#1

Current popular hypothesis: Rapamycin longevity effect may be more relevant to Cmax then the AUC.

In another way, the peak concentrations is more important, Rapamycin reaches its peak roughly at 2 hours, but due to its long half life time, it takes roughly 2 weeks to eliminate. If we can accelerate elimination rate after the peak time, then we can have less side effects while preserving the longevity effect.

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For my limited knowledge, Rapamycin is metabolized mainly by enzyme CYP3A, then the majority matabolites excreted in feces, if we can induce enzyme CYP3A, then we can increase rapamycin elimination rate.

https://www.pharmgkb.org/pathway/PA166165039/overview

If my understanding is right, then we can induce CYP3A in day 2 or day3 (after initial dose), hence shorten the half life time, then we have less side effects.

There are drugs that inhibit or induce CYP3A, but most inducers of CYP3A not act immediately, they need 2 weeks long or more to induce CYP3A, it is not appropriate in this scenario.

https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers

However, I found there are some researches show that fasting increases CYP3A4-mediated metabolism, but I am not sure if that also works on rapamycin.

https://sci-hub.se/10.1124/dmd.114.062299

In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2,
CYP2C19, CYP2D6, and CYP3A4 (P < 0.05)

Conclusions

Short-term fasting differentially alters midazolam metabolism by increasing CYP3A4-mediated metabolism but by decreasing UGT-mediated metabolism. In contrast, a short-term HFD did not affect systemic clearance of midazolam.

Do you know any way to accelerate the clearance of rapamycin?

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What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?
Rules of Thumb?
#2

Yes - there is this drug:

Rifampicin is the most powerful known inducer of the hepatic cytochrome P450 enzyme system, including isoenzymes CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, and CYP3A7.[41] It increases metabolism of many drugs[42] and as a consequence, can make them less effective, or even ineffective, by decreasing their levels.[43] For instance, patients undergoing long-term anticoagulation therapy with warfarin have to increase their dosage of warfarin and have their clotting time checked frequently because failure to do so could lead to inadequate anticoagulation, resulting in serious consequences of thromboembolism.

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#3

Curcumin induces CYP3A4. This study showed curcumin along with everolimus sped up clearance of everolimus in rats Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies | Scientific Reports

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#4

That’s great that it directly tests coadministration of Rapamycin(Everolimus) and Curcumin, and it decreased AUC by 70.6%, it seems that Curcumin significantly decreased the absorption of Everolimus.

Can we infer that “sequential” administration of Rapamycin then Curcumin also has the similar effect of "coadministration " of Rapamycin and Curcumin?

I.e. coadminstration of Curcumin decreased AUC of Everolimus mainly by decreasing bioavailability of Everolimus, but if there already existed high Everolimus blood concentration, then does sequential administration of Curcumin also increase the clearance of Everolimus?

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#5

One would assume that yes it still would speed the clearance of any CYP3A4 substrates which exist in the bloodstream. I think you want to make sure that the curcumin doesn’t have added piperine.

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#6

Hi elixir, can you explain why not to add piperine in the curcumin? Thank you.

#7

Curcumin bioavailability is very low so most formulations have a way to either deliver more (like Meriva) or slow the metabolism (with piperine for it’s CYP3A4 inhibition).

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#8

Great, Rifampicin increase both presystemic and elimination phases, but it looks like it takes 5-day pretreatment to activate its induction effect.

https://sci-hub.se/https://pubmed.ncbi.nlm.nih.gov/17381666/

Our results have suggested that
rifampin enhanced the metabolism of risperidone
during both presystemic and elimination phases

CONCLUSION
This study shows that 5-day pretreatment with
600 mg of oral rifampin causes a significant
reduction in plasma concentration of risperidone
by enhancing its metabolism in the liver rather than
the small intestine.

I found there are also some moderate/strong Cytochrome P450 3A inducers, but I am not very familiar with these drugs, anyone has any opinions on them?

Considering the safety and there was a trial of Curcumin with rapamycin (everolimus), I would like to try Curcumin next time, but any opinions of other inducers are also welcomed.

https://www.uptodate.com/contents/image/print?imageKey=CARD%2F76992

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#9

If you’re just trying to shorten the half-life of rapamycin, you might just move over to Everolimus: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?

#10

But is Everolimus a more potent mtorc2 inhibitor than Sirolimus?

Highlights

  1. Everolimus has different clinical pharmacokinetics than sirolimus, most importantly a shorter elimination half-life.

  2. Everolimus is metabolized differently than sirolimus and has different affinities to active efflux drug transporters.

  3. Everolimus affects the mTOR pathway differently than sirolimus and has a higher potency in terms of interacting with mTOR complex 2.

  4. Everolimus distributes differently into tissues and sub-cellular components.

  5. Everolimus has the potential to antagonize calcineurin inhibitor neuro- and nephrotoxicity at clinically relevant concentrations.

  6. Head-to-head prospective clinical trials to directly compare sirolimus and everolimus are lacking.

#11

On the issue of mTOR inhibition - I had read the same paper you’ve read, but Dudley Lamming, who I think is a much better and more experienced person when it comes to mTOR and rapamycin studies says no, that is not true. They see less mTOR2 inhibition with Everolimus.

I recommend you watch this video, at least the mTOR 2 inhibition sections (some of the questions / comments by the transhumanist participants in the video seem like a waste of time).

A good presentation covering rapamycin and rapalogs by two experts in the field; Dudley Lamming and Adam Konopka. Covers rapamycin, as well as rapamycin/metformin simultaneous use, everolimus and mTOR2 inhibition, immtor, etc.

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#12

Interesting, I will definitely watch this presentation.

#13

I have finished the presentation, very informing, Dudley Lamming clearly explained mTorc1 and mTorc2, and mentioned that Everolimus disrupts less glucose homeostasis than sirolimus.
RapAdmin, do you know any expert or MD in the field has changed sirolimus to everolimus?

#14

I’ve not heard of any doctors, though Blagosklonny is promoting this idea of using everolimus instead of rapamycin it seems:

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#15

Do we have any evidence that AUC correlates with side effects and not peak levels?

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#16

some side effects are correlated with peak levels (diarrhea, GI issues, etc.) but the bigger side effect issues (immune suppression) are correlated with chronic (daily) and ongoing rapamycin use and trough levels (the higher the trough levels, the greater the immune suppression)

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#17

Rifampicin + Rapamycin +Allantoin produced the greatest increase in c elegans lifespan ever achieved

Does anyone know if Rif and Rap have ever been used together in a mouse study?

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#18

Isn’t Allantoin lethal if ingested by humans?

#19

How would Rifampicin enhance rapamycin - by speeding up the metabolism of it?

#20

I have no idea. We need to read up, its not exactly obvious:

The effect of rifampin on the pharmacokinetics of sirolimus in healthy volunteers

Sirolimus, metabolized primarily by intestinal and hepatic CYP3A4, is a substrate for P-glycoprotein. CYP3A4 inducers would be expected to decrease sirolimus exposure. This open-label, nonrandomized study investigated effects of CYP3A4 induction, by rifampin, on sirolimus pharmacokinetics. Healthy volunteers received sirolimus 20 mg on day 1. After washout period, multiple 600-mg rifampin doses were administered daily for 14 days. On day 9, one 20-mg sirolimus dose was administered after an overnight fast (≥10 hours). Whole blood samples for sirolimus collected for 144 hours after each dose were analyzed by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, assessed using noncompartmental methods, were compared using analysis of variance. Geometric mean ratios of Cmax and AUCinf were 29% (90% CI: 26, 32%) and 18% (90% CI: 16, 21%), respectively, with rifampin co-administration versus sirolimus alone. Corresponding decreases in Cmax and AUC were 71% and 82%, respectively, which would likely cause trough concentrations to fall below the recommended therapeutic range. Mean CL/F increased approximately fivefold with rifampin versus sirolimus alone. Co-administering sirolimus and potent CYP3A inducers is not recommended. If co-administration is necessary, dose adjustment and concentration monitoring should be conducted.

https://accp1.onlinelibrary.wiley.com/doi/abs/10.1002/cpdd.40

Effect of rifampicin to inhibit rapamycin-induced autophagy via the suppression of protein phosphatase 2A activity

Here, we demonstrate that the rapamycin-induced autophagy is dependent on protein phosphatase (PP) 2A activity and rifampicin inhibits the activity of PP2A by reducing expressions of PP2A subunits A and C. In addition, rifampicin slightly, but significantly, inhibited the rapamycin-induced dephosphorylation of p70 ribosomal protein S6 kinase (p70S6K) at Thr421/Ser424, which are regulated dually by both rapamycin and PP2A, but not at the rapamycin dephosphorylation site located at Thr389. These results show that rifampicin inhibits rapamycin-induced autophagy, at least in part, via the suppression of PP2A activity.

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