SNK
#167
I’m assuming you’d want to get to zero to allow for Mtorc2 activation? But I thought that at relatively low levels (maybe not even that low) of RAPA in blood Mtorc2 seemed to activate just fine? Any other reason you want to get to zero?
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Just trying to balance the risk vs reward. I don’t want rapa to accumulate, and I don’t have to give up much (if any) upside to be certain.
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Curious
#169
There is quite alot of research on CYP3A4 and but I can’t say that I have seen any good review.
It is difficult to draw conclusions but hopefully members of this forum can contribute with more knowledge.
Since I try to inhibit CD38 with Apigenin, the effect that apigenin might have on CYP3A4 makes me wonderiwhat effect it has on rapamycin metabolism in vivo.
Curious
#170
there are quite a few substances that can inhibit CYP3A4. Milk thistle, bergamottin, And some say quercetin and curcumin can inhibit and other papers point at Curcumin as an activator of CYP3A4. Thymoquinone the bioactive substance in black seed (Nigella sativa) plant is an inhibitor. And apigenin and chrysin is mentioned as inhibitors. Irreversible inhibitors, meaning that they inhibit CYP3A4 even after they are cleared from the human body. With a reversible inhibitor, the inhibition stops/can be stopped when the inhibitor is cleared from the system.
Irreversible interactions are important since irreversible inhibition cannot be overcome by discontinuation of the inhibitor and the enzyme is inactivated and time is needed for a new enzyme to be re-expressed. As the half-life of cytochromes P450 is between 24 and 72 h, regeneration of enzyme activity can take up to two weeks, preventing successful therapy. This is especially of importance in cases where the medicinal drug is exclusively metabolized by the inhibited enzyme .
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stealle
#171
I think this makes total sense. But, I think there is a big difference between a fatty meal and a tablespoon of olive oil. If you take a drug with a meal (especially a large meal) it’s going to dissolve and get mixed around in the meal and most likely get absorbed/digested over the 1-2 hours it takes for your stomach to empty. Whereas taking it with a very small fatty meal such as a can of sardines, as I’ve heard @RapAdmin doing, or even better yet an empty stomach with the exception of a tablespoon of olive oil I think would be ideal. There would be so very little in the stomach to compete for rapid absorption. Just my thoughts
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Just searching around to see if I can find evidence of what you are suggesting…
I came across this:
Notes for Professionals: Food may affect the exposure to sirolimus. As compared with the fasted state, administration of sirolimus oral solution with a high-fat meal decreased the peak blood concentration of sirolimus by 34% , increased the Tmax 3.5-fold, and increased the AUC by 35%.
Source: Drug Monitoring of Sirolimus and Everolimus, Victor Armstrong, Frank Streit
https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1439-0477.2003.03040.x
But nobody seems to have done any studies on dosing with minimal amounts of fat or olive oil, that I can find.
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stealle
#173
That’s interesting. It says “meal”. So, I can’t help but think that is quite a bit different than a tablespoon of olive oil. Leaves me wondering what to do. I guess I could test a peak with and without a tablespoon of olive oil to see the difference. I already plan on testing a peak with and without grapefruit juice. Geeze! It’s only time and money I guess.
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stealle
#174
I don’t think that will make a difference. You have blood flow to every living part of your body. Any part of your body that requires blood flow it getting blood flow. Without blood flow body tissues become ischemic and die. And, blood circulates quickly throughout the body. As long as there is blood flow rapamycin is getting there. There is the blood brain barrier but rapamycin crosses it and NO does not effect the way drugs cross the BBB as far as I know.
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stealle
#175
Well, this isn’t a study but I just stumbled across this n-1 from @hitch in another thread. Very interesting. Seems like he didn’t peak as well with 2 tablespoons of olive oil. Either that or as he mentioned perhaps it delayed the peak. I wonder if each test was exactly two hours.
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hitch
#176
They say:
“Sirolimus was absorbed more slowly when administered after a high-fat meal than when administered after fasting, as shown by statistically significant reductions in peak concentration (Cmax) and the ratio of Cmax to the area under the curve (AUC)”
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This is useful. Thanks. From the same paper. So much for the formulaic approach to calculating rapa dosing with fat (and probably GFJ):
“ the geometric mean ratio of the fed/fasting AUC values was 1.35, with a 90% confidence interval of 1.26 to 1.46.”
A 90% confidence for somewhere between 26% and 46% better bioavailability with fatty meal.
On this site we’ve seen widely varying effects of GFJ: 0-8X.
Get tested is the way to go.
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There are two big problems with this assumption. Firstly, you can’t catch the peaks exactly so we can’t read much into comparison of two measurements around the time the peak is expected. The other problem is that fat will influence the digestion of the rapamycin and probably delay and slow down the absorption. So we cannot conclude anything from these two measurements. To everyone: Please measure at least 24 hours after dosing, preferably 48 hours and then you can do comparisons between different doses/administrations.
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Vlasko
#179
Fat, fiber, and meals aside, even posture after taking pills can delay dissolution and absorption. Given how long the half-life is, I really don’t see the logic in trying to catch an exact peak. Gastric emptying can also be variable with each administration even if conditions are duplicated.
Below is info on non-enteric coated pills. But the same issue will likely arise with whole pills passing through.
The info below might be helpful for people taking a pain reliever and wanting it to kick in as fast as possible:
“Most pills do not start working until the stomach ejects their contents into the intestine. So the closer a pill lands to the lower part of the stomach, the antrum, the faster it starts to dissolve and empty its contents through the pylorus into the duodenum, the first part of the small intestine. If you’re aiming a pill for this part of the stomach, posture is critical to both gravity and the natural asymmetry of the stomach.”
“The team tested four postures. Taking pills while lying on the right side was by far the best, sending pills into the deepest part of the stomach to achieve a dissolution rate 2.3 times faster than even an upright posture. Lying on the left side was the worst. The team was very surprised to find that if a pill takes 10 minutes to dissolve on the right side, it could take 23 minutes to dissolve in an upright posture and over 100 minutes when laying on the left side.”
The best way to take a pill, according to science | Hub.
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SNK
#180
Very interesting (if true) and very weird also. I don’t know about the absorption part but I have realized that I always default sleeping on my right. Perhaps it my bodies way of emptying the stomach ASAP so I can get a restful sleep.
The vagus nerves on the right and left perform different functions such that lying on the right is more calming.
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I spend ~80% of my time sleeping on my right side. It just seems more comfortable for me, yet every article on the best sleeping position suggests the left side is healthiest.
“Which is the healthiest side to sleep on?
And sleeping on the left side is best because it keeps pressure off internal organs and promotes healthy blood flow.Mar 17, 2023”
Mayo Clinic Minute: What is the best sleeping position? - Mayo Clinic News Network.
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SNK
#183
Are you kidding me (these studies). I literally feel I’m short of breath when sleeping on the left. I could be an aberration.
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man_li
#184
Eat grapefruit or drink grapefruit juice is not convenient, I just found a company named ‘True Citrus’, they have some products which are crystallized lemon/lime/grapefruit powder.
So I wonder this crystallized grapefruit powder would works or not works? Have anyone tried? Can someone give some advice? Thanks!
You can google ‘True Citrus’ and easily find the product (Amazon available too).
https://www.walmart.com/ip/100-Pack-True-Grapefruit-Sugar-Caffeine-Free-Powdered-Drink-Mix/524174901
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Interesting idea… but I have no idea if it will work or not, and haven’t seen anyone trying something like this yet. It would be great if you could try it and do a blood sirolimus level test afterwards to get a rough idea of if it works or not… How to get a Rapamycin (sirolimus) Blood Level Test
People have tried some similar things - like using the naringen supplement which may also work: Naringin instead of Grapefruit Juice
I recommend you read the entire Grapefruit and Rapamycin thread too - lots of good info and experiences: Rapamycin and Grapefruit Juice
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man_li
#186
I have just started taking rapamycin yesterday. My dose is 1 mg/week now. I will increase 1 mg per week, and my target is 6mg/week. I am not live in US or Europe, there is no agency to do a blood sirolimus level test.
I also found a product named “Senolytic Activator” from LifeExtension company. It said to be taken once a week. So I think it’s proper to combine with rapamycin. And ‘Senolytic Activator’ ingredients like quercetin & apigenin which both can inhabit CYP3A4, this should lift the bio-availability of rapamycin.
https://www.lifeextension.com/vitamins-supplements/item02301/senolytic-activator
I want to take rapamycin together with ‘Life Extension’ Senolytic Activator & ‘True Citrus’ grapefruit powder, both once a week)
Does anyone think it’s a good idea? Thanks!
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