Improve Bioavailability of Rapamycin (pt 2)

Depending upon what foods you take with rapamycin, the bioavailability can significantly increase or decrease. This in turn can impact how much rapamycin you need, and in turn the average monthly cost of using rapamycin. To minimize variability, rapamycin should be taken consistently with or without food.

Note: Taking grapefruit (eating the fruit or drinking the juice) with some medications can cause serious liver damage, so be extremely careful with the information below, and be sure to consult your doctor. This is not a recommended protocol for people, but is only offered here for informational purposes.

What are key options to consider for how I take rapamycin?

  • With Fatty Meal
  • With Grapefruit Juice
  • With the anti-fungal drug called “ketoconazole”

The important points to note here are:

  1. If your take your rapamycin with a fatty meal (I take it with a can of sardines for example) you typically increase the bioavailability by about 35%. This saves you money because if you want to be taking an equivalent of 4mg of rapamycin, you only need to take 3 x 1mg tablets with a fatty meal to get the same effect as you would taking 4 tablets of 1mg.
  2. Studies have shown that taking rapamycin with grapefruit juice (from frozen concentrate, in the study), you can get on average a 350% increase in bioavailability. This suggests that instead of 3.5 mg of rapamycin, you could instead take just a single 1mg tablet with grapefruit juice (GFJ) to get the same “effective dose” of rapamycin. (Note: that is, the multiplier is 3.5X the dose you take). But there seems to be significant variation in the effectiveness of different grapefruit juice types (fresh, frozen, etc. - suggested in the paper), and in each individual’s biology and resulting blood/sirolimus levels that result in this scenario - so there is some uncertainty in this approach. It seems that the best time to take the grapefruit juice (or eat a grapefruit) is about 1 hour prior to taking the rapamycin (based on this information). There are some important considerations and limitations - so read more down below before you jump into doing this.
  3. In the same study that evaluate grapefruit juice as a way to increase the bioavailability of rapamycin, they also revealed that the drug ketoconazole also greatly increased the bioavailability of rapamycin - but in a much more precise manner. It consistently increased the bioavailability by 5.6 Times the rapamycin dose. Ketoconazole is an inexpensive generic anti-fungal medication that widely available around the world that does the same thing in the small bowel that grapefruit juice does.

Lets look at the cost impact of using grape fruit juice (GFJ): If you’re paying the typical street price of pharmacy-purchased rapamycin in the US of approximately $5/1mg tablet, and on a weekly regimen of 5mg you have a total cost of $25/week or $100/month. If you’re on a weekly regimen of 10mg you have a total cost of $50/week or $200/month.

If instead you take your rapamycin with grapefruit juice (an 8oz glass) and you want the same effective dose, then your cost structure looks something like this:
On a weekly regimen of effective dose of 5mg, you only need 2mg of rapamycin with GFJ you have a total cost of $10/week or $40/month. If you’re on a weekly regimen of 10mg you have a total cost of $20/week or $80/month.

Precise Dosing Information on Grapefruit Juice / Sirolimus Combination:

“small bowel enterocyte CYP3A4 protein levels begin to decrease within hours of grapefruit juice administration and the effect is maximal if grapefruit juice is ingested simultaneously or within the previous four hours of drug administration.”

The Upsides:

  • Less rapamycin needed (cost savings)
  • Potentially fewer side effects - the combination (GFJ/Rap) could help patients avoid side effects associated with high doses of rapamycin

The Downsides:

GFJ interactions with other medicines: The key issue is you have to be very careful if you take other medications in addition to grapefruit juice. Common medications like statins, blood pressure medications and others can have bad effects when taken with grapefruit juice - so talk with your doctor and do research before considering this.

Uncertainty / Variability of Sirolimus Levels: In the grapefruit juice/rapamycin studies they found that some grapefruit juice didn’t work at all in increasing blood sirolimus levels, and they then tested and tried frozen GFJ concentrate and it worked at the the level reported on in the study. Given that they did not test different brands of grapefruit juice, or fresh grapefruit juice (or just eating the fruit) - we don’t have a good idea on exactly how much variability there might be in these different methods of consuming grapefruit juice, and the different levels of CYP3A inhibition provided by each method. Given this, we really don’t know how much of a multiplier effect you get with GFJ. It might be 350%, but it might also be some other variable.

From news on the study:

“The variation in potency of the grapefruit juice itself may be far greater than the variation in the enzymes that break down sirolimus,” Cohen said. An early version of the study used canned grapefruit juice, generously donated by a Chicago-based grocery chain. But tests of the product found it lacked the active ingredients. So the researchers shifted to a frozen concentrate product supplied by the Florida Department of Citrus.

From the research paper:

Interestingly, different grapefruit juice formulations appear to vary in inhibitory potency and therefore, in consultation with the Florida Department of Citrus, we employed a frozen concentrate product that was tested for furanocoumarin levels prior to delivery of each batch. This ensured consistency across cohorts and is something that must be kept in mind for future studies or applications.

Although the magnitude of the interaction is highly variable, it is reproducible within individuals and seems to be dependent on small bowel CYP3A4 content, i.e. persons with the highest intestinal CYP3A4 content have the largest reduction in enzyme levels and subsequently the greatest effect on drug metabolism

ketoconazole to Improve Bioavailability of Rapamycin

Another, perhaps better and much more predictable option is taking the rapamycin / sirolimus with another drug called ketoconazole that has the same effect as grapefruit juice, without the variability.

For the sirolimus plus ketoconazole study, sirolimus was administered in week 1 and ketoconazole was added to all subsequent doses at a fixed dose of 200 mg from week 2 on day 1, followed by 200 mg daily on the next three subsequent days. (Important Note - this was an application in cancer patients, so they were taking extremely high doses of rapamycin daily. This is not the case in an anti-aging application where a low dose (5mg to 10mg) rapamycin is typically taken only once per week). So - in an anti-aging application it sounds like the Ketoconazole would only be taken on the day a person would be taking the rapamycin.

In the study they say:

“Since we were trying to inhibit CYP3A, we used the standard dosage approved for fungal infections and prophylaxis, 200mg”

Our studies demonstrate that weekly oral sirolimus can achieve drug exposure (AUC) similar to that observed with its parenteral prodrug, temsirolimus, and the recommended phase 2 doses from this study are 90 mg, 16 mg, and 35 mg when administered alone, with ketoconazole, and with grapefruit juice, respectively. Notably, the target AUC was attainable at significantly lower sirolimus doses when combined with CYP3A inhibitors, either ketoconazole or grapefruit juice. In fact, when siroliums was combined with grapefruit juice, target AUC was observed at 15, 25, and 35 mg. Toxicity observed with weekly sirolimus was typical of other mTOR inhibitors with glucose, lipid, and hemotologic alterations being most common. In general, weekly sirolimus was well tolerated with relatively few serious adverse events or dose-limiting toxicities as defined in these studies.

So - in this study they found that when taking 16 mg rapamycin with 200mg of ketoconazole, it was equivalent to taking 90mg of rapamycin. So this means that the ketoconazole provides a 5.6 X multiplier effect on the rapamycin.

This translates to an anti-aging application in this way. If the typical dose of rapamycin in anti-aging applications is from 5mg to 10mg per week, if you took ketoconazole at the same time as the rapamycin you would only need to take 1mg of rapamycin, or 2mg of rapamycin per week. So - the typical years supply of sirolimus now would last you 5 years (so, only $100 per year).

The downside of this approach is that ketoconazole may impact other drugs you might be taking - so you have to do your research, discuss with your doctor, and it might not work for many people.

The other downside of this drug is that it can be very damaging to the liver:

Ketoconazole may cause liver damage, sometimes serious enough to require liver transplantation or to cause death. Liver damage may occur in people who do not already have liver disease or any other conditions that increase the risk that they will develop liver damage. Tell your doctor if you drink or have ever drunk large amounts of alcohol and if you have or have ever had liver disease. Do not drink any alcoholic beverages during your treatment with ketoconazole because drinking alcoholic beverages may increase the risk that you will develop liver damage
Source: MedlinePlus Ketoconazole

The benefit is that ketoconazole is a very inexpensive medication, easily available from India at low cost. And Janssen Pharma is one of the producers, so you have a reasonably trustworthy source.

Janssen Pharmaceuticals Nizoral Tablet Ketoconazole 200 MG - Example on Indiamart Vendor

Nizoral

More information on Ketoconazole:

See for more info:

The full Rapamycin / Sirolimus package insert with details on dosing, etc:

021083s059,021110s076lbl.pdf (483.3 KB)

Grapefruit juice as a means to save money, and reduce side effects of Rapamycin:

https://www.uchicagomedicine.org/forefront/news/grapefruit-juice-lets-patients-take-lower-dose-of-cancer-drug

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a lot of people are ordering from India might be getting fillers or slightly tainted but full-potency pills, and reducing the number of pills via grapefruit juice helps with that problem

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I only have ketaconazole shampoo at the moment. Before I do anything drastic, I should get hold of the pill form :stuck_out_tongue:

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Itraconazole is an alternative to ketoconazole;

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Yes - it seems to have about a 3 fold increase effect:

The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. Itraconazole exposure increases to 370%, when combined with sirolimus (370%).This can lead to higher incidence rate of side effects. Sirolimus exposure increases to 306%,when combined with itraconazole (306%).

https://epha.health/clinic/advice/en/for-drug-itraconazol-sirolimus/

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It seems that resveratrol also inhibits CYP3A4 enzyme activity–but I don’t know by how much.

I’d love to find a way to stretch my rapamycin further, but am hesitant about grapefruit. I like to fast on my rapamycin days, and a bolus of fructose in the form of grapefruit juice at the same time as rapamycin seems like a recipe for an extra large glucose spike. Anyone experimenting with the grapefruit multiplier? Or pulsed resveratrol on same day as rapamycin?

“Different studies suggest that RE alters or inhibits CYP3A4 enzyme activity.”

I’m not sure about resveratrol either, but found this:

Medicines that are potent CYP3A4 inhibitors include (but are not limited to) clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, and verapamil9.

and this:

Herb and Food Interactions

Popular dietary supplements and foods that have a high risk for interaction with medicines metabolised by CYP3A4 include (but are not limited to) the following.

Goldenseal

Goldenseal (Hydrastis Canadensis) is often taken to try to prevent common colds and upper respiratory tract infections. It has been reported to reduce CYP3A mediated activity by 88%, equivalent to that seen with clarithromycin12.

Black pepper

Black pepper (Piper nigrum) has been used as a flavouring agent and medicine. When used for flavouring food it is not likely to affect the metabolism of most medicines12. However, excessive use or use in dietary supplements (piperine or piperamides greater than 10 mg) may produce clinically significant interactions, including CYP3A4 inhibition12.

Schisandra

Preparations of fruits from woody vines of Schisandra species are used in traditional Chinese, Japanese and Russian medicine, often as hepatoprotective agents12. Currently available clinical data strongly suggest that Schisandra extracts pose a significant risk for elevating blood levels of medicines that are CYP3A substrates12.

St John’s Wort

This is used for its antidepressant activity. The active substance is hyperforin, the most potent known activator of PXR12. Clinical studies have demonstrated that products containing less than 1% hyperforin are less likely to produce interactions12. However, most products contain 3% hyperforin12.

Grapefruit

Grapefruit (all sources) is a potent inhibitor of intestinal CYP3A4 that has been proposed to interact with more than 44 medicines and result in serious adverse effects13.

Healthcare professionals should ask patients about their use of complementary and alternative medicines when considering the use of a medicine that is altered by CYP3A4.

Source:
https://www.medsafe.govt.nz/profs/puarticles/march2014drugmetabolismcytochromep4503a4.htm

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And apparently some compounds, like curcumin, have the opposite effect.

“In conclusion, oral intake of curcumin significantly decreased the bioavailability of [everolimus]…mainly through marked activation on CYP 3A4.”

https://www.nature.com/articles/srep06587

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Repeated administration of berberine (300 mg, t.i.d., p.o.) decreased CYP2D6, 2C9, and CYP3A4 activities

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Thanks! I’ve been taking metformin on the day I take rapamycin (and just on that day), but maybe I should switch up to berberine instead.

The idea of resveratrol with rapamycin got me into some articles that I don’t fully understand. There seems to be a synergistic effect beyond anything to do with CYP3A4, but I can’t tell whether it’s “good” for healthy people. It seems that adding resveratrol to rapamycin pushes (tumor) cells from autophagy to apoptosis. While I understand the difference between autophagy and apoptosis, I don’t understand the functional difference in terms of longevity for a non-cancer patient.

I read that berberine’s bioavailability is poor.
so liposomal berberine or dihydroberberine are better option.

Interesting report here where they look at the trough levels: Sirolimus-itraconazole interaction in a hematopoietic stem cell transplant recipient - PubMed

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Also that’s an interesting link you posted. If rapamycin’s bioavailability is indeed 14%, then the max improvement in bioavailability one can get using any interactions is 7x.

Any idea about if piperine helps?
What’s your latest “improve bioavailabiliity” regimen? (same as in the initial post?)
Preferences between GFJ and ketoconazole?

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These multiples (3.5x, 5.6x, 7x, etc.) always make me wonder about duration and half-lives. Presumably, grapefruit juice clears out of your system within a few hours. Do you keep drinking more all day?

Similarly, google tells me ketoconazole half life is two hours, though antifungals can do odd things to the liver, so I’d tend towards GFJ if given only those two choices.

Yes… None of the studies translate really well to pulsed dosing, anti aging applications.

The studies were done in daily dosing applications for cancer and transplant patients.

So there is still a lot we don’t know.

I only take rapamycin with a high fat meal right now. But i like the known and consistent results of ketocanazole when combined with rapamycin. GFJ is easy to get and use, but we really can’t be too confident on the bioavailability increase, given the variability reported in the studies with different types of grapefruit juice…

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I’m thinking that these could be useful in combination for the last dose before a rapa break, or when the dosing interval is pretty long.

So it shouldn’t really matter much if there’s too much bioavailability or if the half life is also increased.

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Looks like metformin also inhibits CYP3A4. I’ve been taking it (only) on my rapamycin day since it’s my rest day and in case rapamycin spikes glucose, but it seems it may also be increasing the effective dosage.

All these interactions are both helpful and concerning. I’m still on 6mg per week, but this is adding support in favor of switching to a higher dose every two weeks.

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CYP3A4 is an enzyme that increases elimination of rapamycin and many other drugs from the body. By inhibiting it, one could potential increase the rapa AUC during the dosing regimen, and perhaps one would not reach the intended trough.

from this article:

Physicians should avoid a concomitant use of rapamycin with potent inducers or inhibitors of CYP3A4 that may decrease or increase blood levels.

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This same caution applies to berberine, which some use instead of metformin.

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