Fatty food or oil to increase the effective dose of rapamycin?

#1

@alexchamp and I had a discussion regarding oils and a great question Alex ask was like “What is it in fatty food or oil more specific that increases the effective dose of rapamycin? Is it for example the omega 3 content or something else?”

This is a very interesting question! Because if we understand better what specific things are triggering improved absorption than probably this can also increase the absorption of other supplements, drugs and even nutrition in our food which we eat.

I know some rapamycin users take wild sardines to increase the absorption of rapamycin. Taking rapa with fatty food can increase the dose by 35% according to this study. The effect of a high-fat meal on the oral bioavailability of the immunosuppressant sirolimus (rapamycin) - PubMed

Do someone know if there are fats or oils that are better than other in increasing the absorption?

OBS! People like Alan Green and Mikhail Blagosklonny don’t recommend using fats or grapejuice for increasing the dose. One reason for this is that it’s hard to know what dose you get every time you take rapa. But my point with this discussion thread is more to understand the underlying mechanism behind why the absorption is increased by fatty food or oils. All feedback is welcome!

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#2

Interesting question… I think we need to dive deeper into the research papers to understand that. Here is the full paper that you linked to in the previous post above:

It has been shown that a high-fat meal in stable renal transplant patients increased the oral-dose AUC of cyclosporine from Sandimmune® by 26%.17 A comparison of the affect of a high-fat meal on cyclosporine dosage forms in renal transplant recipients revealed that the cyclosporine oral-dose AUC was further increased by 22% after switching from Sandimmune® to Neoral®.18 It has been suggested that the increased absorption of cyclosporine may be partially due to an effect of dietary fat on intestinal metabolism.19 By contrast, a moderate-fat meal in liver transplant patients decreased the oral bioavailability of tacrolimus by 27%. The purpose of the pharmacokinetic study described in this paper was to assess whether administration of sirolimus with a high-fat meal would alter its oral bioavailability.

After an overnight fast, each subject either ate a high-fat breakfast over a 20-minute period or continued to fast, as determined by a randomization schedule. The breakfast consisted of two eggs fried in butter, two pieces of bacon, two pieces of toast with butter, 4 ounces of hashed brown potatoes cooked in butter, and 8 ounces of whole milk.

RapamycinHighFat
RapamycinHighFat794×1326 59.7 KB

Discussion:

Sirolimus is similar to tacrolimus in chemical structure, and these two compounds also resemble each other with respect to some pharmaceutical and pharmacokinetic characteristics. The similarities include high lipophilicity, very low solubility in aqueous media, and high B/P ratio.

This study showed that administration of sirolimus following a high-fat meal slows the rate of absorption and modestly increases the extent of systemic bioavailability from a nonaqueous oral formulation. In the case of tacrolimus, a 71% mean decrease in Cmax and a 39% mean decrease in AUC0-t was observed when the marketed capsule formulation was administered immediately following a high-fat meal relative to when it was administered in the fasting state.

A variety of mechanisms have been invoked to explain an increase in the extent of oral availability
when a compound is administered with food. Food-induced delays in gastric emptying and a slower input rate into the proximal intestine may prevent saturation of absorption mechanisms, particularly if there appears to be a local absorption window. Both dietary fats and food-stimulated secretions such as bile salts may facilitate solubilization and dispersion, particularly of lipophilic compounds. Increases in sphlanchnic blood flow and competition by food components for metabolic enzymes may reduce the extent of first-pass metabolism.

In the case of sirolimus, food did not alter elimination, as shown by the absence of an effect on the terminal disposition half-life (Table I) and the strikingly similar postabsorption profiles in the presence and absence of food (Figure 1, panel A). The 35% increase in systemic availability of sirolimus was probably due to some combination of facilitated absorption and inhibition of CYP3A4 and P-gp in the intestine.

The Effect of a High-Fat Meal on the Oral Bioavailability of the Immunosuppressant Sirolimus (Rapamycin)

http://sci-hub.wf/10.1177/009127009903901107

Related Papers referenced in the above paper:

Welling, Peter G. (1996). Effects of Food on Drug Absorption.
http://sci-hub.wf/10.1146/annurev.nu.16.070196.002123

The effects of food on drug bioavailability

Interactions affecting drug absorption

http://sci-hub.wf/10.2165/00003088-198409050-00002

The influence of food on the absorption and metabolism of drugs: an update

http://sci-hub.wf/10.1007/bf03189714

Effects of dietary fat on drug absorption

http://sci-hub.wf/10.1016/0009-9236(95)90167-1

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#3

I’m not the smartest guy in the group, but my simple logic says that sirolimus is not soluble in water, but it is soluble to varying degrees in different types of oils such as oleic acid which would make it more available for the body to absorb. This article may be of some help: Optimized formulation of solid self-microemulsifying sirolimus delivery systems - PMC

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#4

Bile acid secretion necessary for the absorption of fats and fat soluble substances

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#5

So, people without a gallbladder may not get this advantage? Just a thought. I believe oils of medium chain length - like coconut oil, do not require bile and better for people s/p cholecystectomy?

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#6

@Jay I found out quickly, I was not the smartest guy in the group and exactly why I love this forum!

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#7

That just does not make sense to me.

Today I’m going from 6mg/weekly on an empty stomach, to the same but with 3.75 ounces of sardines in olive oil in an attempt to ^ blood levels.

Now, answer this: I do the above for 4 weeks. Then, on the 5th, I get a blood level 2.5 hours after ingestion, then let’s say, at 3pm the next day (day 2), and another at 3pm on day 5.

We know that rapa dives on day one, it’s bimodal (I think). I have max blood level and I can estimate my excretion half-life such that I’m sure that by day, what, 5,6 or 7, it’s subclinical, as it should be.

Then for the next 10 weeks I do the same as above.

Why would I not, with that data,now know the dose?

And w/ GFJ. If I bought, for instance 5 bottles of GFJ, drank, let’s say 5 ounces w/ the Sirolimus and take 2mg, I might get the same result as 8-12mg. Then, if I do the blood testing it seems that I would “know” what dose I was getting.

Heck, take a bottle, divide it into 5, 6oz units, put it into a container and freeze. Then, you have the same batch of GFJ and 5 bottles would give you a fairly reliable “knowable” dose response for the next 30 weekly doses. Buy 10 bottles, now you have defined your GFJ for over a year.

Occasionally pull a 2.5 hour dose to check. The elimination half-life should remain stable, it seems.

Am I missing something?

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#8

Ouch… that graph pretty much says, in a way, “no difference,” though there is. On an empty stomach it spikes. W/ the meal it flattens the curve, but increases the dose over time. I wonder which is best?

The bile concept seem fairly immaterial as, in the graph, the initial spike is higher w/out any fat.

Jay, I think (correct me if I’m wrong) that the article looks at a liquid vehicle for dosing. We use tablets which have an acid-resistant covering to protect the rapamycin in the stomach.

lol…the more I learn the more confused I get.

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#9

Yes - they used a liquid version of rapamycin. If you can find a similar graph using rapamycin tablets please post.

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#10

The only reason to use GFJ is to save money on the drug, so Dr Green is basically saying it’s not worth the risk. You could side step the risk with your testing protocol, but most people won’t put in the effort or spend the money. I know I haven’t, although I know I should. But nice idea about freezing a batch for less frequent testing!

However it’s much easier to standardize the amount of oil in meal, and the impact of oil is much less significant that GFJ, so I don’t see the objection there. I also don’t recall Dr Green or Blagosklonny calling out oil/fat specifically.

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#11

I find it interesting that although you should take the test. You haven’t… but part of it might be just the hassle of getting the Labcorp order.

Because my physician has already prescribed me rapamycin. When I go in every four months for a full panel blood test, it’s nothing to do one blood test for trough and the other for post dose 2 and a half hours.

I probably have more information then most on what my dose plus grapefruit juice gets up at and very confident, and how much rapamycin is in my body.

I’m using grapefruit juice to hold back extra pills. I’ve already got a 4 year supply. My fear is at some point. This is gonna take off, and it might be very difficult even with prescriptions to get your medication filled. Maybe I’m paranoid, but this is too big a thing not to be.

I feel the improvements I gained lack of inflammation… lack of Arthritis. No calcium/plaque in my blood…euphoria. Memory improvement… skin quality…no sarcopinia, too many great things not to want to stay on rapamycin for the rest of my life.

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#12

That, I have never seen, but hoping someone might have created one.

Yet, though I cannot, at the moment say where, there was a study done, looking at a “fatty” meal which in reality was a normal SAD breakfast, and if I remember correctly, there was really not much difference between the fasting and the meal with toast/butter + bacon + egg.

I paid $2/mg Zydex. With a script today at Goodrx it’s about $1/mg. 2mg at $4 beats $24- so, yes that was what I was hoping.

#13

Friday was the 1st day I took six milligrams. Friday was also the day I found that I have advanced prostate cancer which sort of puts testing on the back burner. Straight 6mg dose is so standard the only reason I’d actually do a trio of tests is to create a baseline to move to higher doses. I’ve only glanced at the testing regime and there is a lab that is near me that would work (an hour drive).

We think alike, for the concept of taking it off of easy importation is a possibility. Although with the recent drop at local pharmacies, and the total lack of any “pointable,” OMG the fellow too Sirolimus and his liver detonated," is a +. I don’t think, in the absence of notable injuries among the thousands who are taking it, that they’ll bother.

Would you mind sharing what your 1mg dosing equivalent is at? Agetron, any thoughts suggestions what what you would do if you were just diagnosed with prostate cancer? Increase, stay the same? My Ca has not been staged, or even MRI’d but with a PSA of 54 it’s automatically high risk for metastasis.

I like your photo of your biceps and admire you. I’ve increased my biceps circumference by 7/8" over 4 months, I’m good with that at age 74, now, hopefully to increase it another 2".

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#14

You wrote: Agetron, any thoughts suggestions what what you would do if you were just diagnosed with prostate cancer? Increase, stay the same?

Hey Justin… shitty news… excellent attitude. FYI - evidence based medicine, optimism, positive attitude turns on the immune system.

Dosing rapamycin is kind of the dilemma from my perspective. I found that when I increase rapamycin… my physilogical system ages both in inflammation and methylation. So from a, lifespan and health span perspective, Higher doses doesn’t seem to work for me, but and that’s a big but. Mikhail Blagosklonny who had cancer and was advocating higher doses. As high a dose of rapamycin as you can take without side effects. Blagosklonny was able to keep his cancer at bay for a decade or more.

So from that perspective, with cancer more might be better. But I just don’t know. I wonder if anyone else with more of a medical background would please chime in.

As to your comment on my biceps. In general, a great ovvrrall physique. Thanks. It is amazing to wake up every morning… look in the mirror before hoping in the shower and realize. I don’t look any older than 50 with strength and no pain.

Justin sounds like you’re rocking it too. The best prevention for illness and disease is health. So certainly stay on that path and shoot me a private message of those biceps.

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