Interactions with rapamycin
The enzyme CYP3A4, located primarily in the liver and intestines, metabolizes rapamycin. It is well known that grapefruit juice inhibits the enzyme. So taking grapefruit juice with rapamycin increases your effective dosage. However, some common supplements activate CYP3A4 thereby metabolizing more of the rapamycin and effectively reducing your dosage. DIM, diindolylmethane, is one such supplement. Based on its effect on rapamycin and since its benefits are not that impressive I didn’t mind giving it up. Curcumin, however, another supplement that markedly activates CYP3A4, is different. Curcumin’s many important benefits are well documented and include studies that have shown it increases life span in mice and rats. It also has notable effects on inflamamation and symptoms of osteoarthritis.
This poses a dilemma since I don’t want to give up either product. The only solution that comes to mind is to avoid curcumin totally during the 1st week after rapamycin dose. Since I’m on a biweekly schedule, resume curcumin during the 2nd week, the trough week, when I am wanting to wash out the residual rapamycin anyway. There is a problem with that too, since despite a short half life of about 6-7 hours, curcumin can still be found in the system days later, especially if taken with piperine. Perhaps it would be better to pause curcumin a couple of days prior to rapa dose.
Has anyone else grappled with this issue and perhaps come up with a recommended solution?
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I wasn't aware of the Curcumin/CYP3A4 interaction. I take Curcumin daily (500 mg).
Not sure what literature you are referencing, but this study seems relevant:
Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies
https://pubmed.ncbi.nlm.nih.gov/25300360/
"This study investigated the effect of co-administration of Curcumin on the pharmacokinetics of Everolimus (EVL) in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC0-540 of EVL by 70.6% and 71.5%, respectively, and both dosages reduced the Cmax of EVL by 76.7%"
Significant impact indeed.
Now, my taking 500mg for say a 60 kg weight = 8.3mg/kg, FAR below the dosage in the rats. Without trying to do extrapolate metabolism from rats to humans, I'd guess my CYPA34 activation taking 500mg Curcumin is FAR LESS than the rats. For discussion sake, let's assume human Curcumin/CYPA34/Rapamycin AUC reduction of 20% vs say 70% in rats.
We know that taking the grapefruit juice protocol can increase Rapamycin AUC by 350% in HUMANS. https://pubmed.ncbi.nlm.nih.gov/22872575/
Then by simpleton math, reducing Rapamycin/GFJ efficacy (AUC) from say 350% to even even 300% whilst taking Curcumin, is thus hardly a significant big picture boost reduction concern. Certainly, you can address with a Rapamycin intake bump.
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Thanks for bringing perspective to the issue, Mac!
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I took another look at the curcumin study. If one does the actual animal to human dose conversion, the human equivalent dose would be about 500mg. (Divide rat dose of 50 mg/kg by 6.2 to get equivalent human dose of 8mg/kg. So for a 60 kg human that’s 480 mg). Based on the study this means that taking 500 mg of curcumin with rapamycin would, as feared, markedly lower the effective dose of rapamycin.
Unless someone has a better suggestion, I plan to avoid curcumin on the day of, the day before, and the day after rapa. When I resume curcumin 2 days after rapa, I suppose the liver will metabolize some of the circulating rapa but since my overall regimen is largely inhibitory as far as its effect on CYP3A4, that should be an offsetting factor to some degree that would be very difficult to calculate. Additional comments are welcome.
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Did some more digging, observing mostly CYP3A4 INHIBITION findings with Curcuma Longa (the active ingredient in the Curcumin I take).
Here's one pretty definitive IN VIVO humans that I think puts this issue to bed
Effect of Curcuma Longa on CYP2D6- and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human subjects
https://sci-hub.se/https://doi.org/10.1007/s13318-014-0180-2
"C. longa rhizome extract inhibited the formation of DOR [CYP2D6] as well as 3-MM (CYP3A4] metabolites, in a concentration-dependent manner. This in vitro INHIBITION was observed as concentration dependent and suggested that C. longa has potential to alter the pharmacokinetics of CYP2D6 and CYP3A4 substrates"
CYP3A4 was far less impacted by C. Longa compared to CYP2D6, but the latter enzyme is not relevant to Rapamycin as some other drugs referenced in the study.
Here are some papers finding inhibition or very little impact:
https://pubmed.ncbi.nlm.nih.gov/17270371/
https://pubmed.ncbi.nlm.nih.gov/20509107/
https://pubmed.ncbi.nlm.nih.gov/33677011/
