P450 inhibitors to avoid when taking rapamycin -- and for how long?

I recently started rapamycin (sirolimus). I would like to determine if the supplements below should be avoided when taking rapamycin due to inhibition of the CYP3A4 (p450 3A4) liver enzyme pathway used to metabolize rapamycin. For those that discontinue use of p450 inhibitors when dosing rapamycin, do you avoid them on same day, two days, or more?

  • CaAAK
  • Urolithin A
  • Fucoidan (in form of DoNotAge Sirt6 Activator)
  • spermidine
  • NMN
  • sulforophane
  • Lion’s Mane mushroom
  • Cacao flavanols (in form of CocoaVia)

Here are the supplements that I have identified as CYP3A4 inhibitors via the list on this forum and some additional research: green tea, curcumin, black pepper extract, CBD, berberine, echinacea, ginger, st. john’s wort, garlic, licorice root, rosemary extract, panax ginseng, quercetin, pomegranate extract.


Good job on the research. I take a little over a pint of Grapefruit Juice with the Rapa, this increases it’s potency by 3-5x by inhibiting the intestinal cyp3a4. I don’t think it affects the liver by much. Maybe whatever it is in the GFJ that inhibits cyp3a4 doesn’t make it through to the bloodstream? So my 4mg (=$4) really is about 15mg.

I think curcumin goes the other way, but could have that wrong.

I try not to eat much after dosing for awhile and skip my stack for that morning.

To get the exact data, you’d need to research each compound and the 1/2 life of the CYP3A4 or P450 inhibition. For grapefruit, for example it says: “The half life of the effects of grapefruit juice is estimated to be around 12 hours, but these effects may last from 4 hours to 24 hours”. Source: Drug Interactions with Grapefruit

I am concerned with not just consumption of inhibitors before taking sirolimus, but also after. I’d like to better understand metabolism / pharmacodynamics of sirolimus such that I know when I’m “in the clear.” Does P450 inhibition matter past the 12 hour point? When does the liver stop becoming the determinant of metabolism and adipose tissue / blood metabolism become the driver of decay?

Those are good questions. I’ve never seen any discussions around any potential issue with grapefruit juice (or any other CYP3A4 inhibitor) acting on drugs taken before the ingestion of the GFJ - so I tend to think that it is not a problem, but I don’t know for sure. Perhaps some of the doctors or pharmacists in our group can comment?

Mark did you ever find a more complete answer to your question? I wonder the same about some of those supplements you listed

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