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:
- 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.
- 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.
- In the same study that evaluated 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.”
- 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
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
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
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: