Rapamune's bioavailability increasing technology

I just read that Rapamune contains 3,17% alcohol. Alcohol is known for its inhibition of CYP3A4.
Other tablets like Zydus doesn’t contain alcohol - at least as far as I know - or contain less alcohol then Rapamune (Rapacan: 2,5%).

So my guess is that Rapamune’s patented bioavailability increase by 33% is because they just used more alcohol.

Alcohol is often used as a preservative agent but it seems like that other rapamycin preparations doesn’t contain it or containing just less then Rapamune.

I’m just feeling a wee bit stupid asking myself if THAT is Pfizers “special technology”… but could it be? Any hints?


I think you’re talking about the liquid formulation… from the FDA Filing (see below).

Rapamune tablets use a special nanocrystal technology licensed from Elan, a biopharm technology company: Rapamycin and NanoCrystal Formulations

Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.

Rapamune® is available for administration as an oral solution containing 1 mg/mL sirolimus. Rapamune is also available as a white, triangular-shaped tablet containing 1-mg sirolimus, and as a yellow to beige triangular-shaped tablet containing 2-mg sirolimus.

The inactive ingredients in Rapamune® Oral Solution are Phosal 50 PG® (phosphatidylcholine,* propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Rapamune Oral Solution contains 1.5% - 2.5% ethanol.*

The inactive ingredients in Rapamune® Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl-alpha tocopherol, and other ingredients. The 2 mg dosage strength also contains iron oxide yellow 10 and iron oxide brown 70.



I was looking for other CYP inhibitors that might increase the bioavailability of rapamycin other than Ketoconazole (Ketoconazole is known as a potent inhibitor of CYP3A4) and grapefruit juice. My understanding is that suppressing drug-metabolizing enzymes will increase the bioavailability of rapamycin. CYP3A4 is the main enzyme involved and to a lesser extent P450.

Since my rapamycin sources are relatively cheap I really don’t need any enhancers. But for those who have difficulty or are not able to obtain it cheaply. Here are some possible bioavailability enhancers. Or maybe you were taking enhancers and didn’t know you were.

  1. Quercetin is a flavonoid found in various fruits and vegetables, such as apples, onions, and berries. It can inhibit several drug-metabolizing enzymes, including cytochrome P450 3A4 and P-glycoprotein. Consequently, it has the potential to affect the metabolism and absorption of certain drugs.

  2. Fluoxetine(Prozac) If you don’t have any Prozac you surely must have a friend that could maybe give you one capsule a week. The odds of you not knowing someone on Prozac are small. Just ask around. NOT MEDICAL ADVICE

  3. Coffee. Maybe the effect is small, but who knew?
    (Coffee is the main source of caffeic acid in the diet)
    See: Evaluation of Inhibitory Effects of Caffeic acid and Quercetin on Human Liver Cytochrome P450 Activitiesherb–drug interaction potential of caffeic acid and quercetin mediated by cytochrome P450 (CYP) inhibition

  4. Echinacea purpurea

  5. Schisandra fruit extract. “An extract of Schisandra fruit has been shown with a potent inhibitory effect on human liver microsomal erythromycin N-demethylation activity mediated by cytochrome P450 3A4 (CYP3A4). The present study was conducted to identify Schisandra fruit components having inhibitory effects on CYP3A4”

Feel free to comment or criticize, you won’t hurt my feelings. I am not well-grounded in biology so I may be interpreting the findings incorrectly. If anyone has any thoughts on CYP P40 inhibition and rapamycin bioavailability please share.




thanks, interessting idea. Quercitin and maybe coffein may be a good try if Rapa is metabolised on other pathways then CYP3A4. I’ll have a look.

But some thoughts and concerns:
GFJ is a irreversible inhibitor, that means it just “kills” the CYP enzyme so it has to be build up again by the liver.
I don’t think that more substances that inhibit CYP3A4 will be more effective because if its not there, it won’t have any further effect.

We know that Ketoconazole is more effective then GFJ. It is possible that 350ML GFJ doesn’t irreversible inhibit all of the CYP3A4 enzyme (so I try just to eat more grapefruits). But it is also worth thinking that Ketoconazole has got another effect I don’t know.
I also don’t know if they tested ketoconazole in people with active CYP3A5. 3A5 is most common in asians, but some europeans have also an activated 3A5 so it just doubles the metabolisation.
And taking more substances always mean that you propably get serious drug interactions you don’t want.

But taking Rapa with more GFJ then 350ml equivalent just means that I have to do a blood test to get the answer if its working. And the least I want to have is more Rapa then I need.

But a combination of some substances may still be possible. One have to keep an eye on:

a) some effects dont last very long and others will only work if you consume something for 10 days in higher doses.

b) most of the substances that inhibit CYP3A4 (or other enzymes) also induce them and vice versa
They class inhibitors only as inhibitors if the effect is more inhibiting then inducing.
The question here is: in which timeframe you get the effect you want. Some substances inducing CYP3A4 at first and then they inhibit it. Its just one GFJ-box short of a sixpack. :wink:

c) its highly individual and we just don’t know if our CYP3A5 is active or not. Maybe we have to test ourselfs.

If someone tries to combine substances, one should also keep an eye on what causes the effect of the inhibition. For example:
Grapefruitjuice is effective because of the special furanocumarin-combination. I wrote about it some time ago.
Long story short: You need a specific mixture of furanocumarins to get the effect. If you chance the mixture, it will be propably lesser effective.
st. johns wort’s (Hypericum perforatum) effect is also caused by one specific furanocumarin. If you mix st. john with GF, you will maybe change the balance of the furanocumarines in GF.
I cant remember which furanocumarins are in GFJ. If Hyperforin is in it, I wouldn’t combine them.

Btw: Just don’t eat some inducers like garlic and leek (i eat a lot of them) doesn’t mean that I have a higher CYP3A4 activity. I actually get rid of it if I drink GFJ. So it I think it doesn’t matter.

And the last thing is:
taking more substances always mean you get a higher risk of serious drug interactions. So I would try not take any extracts just to be safe.

Its frustrating. I’ve been reading for a while about the biology behind it. In some cases biologists and pharmacists only have a guess about the bioplausibility. It means nothing. But nevertheless the list of CYP3A4 affecting substances is long and still incomplete as the list of substances that increases the bioavailability of Rapa.

And BTW, I am also not a biologist. I doesn’t even know about the different pathways my body matabolises Rapa.


"Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, as in the treatment of HIV (e.g., lopinavir/ritonavir) and more recently COVID-19 (Paxlovid or nirmatrelvir/ritonavir). Despite its clinical importance, the exact mechanism of ritonavir-mediated CYP3A4 inactivation is still not fully understood. Nonetheless, ritonavir is clearly a potent mechanism-based inactivator, which irreversibly blocks CYP3A4. "

“Sirolimus and everolimus half‐lives increased from 96 to 249 h, and 42 to 118 h, respectively. There were no major safety or tolerability issues in this study. The ritonavir‐containing 3D regimen resulted in a significant increase in sirolimus or everolimus exposure, consistent with the known strong inhibitory effect of ritonavir on CYP3A requiring dose and/or frequency modification when co‐administered with each other.”

Ritonavir has been in clinical use quite some time so it is a wellknown substance with well known effects…




Talha B, Dhamoon AS.

Continuing Education Activity

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I was using ruby red grapefruit juice to great effect. The problem was that it is not known how effective different batches were because they are not always sourced from the same area.
The rapamycin would sometimes give me diarrhea at the same dose when using grapefruit juice. This told me that I wasn’t getting the same effective dose every time. So, I switched to taking rapamycin with olive oil and the effects are more consistent. If getting rapamycin was problematic, I would still use grapefruit juice to stretch my supply.

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Do you take olive oil together with rapamycin or before the rapamycin?


I eat wild caught sardines in olive oil with rapamycin. And GF juice.

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I use a small paper cup and drop my rapamycin tablets into about 25 mL of olive oil and drink it like a shot of tequila followed by a large cup of coffee. Nothing wrong with taking rapamycin with a fatty meal like sardines. I am just not fond of sardines.


I love it… “Longevity Shots”. Soon to be at a bar near you …

I think my procedure is a little bit funny, so…
I eat 2 grapefruits and then go into the kitchen and prepare a meal with >30ml of olive oil (and other stuff).
at least half an hour later I take Rapa & eat my dish while laying on my right side on my sofa (at least for 5 minutes).

Every time I do this, I think about 2 things:

  1. how could the romans eat like that?
  2. I am deeply grateful that laying on the right side increases bioavailability. It could also have been a handstand.

I think I will have a coffee before and after the meal. Or having a tiramisu with olive oil and without sugar. But I think I will just drink a cup of coffee.

insofar … my rapamycin-ritual is becoming a bit religious I think


“Or having a tiramisu with olive oil and without sugar”
No, no! How can you have tiramisu without sugar? :sweat_smile: :sweat_smile:
A little sugar now and then won’t hurt you.

What about pomegranate juice?

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