hepatic CYP3A4 Inhibition:

Intestinal CYP3A4: Grapefruit juice strongly inhibits CYP3A4 in the small intestine, leading to significantly reduced first-pass metabolism of many drugs. This results in increased drug bioavailability and higher plasma concentrations.

Hepatic CYP3A4: The inhibition in the liver is weaker because the compounds in grapefruit juice (mainly furanocoumarins) are metabolized before reaching systemic circulation in high enough concentrations to significantly inhibit liver CYP3A4.

Key Points:
The primary site of inhibition is the intestine. This is why oral drugs that undergo first-pass metabolism are affected the most.

Liver CYP3A4 inhibition does occur, but it is usually not strong enough to dramatically impact drugs that are mainly metabolized in the liver after systemic absorption.

The effect is long-lasting (up to 24–72 hours) because grapefruit juice causes irreversible enzyme inhibition, meaning new CYP3A4 enzymes must be synthesized.

#12

Thank you, a clear description

#13

re: using grapefruit juice - do you drink it at the same time you’re ingesting the rapamycin? before or after?

i haven’t measured lately, but the two times i did, there were only trace amounts after 24 hours. i have since been using 2 drcaps, a smaller one inside a larger one, which are supposed to be acid-resistant, and upped the dose to 12mg, but have not had blood work done since. wondering if taking w/grapefruit juice would help get it into my blood…

thanks,

doug s.

#14

Have not yet used GPJ, only Rapa 14 mg. If you only had trace amounts after 24 hrs you may have same problem as me, i.e. short half time due to genetic CYP3A4 rapid metabolization. You may want to have a pharmacogenetic test. Cheers, M.

#15

i definitely have a high metabolism rate; i’m 6’-0", and my weight is typically ~150lbs, regardless of how much i’m eating. and i’m in my late 60’s.

still wanting to know if i should use gfj to wash down the drcaps w/the rapamycin powder inside.

#16

Suggest you work through the site to build your own opinion, lots of data here.

#17

i’ve looked, but not in a while. i don’t remember seeing anything re: when you should drink the gfg.