#162

Here’s a reference to timing of GFJ with Rapa

“ According to a statement from the University of Chicago Medical Center in Chicago, Illinois, where study director and cancer specialist Ezra Cohen, MD, practices, the effect of grapefruit juice begins within a few hours of ingestion and wears off gradually after a few days.”

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#163

In answer to the original question, my monthly dosing cycle has evolved over time, currently is as follows:

Start of Week one and week 3

  • 1 entire peeled grapefruit blended in my Vitamix with a little sugarfree lemonade

  • 1 ½ hours later, take 7mg sirolimus, estimated 3.5 fold increase in equivalent dose to yield ~25mg

  • 3 hours later assume Tmax (delayed by the grapefruit) has been reached. Resume my usual activities that may reduce mTOR inhibition, e.g., smoothie with protein and leucine, resistance training, etc. I’m more interested in a high Cmax, less interested in a high AUC.

Start of Week two and week 4

  • 4mg sirolimus as a maintenance dose. I wish to avoid a complete washout in fear that could encourage mTOR rebound.

End of week 4

Senolytic cocktail to coincide with sirolimus trough, taken the last 3 days of monthly cycle.

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#164

Thanks for sharing your detailed protocol. I understand all you objectives but did you test the values in your blood? As I can see with my tests, the dosage has very different effects in individuals. How many ng/ml do you target at which point?

#165

I haven’t tested my blood concentrations under this protocol.

Past tests, however, have convinced me that the effects on me were about as expected, i.e. about average.

It would indeed be interesting to know what is the Cmax I achieve, or the concentrations at various time intervals, but I don’t have a specific ng/ml target because my dosage is guided by achieving the highest concentration that doesn’t produce intolerable side effects. At present, a dosage of 6 to 7mg sirolimus with grapefruit seems as high as I should go.

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#166

I tend to agree that the serum ng/ml issue is not the priority. The priority is to know what it does, both positively and negatively.

As I see it the effects on mitophagy are the key positive priority and the damage on glucose, lipids and cell division (including the immune system) are the things to avoid.

Hence we need to look at those.

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#167

I don’t think it’s accurate at all that it takes a while for the effect of grapefruit to begin. It has effects very quickly. In this study, grapefruit increased the absorption of a drug by just as much when it was taken at the same time as the drug as it did when taken 1, or 4 hours before ingestion of the drug. When taken 10 hours befor the drug the effect was only about half as strong. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects - PubMed

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#168

I agree that the priority is to know what it does. Unfortunately we can’t know most of the important stuff it does. We can only observe limited set of effects. Therefore, blood tests are still one of the best ways to predict what effect we get. I think blood levels, when compared to effective levels in transplant patients an mice, are the best proxy we have of effective system wide mTOR inhibition. Side effects like mouth ulcers, increased lipids and blood glucose are also useful, but they are far too tissue specific. Two people could have relatively strong whole body mTOR inhibition from rapamycin while only one of them experiences mouth ulcers or significant changes in blood lipids or glucose just because he for some reason has a liver or mouth mucus membranes that are more sensitive to mTOR.

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#170

I’m feeling that during my break my symptoms started to creep back. Actually since lowering the dosage it seems to creep back. Maybe for some of us with auto immune issues we need higher dosage. I was taking 20mg with GFJ weekly and it seems to work well. However psychologically it seems too high. Maybe 10mg a week or 8mg a week is better. Has anyone else noticed more is better?

FYI my 12 hour blood test was about 40ng/mL.

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#171

Taking 20mg weekly even without GFJ would mean continual mTOR inhibition probably both complexes.

#172

I recognise this. If the labs i use offered a rapamycin test i would take this up. I think the glucose effects are likely to be more consistent.

What is needed is a good mechanism for measuring mitochondrial efficiency. Fasting serum ph may help here.

#173

Maybe people should list countries that offer rapamycin blood tests without a doctor’s refferal. That way people can use the chance when traveling and see what blood levels they are really getting. I will start by saying that in Romania, you can test rapamycin at private clinics without a doctor’s refferal.

That would be great. I’m curious why you are so certain that improved mitochondrial efficiency is one of the important effects of rapamycin? I don’t recall mitochondrial efficiency being a factor modified by rapamycin in the short term and mentioned in any of the main lifespan studies on mice, but I don’t remember all the details so I might be wrong (mitochondrial efficiency is not something I was particularly focused on when reading about rapamycin). I certainly don’t remember it being a major factor influenced by rapamycin in humans. Another source of my doubt is that increased mitochondrial efficiency is not universally a good thing. In fact, very mild inhibition of mitochondrial efficiency such as by use of uncouplers or metformin, can actually have beneficial hormetic effects. Are you aware of any studie that show that the benefits of rapamycin in mammals is dependent on changes in mitochondrial efficiency?

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#174

My understanding is that Rapamycin encourages mitophagy. I am not doing a search for this as I am pretty certain this is accepted.

When mitophagy happens the less efficient mitochondria are recycled first and then new mitochondria created from the remaining mitochondria. I don’t think there is a focus on the more efficient when it comes to fission, but there might be.

Hence by getting rid of the less efficient mitochondria the average efficiency increases. The cell manages the mitochondrial copy number.

The efficiency is primarily driven by the mitochondrial DNA.

We then move onto ATP/O efficiency driving the Mitochondrial Membrane Potential (ΔΨm) which is a factor driving citrate efflux. This drives the splicing decisions in the nucleus and that is what I think is a primary cause of the aging phenotype. Another factor in the same pathway is the expression of SLC25A1. (aka the Citrate Carrier).

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#175

You are probably correct based on the published half life; however, some people are fast metabolizers of Rapamycin. Matt Kaeberlein is one of them. If a person clears almost all of the Rapamycin in a mere 3 days, a 20 mg weekly dose might be fine. Ideally we would all do multiple blood tests and determine our Rapamycin half life as a guide to dosage and dose frequency.

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#176

Is this accessible to you?

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#177

Matt Kaeberlein isn’t necessarily a fast metabolizer, and I’m not sure such a thing exists. The issue was an error in how he measured this as there was a combination of absorption peak and lack of tissue redistribution to establish the peak level, which they incorrectly then used to look at T1/2. It must be tissue redistributed first, then you can look at T1/2.

My experience thus far having paired a good number of levels vs. dose vs. weight/body composition is that lower single doses might see a T1/2 in the 25-35 hr range, and as the doses get modest e.g. 12 mg in a 170 lb person, often is in the high 30’s to low 40’s hr range, and as things go higher it comes closer to the published T1/2 for daily doses.

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#178

interesting. i know there is/was an article on this site that had a study and as i recall, 1hr after GFJ injestion was the highest impact. I just can’t find it right now.

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#179

See our past discussions on grapefruit juice and rapamycin:

Here: Improve Bioavailability of Rapamycin (2)

Here: Rapamycin and Grapefruit Juice

Here: Grapefruit interaction with longevity meds?

Here: Rapamycin Interactions with Other Food, Drinks, Supplements and Drugs

Here: Ketoconazole timing for enhanced Rapamycin absorption

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#180

I agree, Olafur.
I have always just taken the grapefruit juice, one fresh squeezed, 5 fl oz with my rapamycin and nothing more and I get the results 2 and a 1/2 hours later of the increase. I do the Labcorp test, and I’ve done this many, many times it’s always the same. Grapefruit juice with the dose. I get my highest result. 3.5 to 6 increase.

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#181

That’s great. Nice to know the increase is consistent. That actually surprises me a little bit given that you only ingest juice from one grapefruit because I read studies showing that you may need a minimum of 200 ml of grapefruit juice to have strong effects and sometimes even 200 ml can cause little to no effect while higher doses cause a strong effect. 5 ounces is less than that so you could be falling a bit short on the dose of the CYP3A4 inhibiting grapefuit compounds sometimes (depending on how much is in that particular grapefruit you buy at any time point). It wouldn’t be a bad idea for you, if you can afford the time and money, to test your levels after ingesting twice as much grapefruit juice. FYI, I tried 200 ml of grapefruit juice and only got a 1.4x increase in concentration but when I tried 400 ml I got a 4x increase. I was a bit shocked by the difference.

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#182

Ahhh… i find that interesting that the quantity at the one dose versus over a period of time can make that much difference.

When I take grapefruit, I consistently use a fresh red grapefruit, and hand squeeze it in slices…so there are no additives. It is pure juice, so maybe that makes somewhat of a difference and getting a very high reading with my rapamycin dose.

Certainly, I could squeeze two red grapefruits and take it at once. I can test with run grapefruit juice and see the results on a Labcorp test. Then the next time, use two grapefruit juice and take the Labcorp test. Will experiment with this in the next few months.

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