My high dose testing did seem to fit, however, with a long half life. It is quite likely a two compartment system anyway.
I did not, however, test for serum half life. Instead I tested for blood panels twice a week. The effect on Neutrophils is quite rapid. (because they have a really short half life).
NGUH, I’m just commenting to give you support!
I find all this information hard to digest as well!!! Because I don’t have a brain for science either, I rely on everyone’s help to figure it all out, so I’m glad you posted your question!
And PS, I don’t accept that you have lack of intellect… our brains are all wired differently and we have strengths and weaknesses in different areas. I’ve met brilliant CEO’s who can’t fight their way out of a paper bag 
And yes, the amount of money one can spend on all these supplements is staggering, so I understand the financial stress of it all. You are very smart not wanting to be wasteful.
I’ve learned some things from the answers here, so thanks again for your post.
Big part of the confusion here seems to be that the half life itself is what varies between people and methods such as grapefruit (GF) ingestion.
It is not so that GF by some magic multiplies Rapamycin, and then comes the independent half life. Instead, and this is why I keep eating GF for a few days, GF slows hepatic removal of Rapamycin and thus increases the half life, especially soon after dosing in oral or rectal applications (because the blood from those places first goes through liver), but also later (blood always still hits the liver once in a while, even if you dose IM).
I agree with you that GFJ will also increase the half life. However, personally I don’t want to increase the half life.
Not really. This has been discussed here already. Here a ChatGPT summary:
Grapefruit juice is well known for inhibiting CYP3A4 in the intestinal wall, which reduces the first-pass metabolism of many drugs. Although grapefruit juice contains compounds such as furanocoumarins that can inhibit CYP3A4 in both the gut and the liver, the impact on hepatic CYP3A4 is much less pronounced. This is because the concentration of these inhibitory compounds is significantly higher in the gut, where they directly interact with the enzyme as the drug is absorbed, compared to what eventually reaches the liver.
In vitro studies have shown that grapefruit juice components can inhibit CYP3A4 in liver microsomes, but in vivo, the effect on hepatic CYP3A4 activity appears minimal and is not generally considered clinically significant. Most of the enhanced drug exposure and related interactions are therefore attributed to the inhibition of intestinal CYP3A4.
This distinction is important because it means that while grapefruit juice can markedly increase the bioavailability of drugs like sirolimus by reducing intestinal metabolism, it does not substantially alter liver metabolism of the drug.
Good publication on subject : Exposure‐Dependent Inhibition of Intestinal and Hepatic CYP3A4 In Vivo by Grapefruit Juice - Veronese - 2003 - The Journal of Clinical Pharmacology - Wiley Online Library
Yes, I measured my peak and half life (see post “Peak Values and Half Life”, unfortunately the graphs didnt come out) and found in multiple measurements a half life of 6-8 hrs, which is plausuîble as I am, according to my pharmacogenetic profile, a rapid metabolizer of 3A4. So I have a good peak but AUC is too low ! I want to increase half life, many 3A4 inhibitors available but problematic or difficult to dose. So i’ll try with GPJ by taking it 2.5 hrs after Rapa, which is where my peak lies. Any comments/suggestions on AUC improvement w/o increasing peak ?
Maxi, this has been discussed previously here but if you are measuring T1/2 within the first 24-48 hours after taking rapa you are likely seeing an artifact of tissue uptake of rapamycin that reduces blood levels dramatically from about 2 -48 hours post ingestion of rapa. If you want an accurate T1/2 you should start your measurement at 48 hours and measure several times every 12 to 24 hours to generate a graph. I think you’ll find your T1/2 is closer to 50-60 hours. This is the same mistake that Kaeberlein made.
Thank you. What dou you mean “an artifact of tissue uptake of rapamycin that reduces blood levels” , I have trouble understanding
Here is what I measured. The first graph is C (ug/l) after ingestion (14mg, no GPJ), the second C (in % of Peak) after Peak Time (several measurements). This checks with what you are saying, but for me hard to understand why this does not represent the usual metabolization and hence half tim. Could you please point me to more information (studies ?) . At 48 hrs I am at percentages of Peak, i.e. in the order of 1 ug/l. How can you measure for additional 48 hrs ? Or does C rise again ? Am I wrong ? Thank you for clarifying.
Pik 3 Curves 14 mg Feb March 2025.pdf (90.1 KB)
Sirolimus Half.Time Exp 15 03 2025.pdf (74.8 KB)
You are probably right. I’ll take more points downstream.
Just use the last 2 points to compute the half-life.
Agree with cl-user, just use the last two points and maybe a 72 hour point to compute the half life. The early blood concentrations are not showing steady state kinetics and will throw the entire model off. After about 48 hours you will be in steady state kinetics and several time points applied to the equations above will give you the T 1/2.
I have not really tried to get into this, but superficially a dimensional analysis gives ln time, not time which confuses me.
The formula I pasted is poorly formatted. It’s ln(2) * (t2 - t1) / ln(c1/c2) which gives the half life in the same unit as t2 and t1.
OK that’s dimensionally correct. I have not engaged brain to work out whether I agree with the formula or not,
I take 7mg/week Rapacan. No explicit boosters, but not on an empty stomach.
55kg
72yo
Tested 3.5 ng/ml at approximately 48 hours, 1.8 ng/ml at 96 hours. Pretty easy to eyeball that and say half life of 50 or so hours.
Anyway, I fed the numbers into 4o and also mentioned that a couple of years ago, I measured 48 ng/ml two hours after taking 10mg. It calculated a proportionate level of around 33 ng/ml as an estimated max level for 7mg.
The results follow:
Sirolimus_PK_Model_With_Formula.pdf (25.6 KB)
Yep this is a good way to measure T1/2. Complete with a graph showing the change from absorption to steady state kinetics and why you need to wait until 48 hours or later to take your two measurements to calculate half life. Thanks for the detail!
