This is a point of ongoing questions and uncertainty… hopefully resolved with more research sooner rather than later…
I think the answer to this would basically address if intermittent dosing is indeed superior to daily dosing, and why. Maybe the ITP should also run a few studies with intermittent dosing strategies.
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They did one such study:
Rapamycin Dosing trial in mice paper that came out last year - Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects - PubMed
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That’s what makes me uncomfortable with people using grapefruit juice with rapa. People post that it ‘increases the bioavailability’. That is inaccurate. Grapefruit increases the half-life by enzyme inhibition. Slower ‘washout’ means higher risk for mTOR2 side effects. Taking rapa with a fatty meal improves absorption (see package insert). More is not always better, esp with drugs!
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Ah… that is very interesting. Now that you mention it, yes - that makes sense. Its the total AUC that increases… and since it doesn’t increase the peak (I don’t think), it must increase the half-life. Any idea how much it increases the half life?
This might be a reason to use everolimus with grapefruit juice over rapamycin with grapefruit juice - no? Because everolimus already has a significantly shorter half life.
But we don’t know what matters: peak blood level, AUC, duration? For renal transplant (I worked in Nephrology a few years) we would focus on troughs- drawn just before the next dose. Occasionally we would have the patient draw at peak- an hour after dose. But that goal WAS to achieve immunosuppression - that’s what we are trying to avoid!
Ideally we want the dose that suppresses mTOR1 with minimal mTOR2 inhibition. Until we have a biomarker, a metric, we guess. Take until you get immunosuppression! High blood glucose- how many are even measuring that? I’m just saying, be smart about this. As a pharmacist, I see so much stupidity when it comes to medications. But my guess, if you’re reading this, then you have read the links at www.rapamycintherapy.com. If not, then you have some learning to do.
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I thought drinking a glass of grapefruit juice with the weekly just inhibits CYP450 3A4 for a short period, enough to help spike rapa levels for a day or so but without affecting the washout period for the rest of the week.
Since grapefruit juice inhibits mainly intestinal CYP450 3A4, it should mainly affect absorption rather than metabolism of rapa (which would take place in liver, unless I’m missing something?). If you take rapa and grapefruit juice every day, the AUC goes way up, of course, because you’re absorbing more rapa repeatedly over the week, but once weekly dosing w/grapefruit should cause an early spike due to increased absorption, with little or no effect on drug catabolism by the liver the rest of the week.
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This is pharmacokinetics 101. Absorption, distribution, elimination. Rapa is fat soluble. Hence absorption is improved by taking with a fatty meal. Yes, there are some cyp 3A4 enzymes in the intestines, but minor compared to the liver.
Rapa then goes through the gut to the hepatic portal vein to the liver where the cyp enzymes can breakdown any poisons you’ve eaten. This is called ‘first pass effect’. Grapefruit juice inhibits p450 cyp 3A4 enzyme which breaks down rapa and so many other drugs- see the warning label on your pill vials! Some drugs are ‘pro-drugs’. Inert until activated by your liver enzymes. Know what you’re taking.
If you graph blood levels over time, you’d see rapid rise, peak and a drop off. The area under ghat curve is literally the AUC. But larger AUC does not mean greater effect of the drug. Rapa may only need a strong peak to affect mTOR1. We don’t really know. Prolonged exposure to rapa is what causes toxic side effects from mTOR2 inhibition (immunosuppression, insulin resistance etc), which is desired for transplant patients.
Bottom line: The package insert says improved absorption with a fatty meal ( or take with a shot of olive oil). But adding a cyp inhibitor, especially a strong one is playing with fire. Prolonging the half-life to what end? Even if you did rapa blood levels day-by-day, how do you interpret that data?
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If grapefruit affects mainly intestinal CYP 3A4, it works via enhanced absorption. Are you claiming that one glass (or one grapefruit) per week also inhibits liver CYP 3A4 to a significant and lasting extent?
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I don’t exactly know what a glass of grapefruit juice once weekly does to sirolimus levels. Do you? Please share the data.
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We also don’t know if rapamycin delays aging or does much of anything positive using current anti-aging dosing regimens in humans. None of us have that data either, so all we can do is make informed choices based on existing evidence. Isn’t that why we’re here on rapamycin.news in the first place?
Back to rapamycin/grapefruit, please see my previous post. If indeed grapefruit mainly affects intestinal CYP 450 3A4, it’s only going to significantly affect absorption, not post-absorption catabolism/elimination/AUC and not when the GF+rapa is only ingested once every 1-2 weeks. It would require that
one glass of GF juice significantly inhibits liver 3A4 and that it inhibits it for days or weeks in the absense of repeated doses of GF, which does not appear to be the case.
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from Dr. Mark Thimineur post in age-reversal forum 2 years ago:
"to answer this with adequate explanation I’ll defer to study of grapefruit juice on drugs called “statins” which treat hypercholesterolemia. Like rapamycin the have low bioavailability (5%) vs 14% for rapa. The reason is both drugs have a first pass effect in which most drug succumbs to the enzymes in the lining of the duodenum. Grapefruit juice irreversibly inhibits the enzyme until more is made which takes 24 hrs to fully reverse. In the presence of grapefruit juice the statin drugs absorb dramatically more with huge increase in plasma concentration. The subsequent hepatic metabolism is unaffected with the same half life with or without grapefruit. But for the 5 half lives needed to clear the drug the levels are increased thereby increasing the area under the elimination curve (AUC) and, in the case of statins producing deadly toxicity. The same for rapamycin - the AUC is increased but not the elimination half life. If grapefruit juice is used there needs to be dose alteration. Ex: a 5mg dose will effectively become 12.5-17.5mg with juice. Notice it is a range because the increased bioavailability has been measured to be a range of 250-350% - so we are not all the same. "
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Thanks for posting that! Since the effect of one glass of GF juice is essentially restricted to the intestine and affects absorption only, the AUC and the elimination over time of a (rapa 5mg + GF juice) dose would be the same as the AUC/elimination of a 12.5 - 17.5 mg dose of rapa by itself.
Given that dosing rapa once every 1-2 weeks appears to have a wide margin of dosing safety, this is exactly what people are doing who want to save money and still achieve effective systemic concentrations of rapa, and it makes sense if they’re willing to put up with some absorption variability. Those who take 2mg with GF should get the equivalent of 5 - 7mg without fear of any more side effects than taking a 5 or 7mg dose by itself.
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Apparently Dr. Green is recommending 5 half-lives for rapamycin dosing intervals:
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So that’s 13 days for rapa. Is he recommending that across the board for everyone, or just the folks taking higher doses?
I’ve read somewhere figures pointing to over 300%-350% increase in absorption.
And the protocol I follow with grape fruit juice - seems to be Dr. Green’s - is a 300/400ml. vase in empty stomach in the morning and after one fasting hour my 6 mg. rapa biweekly dose, so inhibiting action on CYP 450 3A4 enzyme seems to be at its peak. Just my two cents.
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Great thread with references. ONE ‘dose’ of GF juice prior to your rapa makes sense (and cents). Note the effect on statins however. I would not do the GF juice if you are taking ANY other medication that interacts. It’s always a warning label on your pill bottle. What a great group this is.
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Please explain. Five 1-mg pills should contain the maximum rapamycin of 5 mg at the most. Because poor bioavailability and CYPxx enzyme, our gut may absorb only 2 mg. How can grapefruit juice boost the rapamycin absorption to 300% to the equivalent of 15 mg? There are no 15 mg worth of rapamycin molecules around.
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In this quote “The biweekly dose is 30mg sirolimus without grapefruit juice. Every 6 week dosing of 90mg was 30mg sirolimus dosed with grapefruit juice”, Dr. Thimineur seems to imply his 90 mg dose are converted from 30 mg with GFJ. In fact, there are no 90 mg equivalent of Rapamycin molecule in the body.