Rapamycin and Grapefruit Juice

#244

59vw- I agree with you completely.

My calc was certainly too simple- just what dose do I have to take to get my blood to a certain level.
With GFJ, I can multiply my dosage by eight. Without GFJ, I’d multiply dosage by 1.3. And, that is barely valid, as I pointed out that after one 8mg dose, my level was 17 and after the next was 10.9.

I’m not sure I’ll continue with GFJ (or maybe use less?). Rapa is pretty cheap in India. Anyway, I need to do more testing.

What I’d like to know- optimal dosing schedule and amount…

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#245

@Bicep Not sure what you mean by “not smart to check at the 2 hr. level because it is changing so fast it’s not useful”. I assume that you mean that I may or may not have reached my tMax. Well, that is why I’m always testing two hours after dosing. If it were feasible, I’d get my blood checked every 30 minutes for four hours. I am not comparing my results to anyone else, I’m just trying to be consistent.

You also stated that because the dosage and result are in different units, that the numbers are meaningless. Really? I thought it showed me that if I take 4 mg rapa with GFJ and I test my level two hours after dosing then I can expect my blood level to be around 32. Certainly not meaningless to me. I realize the dose is mg and the blood level result is in ng/ml. Just because they are different units doesn’t mean the result is not valid. i.e. if you drink 8oz of a glucose solution and they measure your blood insulin level in iu/ml- is that meaningless? Of course not!

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#246

I don’t understand this either. Rapamycin can peak anywhere from 1-4hours. So if you check your rapamycin level at 1.5 hours the “knife” could be raising or falling. Same with 2 hours or 3 hours. Like hitch said, ideally you would have the lab drawn every 30 minutes to find your personal peak. You could probably narrow it down pretty close by doing it hourly x 3. I am considering doing this. But really, the most important thing would be to get your peak drawn at the same duration every time. Consistency. If the knife is falling at 2 hours, then it will be falling the next time at 2 hours as well. I would think 2-2.5 hours would be right in the middle of the 1-4 hours and that would be best. Rapamycin has such a sharp rising peak AND sharp fall.

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#247

The curve is very steep at this place, so if you miss by 15 minutes because waiting room, your number will be off by quite a bit. Also probably less predictable how fast it goes through the digestive system than how fast it degrades once in the bloodstream. I agree that consistency is important so you should do it the same every time. Mid week you would have more flexibility, but it would be hard to get it timed just right. It’s hard to get things timed to the minute a couple days out.

You both have as good a grip on the curve as I do so I probably should have left it alone. The value is useful certainly. I paid $100 for a reason. I should have used the word precise maybe.

By “this purpose” I meant saying because you took 4 mg and your level is 32ng/ml, that means gfj multiplies your dosage by 8.

#248

That’s an incorrect assumption. It might as well be 4x or 12x or something. You can’t know how much the GFJ increased your blood level unless you test it at least 24 hours after you take ramapycin. Optimally test at 48 hours. Measuring at 2 hours after dosing to try to catch the peak is mostly a waste because you have no way of knowing how close you are to the peak. Do a test 48 hours after dosing with and without grapefruit juice, then you will get a good estimate of how much it increases your personal absorption.

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#249

Would 24 or 48 hours post dose still be better than 2 hours if done precisely each time? 2 hours would give a bigger signal, just given the shape of the curve.

#250

Yes, because even if you’re super precise, there are a lot of factors out of your control that influence when exactly the peak will occur and how sharp it will be. Factors such as gastric emptying rate, the exact amount of liquids in your stomach when you take the rapamycin and more. There will be significant day to day variations in these things even if you do everything exactly the same when taking the rapamycin. Add to this the difficulty in having the blood draw exactly at 2 hours. I doubt you can bring a stop watch to the nurse, show up a bit earlier and tell them to wait until you reach the 2 hour mark, but even if you could there are the other biological factors that would differ from day to day.

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#251

@Olafurpall

I don’t know how I’m making an incorrect assumption. It is a fact that my rapamycin blood level was 31.9 ng/ml approximately 2 hours after my dosing with GFJ. Yes, that might not be my cMax, but unless I wear a “constant rapamycin monitor” (which doesn’t exist), it is impossible to know my cMax.

Yes, my cMax is dependent upon when I test and what is in my stomach and my uptake rate, etc. That is why I try to dose at the same time (9:00 a.m.) on an empty stomach.

You state that there are “significant day to day variations”. That certainly depends on your definition of “significant”. Do you have data to back up your statement, or is it an assumption?

I did test three days after my 4mg w/GFJ dosing (I would have done it at 48 hours, but LabCorp is closed on Sundays). You can read my post about that in the “blood testing” forum. My test showed that my blood level was down to 2.9 ng/ml after 76 hours. Seems like I have a pretty high dissapation rate.

I do think cMax is important, and I do realize that my 2 hour post-dosing test is not exact.

What I’d like to know about dosing rapamycin:

Is having a high cMax the most important thing? I could argue that it might be (I think I read that Dr. Green believes that), as you might want to get the rapa molecule in every cell in your body and a high blood level would help. Or, is a cMax over some number non-optimal?

Is it better to have a lower cMax, but maintain that level for longer? That would indicate daily dosing, maybe with days without dosing.

Is it important to have rapa blood level at zero or close to zero for multiple days before you dose again? Or, only right before you dose again?

It seems that the answers are only best guesses. It would be nice if the NIH would fund some dosing studies…

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#252

Hitch… Doug.
The bad news is that there doesn’t seem to be any consensus about dosage. Is the 31.9 too high? Or is it best to get it as high as possible without getting bad side effects? Should I switch to every other week (14 days) and continue the 4mg with GFJ?

My N=1 a dose of 6mg rapamycin with GFJ gave me 38 ng/mL. I did that for 7 months and went from GlycanAge 37 years biological age to 51 years. A very negative effect.

Reduced my dose to 6mg rapamycin weekly for 4 months… my biological age reduction was back down to 47 years.

Continued 5 more months and now this week back to 42 years biologically. Yeah.

I think more rapamycin (higher than 8mg) is not better.

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See the upward blip on the graph… too much rapamycin 38 ng/mL every 10 days.

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#253

@Agetron The problem is that these epigenetic tests are all over the place. Some are way under and others are way over. My family seems to be on the way over side. Taking Rapamycin reduced my epigenetic age by 7 years, but did nothing to my Levine or Aging.ai scores which are about 12 years younger than my biological age. Of course my epigenetic (spit test) age was 11 years older than my biological age (18 years older before Rapa!).

My father came in at 12 years older - 77 yo real 89 yo epigenetic (Tally Health) - and he works out at the gym regularly, is his ideal weight, is a vegetarian, and takes Metformin and other supplements (just started Rapa). He feels fantastic with no medical conditions (except high cholesterol and ApoB). His epigenetic age was 11 years older as well. He’s one of the healthiest 77 year olds I know!

I don’t really know what to make of these epigenetic tests. I am curious to take one again, but at $150 each, that’s an expensive waste of money IMHO. I’d rather do a full blood panel and body checkup for the same price.

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#254

I agree that a lot of epigematic tests are all over the place. The unique thing about GlyanAge is it’s truly looking at sets of proteins and inflammation.

And if inflammation is not there, it’s not there. It is actually rated as one of the better tests to take even by the PEARL Trial… pre and post testing.

People that are looking at a biomarker…It’s about as good as it gets for now. Because I take it regularly, I can look at changes… and see effects. Takes 3 months for Glycans to respond in body to change… dose change.

Which is why I am cautious about too much rapamycin… high dose might cause negative effects … even cancerous tumors. Alex Vojta shared that from a personal dialogue with a key rapamycin researcher.

So GlycanAge works for me… for now.

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#255

So your dose with glycan age of 37 was 6mg/wk NO GFJ? And that’s the same you are doing now? You’ve decided not to use GFJ at all?

I see why you might not want to experiment anymore since you may have already found your optimal dose. I’m just starting rapa and gradually ramping my dose. But I’m considering a 10 day cycle. Thinking around 10mg every 10 days. I don’t think the 10day cycle caused you a problem. If GFJ, really gives you an 8X effect then you were basically taking nearly 50mg every 10days. I’d be very interested how a more reasonable dose of around 10mg (no GFJ) would have worked for you.

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#256

Correct - I never used GFJ my 1 1/2 year of rapamycin… just 3 pills 2mg. Had a Glycan age of 37 years. Blew them away.

Past 7months and tonight… I am now doing weekly 1 pill of 2mg rapamune with Pink fresh squeezed GFJ (mainly to use less pills), my Labcorp results have lately been 4x’s, - so I am getting an 8.8 ng/mL reading… from 2mg rapamune and GFJ.

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#258

Omega 3s have NOT been shown to be a silver bullet. That’s true. But it keeps coming up as helpful for many different issues and I can get it in food so I prioritize it. I eat a lot of fish and take a quality fish oil (another food). Off the top of my head, helpful for:

  • gut health; slowing passage of LPS (endotoxin) from gut into bloodstream
  • improves cell membranes
  • reduces blood triglycerides
  • anticoagulant (might be too much with warfarin medication)
  • but might contribute to heart rhythm issues
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#259

@Agetron I’m going to take your advice about lower dosing. For the near future I’ll be doing 8mg weekly. I may switch to 2mg with gfj at some point, but my wife and I are going to be out of town for a few weeks and I don’t want to do any more gfj unless I can do blood tests.

Besides your GlyCanAge score evidence, I read a pubmed paper by Joan Mannick that showed low dose rapa (5mg weekly) improved immune response to vaccines in older adults- but the 20mg weekly dose did not.

On the other hand, Matt Kaeberlein (Dog Aging Project) is dosing the dogs in his study with .15 mg/kg. That would be about 15mg dose for me. And he worries that might not be a high enough dose. I heard this on a recent Peter Attia podcast with Kaeberlein and Sabatini.

Another interesting thing on that podcast that Kaeberlein talked about was a study that tested improved immune response in mice taking rapamycin.
Four groups of mice total:
Two groups of young mice, of which one group was vaccinated for influenza
Two groups of old mice, both groups vaccinated and one of those groups taking rapa for six
weeks before the vaccination.
All mice were then injected with a lethal dose of the influenza virus.
All young mice with no vaccine died
All young mice with vaccine survived
Of the old mice with no rapa, only 30% survived (sucks to get old!!)
Of the old mice that had been taking rapa, there was a 100% survival rate.

Interesting stuff.

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#260

Exactly on the Mannick immunity and mouse studies.

For me the higher dose was not good. Was swollen in face and ankles… physically felt run down. On my 2mg rapamycin washed down with fresh, squeezed Pink GFJ… all feels better and biological tests are better too. I have a c-max of 8.8 ng/mL

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#261

Hi, Not sure if i am duplicating something. Sorry if so. I read on Alan Green’s website about an interesting idea.

https://rapamycintherapy.com/patient-bulletin-board

" Cytochrome P450 3A Inhibitors and Induccers

Sirolimus is metabolized by the cytochrome P450 3A enzyme system. Strong inhibitors like Grapefruit juice of P450 slow metabolism and result in prolonged high levels of Sirolimus.

Strong Inducers of cytochrome P450 speed metabolism and quickly result in low levels. CS suggests combining these two. For the first few days after taking a regular dose of sirolimus, drink 8 oz grapefruit juice a day. On day 4 switch to St John’s wort and speed up metabolism.

This requires monitoring of Sirolimus blood levels. CS reported these numbers from Ultra Lab tests.

2/17/23 sirolimus 45.7
2/23/23 sirolimus 2.5

Why is this helpful? The benefits are related to high blood levels. The absence of side effects related to LOW blood levels before the new dose.

In some conditions, such as using Sirolimus as an adjuvant treatment to metastatic cancer; you might desire a very high dose for a few days and then quickly reduce the blood level."

Im not sure about the dose of St Johns Wort or if to take for remaining 3 days… I pinged Dr. Green - will reply when he does.

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#262

This is very interesting. I would like to shape the rapa dose curve if I could.

Fatty meal — slower but better absorption, meaning a lower peak but higher AUC by 30% (20-50 range). This is opposite of what I want.

GFJ (what I think happens) — reduced rapa breakdown in gut for higher absorption by 3-8x for a higher peak and higher AUC. This is not exactly what I want. I’d rather have a high peak but shorter half-life, lower AUC.

St John’s Wort — increases rapa breakdown in gut to lower absorption of rapa. Lower peak and lower AUC. I’d assume that after the first hour or two, rapa is out of the gut and no other gut effects would matter. Is this true? Does St John’s Wort somehow shorten the half-life of Rapa after absorption? If so could I take it 2 hours or 12 hours after rapa dosing to keep the peak but shorten the tail? I don’t think so but that is the idea presented here.

The info below is useful but not clear on this question.

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#263

Have you considered everolimus? Shorter half-life.

When I run out of my current supply of rapamycin, approx. two years from now, I think I will give it a try. Maybe I won’t wait that long because at my age maintaining or improving my muscle mass is important to me.

It might be superior in some areas to rapamycin. It is generally sold in larger doses than rapamycin, typically 5mg. tablets. From India, 5 mg tablets are ~$1.50 a piece, so per mg, they are cheaper than rapamycin. That may also be because of the higher demand for rapamycin. I think that the reason for the higher dosages is that when treating transplant patients with everolimus they have to give larger doses to maintain the AUC levels needed for transplant patients because of the shorter half-life of everolimus ~28 hrs.

“Larger dosage required for everolimus than sirolimus to maintain same blood concentration”

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#264

Jagdish just quoted me $7.50 per 5mg tablet. Ouch.