#81

Wait, you took 2 GFJ doses, but one 24 hrs AFTER your 1st GFJ/Rapa dose?

The idea is to blunt CYPA34 (at your discretion level) before you take Rapamycin. I guess technically 24 hrs later, there’s still Rapamycin in your system (62 hr 1/2 life) and you could be further modulating blood level, but you missed maxxing the peak signal absorption bolus.

I take a GFJ (when doing double GFJ), one the night before, and then another 1-2 hrs before dosing in the morning after.

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#82

Ohhh! Gotcha.

So yes… took a 12 ounce glass of grapefruit 2 hours before rapa. Always take before bed around midnight… and again 8 hours later this morning.

So I will do 3 next time… morning of… night with rapa and next morning.

Thanks!

#83

Joseph, let me know what you think of it. Every time I read it I learn more and am more impressed. Honestly, very similar to when I read Blagosklonny.

#84

Rivasp12,

Skimmed it quickly and I ordered some IP-6 & Inositol today

#85

Is It known if other Citrus fruits act in a similar way? I am yet to dive into it but many others have furanocuomarins.

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#86

Yes - though I haven’t done the research on the level of CYP3A4 inhibition from each fruit - if you’re interested in this, please post what you learn… here is some info I found quickly - but we all probably need to know this list or have a list compiled here on the site.

Grapefruit is the most well-known example, but also Sevillian orange, pomelo and star fruit contain agents that inhibit cytochrome P450 3A4 (CYP3A4), which is the most important enzyme in drug metabolism.

The black mulberry juice showed the most potent inhibition of CYP3A except for grapefruit juice. The inhibition depended on the amount of a fruit juice added to the incubation mixture. The inhibitory potential of human CYP3A was in the order: grapefruit > black mulberry > wild grape > pomegranate > black raspberry.

Leitura Relacionada:

Effect of Fruit/Vegetable-Drug Interactions on CYP450, OATP and p-Glycoprotein: A Systematic Review
http://www.bioline.org.br/pdf?pr15252

Potential Risks Resulting from Fruit/Vegetable–Drug Interactions: Effects on Drug-Metabolizing Enzymes and Drug Transporters
https://ift.onlinelibrary.wiley.com/doi/full/10.1111/j.1750-3841.2011.02155.x

Fruit Interactions with Common Medicines
https://medsafe.govt.nz/profs/PUArticles/March2015FruitInteractions.htm

2 Likes
#87

See figure 3

Also looked at peels

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#88

Here is that figure three from the paper @MAC identified in the above post:

pone.0142757.g002
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Link below to image you can enlarge further:

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#89

RapAdmin, you posted Figure 2, the peels. Something didn’t look right the levels in grapefruit.

Here is pulp Figure 3.

Screen Shot 2022-04-28 at 7.23.56 PM
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Wow, there are some other citrus fruits with much higher active ingredients. And perhaps more importantly, a very large variation within Grapefruit species. Eg. Duncan vs. Marsh, approx 300% more in Duncan.

In case you want a super inhibitor, try COMBAVA

https://www.madacamp.com/Combava

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And the main active ingredient in GFJ: “furanocoumarins of the bergapten cluster, in blue”

What about these bergapten and CYPA34 inhibition?

“The present study has demonstrated a dose-dependent inhibitory effect of some flavones, flavonones, coumarin and furanocoumarin derivatives on the activity of CYP3A4. Grapefruit juice contains many flavonoids and furanocoumarin derivatives that may alter the metabolism of drugs by CYPA34. In summary, the present study has demonstrated that besides the flavonoids, other compounds found in grapefruit including furanocoumarins can produce strong inhibition of CYP3A4. The grapefruit juice-drug interactions could involve CYP3A4 inhibition by more than one component present in grapefruit juice. Bergapten was found to be a very potent inhibitor of CYP3A4. Therefore, it may be an important furanocoumarin responsible for the grapefruit juice drug interactions. Concentrations of bergapten (up to 30 mM) detected in grapefruit and commercial grapefruit juice products (44) appear sufficient to cause significant inhibition of CYP3A4 in this study. However, it should be noted that inhibition of CYP3A4 activity in vitro does not necessarily imply drug interaction in vivo”

I have NO idea what species of Grapefruit I pickup at my local grocer, there isn’t a bar code! Bottom line, there may be SIGNIFICANT in vivo variation in Rapamycin absorption depending on species, size, timing of intake, etc. This is a significant variable in trying to create a reproducible dosing regiment. Maybe a better idea is to source a brand of bottled or concentrate, and inquire with manufacturer if they use the same species for their product?

I might just drop the GFJ and go with straight Rapamycin, much greater control/reproducibility of dosing.

Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds

RapAdmin, maybe a separate GFJ thread?

5 Likes
#90

Thanks for the replies. Amazing group. Hats off.

I got a small mouthsore days after starting rapa (2mg/week) and it puzzled me because I thought the dose was small (and I was used to fasting multiple days, having just got one after a 5 days fasting - and none on longer strikes).

I thought I’d only get mouthsores after higher doses.

But then it dawned on me that I was having rapa with “gallons” of a Brazilian variety of lemon (“limão cravo/galego”; Citrus x limonia, according to wikipedia) and that It could have messed the dosage by inhibition of CYP450 enzimes.

1 Like
#91

Bingo! Concentration x volume = amount of inhibiting agent

https://sci-hub.se/https://doi.org/10.1248/bpb.31.925

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#92

Had heard that [quote=“RapAdmin, post:2, topic:1111”]
10mg with GFJ, or an effective dose of approx. 30mg to 35mg:
[/quote]

Hey MAC and others got my blood test back today with the Sirolimus check - thanks for information on LabCorp doing this.

My blood was drawn exactly 32 hours after taking 5 pills 2 mg (10mg total) with 10 oz. pasteurized grapefruit juice (GFJ) with the pills and a 10 oz. glass of pasteurized GFJ the next morning… 8 hours later.

Was not sure if the pasteurized GFJ would enhance the dose. I had heard 2 days or 48 hours hours should be the half life. Here are the results. It seems even pasteurized GFJ was effective in upping the dosage level.

Rapamycin - Sirolimus test 32 hours after ingestion
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Rapamycin Sirolimus pills 2mg each
Rapamycin Sirolimus pills 2mg each616×691 113 KB

Rapa - GFJ 1
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Rapa - GFJ
Rapa - GFJ1920×3085 484 KB

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#93

Surprising results like this are why we do blood tests. Maybe you were around 14-18 ng/mL at peak, but we know levels vary hugely by individual. Your peak range is close to mine (17mg/nL with 5mg + about 9-10oz whole grapefruit several hours before to allow time for the inhibition of tthe breakdown enzyme CYP3A4).

We’ve seen far higher peaks with no known side effects, so this seems safe. Just watch your blood panels as usual, retest peaks and troughs occasionally.

1 Like
#94

Thanks for sharing your results.
Interestingly, time-to-peak (Tmax) also depends on whether one is taking 1 mg, 2 mg, or 5 mg tablets of sirolimus. If you’re taking 2 mg tablets, according to this table your peak blood level should occur a little under 3-hours after taking the pills.

Sirolimus tablet pharmacokinetics
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Also, from the FDA drug insert for Rapamune tablets:

“After administration of Rapamune Tablets and a high-fat meal in 24 healthy volunteers, Cmax, Tmax, and AUC showed increases of 65%, 32%, and 23%, respectively.”

4 Likes
#95

Thanks Brandy - I hadn’t realized the form (individual tablet dose 1mg, 2mg, 5mg) was a factor too not just the quantity of mg dose - in my case 10mg total! I posted too, because it appears that even pasteurized GFJ can provide a multiplication of benefit. However, at my last dose this week, I am off pasteurized GFJ and taking a whole ruby red grapefruit and juicing the inner flesh and fruit into a drink I take 2-hours before - will take one with and one 8 hours after. I also eat a a 14-16 oz. steak 2 hours before I dose (can’t do those sardines - LOL) Found this: A 4-ounce cut of beef steak offers about . 5 grams of polyunsaturated fats and 4.5 grams of monounsaturated fats. So, I am getting about 20 grams of polyunsaturated fats and 18 grams of monounsaturated fats (about twice the daily recommendation) with my rapa. All polyunsaturated fats and monounsaturated are good fats.

I will do a sirolimus blood test again in 4-months - I will schedule my draw in such a way that I do everything I normally do - 14 oz. steak, fresh juiced grapefruit both 2 hours before my dose and do my draw 3 hours after my dose - so I can get my T-max reading. The long wait.

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#96

Agetron, it’s a ballpark calculation, but according to the info you provided my estimate would be that the your peak blood level would occur around ~3.7 hours after your dose of five 2 mg sirolimus tablets (accounting for the additional ~32% increase in Tmax from your high-fat meal). Regarding the grapefruit juice protocol, from my reading of the literature, the grapefruit inhibits the CYP3A4 enzyme in the intestine, thereby increasing absorption of the sirolimus from the bowel. The grapefruit juice does not affect the liver CYP3A4 enzyme. Therefore, your taking GFJ 8 hours after the dose would have no additional benefit. My personal protocol is to eat 2 grapefruits as an after dinner dessert the night before my dose, and then 2 more grapefruits about an hour before taking the tablets the next morning. For my fat source, I take the tablets with an avocado or two.

3 Likes
#97

Huh… thought it was about the liver… not gut. Good to know.

It’s Rapa night… worked out til 8pm …I had my 14 oz. Ribeye steak… and GFJ an hour and a half ago.

Will have a second glass with the pills in a half hour and maybe skip morning GFJ.

I had heard that GFJ the next day still had benefits. But, maybe not.

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#98

A couple of weeks ago, I posted the result of my peak rapamycin blood test. I ate a lot of grapefruit before and with the 12 1mg Zydus brand pills. Blood was drawn, in accordance with the lab’s protocol to test peak sirolimus, 2 hours after the dose. The result was 68 ng/mL. 14 days later, I went back to the lab and had blood drawn for a trough reading. The result was 1.9 ng/mL.

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#99

Here is one article confirming this. My interpretation is that GFJ will not affect the half-life of rapa once the rapa is absorbed.

Grapefruit juice consumption for 5 days caused a mean 62% reduction of small bowel enterocyte CYP3A4 and CYP3A5 protein content associated with a greater than 3- and 5-fold increase in felodipine AUC and C max, respectively. In contrast, liver CYP3A4 activity, as measured by the erythromycin breath test, and colon CYP3A5 protein content were not altered.

3 Likes
#100

Argonaut, thank you for sharing. Are you planning to make any modifications to your dosing protocol based on these results?

1 Like