#297

@Olafurpall Measuring my rapa blood level at 48 hours after dosing will not give me my cmax. Measuring 2 hours after dosing will likely not give me my exact cmax either (but it’s close). I am more interested in knowing my cmax than my level at 48 hours. Also, if every blood test I take is at 2 hours after dosing, I should see a pattern (for myself)- I’m also interested in knowing how I react (e.g. I took the Siroboon brand today for the first time and I’d like to know if it is equivalent to Biocon).

Is the goal for taking rapamycin for longevity to get the molecule into every cell? Does having a higher cmax help with that? How important is it that rapa be cleared from your blood before you dose again? It seems that most of us are dosing once per week- some once every ten days or two weeks. Is taking a higher dose (say 15mg) and waiting two weeks better than taking 8mg once per week. Aren’t the “two week” dosers wanting to get a higher cmax followed by a longer period with no rapa in the blood? And, of course, there are some that are taking 1mg daily.

Is there any evidence that one of these strategies is better than others? And, could it be age dependent- someone starting rapa at age 30 would want a lower dose than someone starting at 65? What about overall health- does someone that is less healthy need a higher dose? I certainly don’t know the answers…

As I’ve said before- we are on the cutting edge and I hope it doesn’t cut too deeply!

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#298

Ok if you’re trying to get your cmax, even though it won’t be very accurate, then of course measuring at 2 hours will give some rough estimate, much closer than measuring a 48 hours. What I was talking about is that if you want to find out how much of a multiplication you get from taking rapamycin then measuring at 48 hours is going to give you a much more accurate indication of that then measuring at 2 hours.

Anyways. I’m curious to know why you want to know your cmax specifically? Is there some concentration that you hope to reach or do you want to compare it to the cmax of other people or that which is seen in some studies?

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#299

@Olafurpall I’m not certain that knowing the cmax is important. But, it might be. It really relates to the questions I asked (the second paragraph) in my last post (i.e. what is the best dosing strategy).

I’m a data guy- I’d like to know my cmax and how fast the rapa is cleared from my blood (everything from start to finish).

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#300

@Hitch The best way to determine cmax is to take multiple measurements between about 30 minutes and 2.5 hours so you can follow the blood peak. That would be expensive at $60 a measurement. A reasonably accurate and reproducible way to determine your C-max with one measurement is to measure at 48 hours. Your level at 48 hours is related to your C-max and will be higher if your C-max is higher. If you look at figures 1 and 3 from this paper you will see that at a dose of 3 mg / m^2 (roughly 6mg in a 70kg individual)
the Cmax in 6 individuals ranged from 20 ng/ml to 40 ng/ml (Figure 3). If you look at the blood levels of the same 6 individuals at 48 hours you see that the blood levels ranged from 1.2 to 1.75 ng/ml (Figure 1). So a level of 1.2 ng/ml at 48 hours is roughly a cmax of 20 and a level of 1.75 ng/ml at 48 hours is roughly a cmax of 40 ng/ml. Using data from these two figures you can extrapolate back to cmax from your 48 hour values. The conversion appears to be that your level at 48 hours is approximately 1/20th of your C-max. (range 17x to 23x). By doing it this way you can also determine if your absorption is within the range of the 6 subjects in the paper by comparing your level at 48 hours to the subject range of 1.2 to 1.75 ng/ml. Once you’ve determined the conversion, it should hold for adding GFJ to the mix. I would think you might need a different conversion factor if you also add EVOO as that seems to change the C-max to steady state transition.

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#301

I would gladly take it with Ketoconazole. I did some research into other CYP3A4 inhibitors a while ago and I must say that in terms of CYP3A4 inhibition, short period in which it inhibits CYP3A4s and its short elimination half-life and consistency make it superior to anything else. There is this unfortunate liver damage that might be a problem but probably not from once weekly administration but it is impossible to source Ketoconazole in EU. You need a special prescription and price is just exuberant / around 600 EUR for 24x200mg pills.
Second best is Ritonavir, cheap and available. Very consistent too, with short period of inhibition onset, but it is a irreversible inhibitor of CYP3A4 which complicates the whole AUC, half-life and elimination of rapamycin.

Will try to find a meta analysis that I found a while ago on Ketoconazole and CYP3A4… was searching again, but can’t seem to find it.

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#302

Since “some people have a lot more CYP3A4” than others, this means two people taking the same dose of rapamycin can have a very different c-max regardless of grapefruit juice. I think everyone taking rapamycin should do a rapa level test at least once regardless of taking grapefruit juice or not. This can at least give you some additional data specific to your body on how to dose…

… And this info from 59vw sounds like a great way to do it. I think at some point I will do a sirolimus test at 48 hours and 96 hours. This should be a fairly economical way of telling me a close estimate of c-max and half-life. I’d like to do this with a round of rapamycin alone and a round with gfj. Unfortunately this will be difficult for me to do anytime soon. It’s very difficult for me to get away from work twice in one week to go to a lab. It might require a staycation.

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Siroboon Sirolimus / Rapamycin Lab Blood Test Results
#303

A reasonable suggestion. Does anyone know of a lab that offers this service in the UK?

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#304

Does this work? Sirolimus – Private Blood Tests

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#305

@RapAdmin

Any idea if taking Artichoke extract and Milk Thistle to prevent raised ALT and AST levels from all the medications I take, can interact with Rapamycin absorption?

Also just to be safe I do not take Citrus Bergamot 24hrs before or after my Rapa dosage as it has grapefruit like qualities which can inhibit some CYP enzymes, albeit pretty weakly.

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#306

No - Sorry, I’ve not looked into this issue at all.

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#307

If anyone is on a liver cleanse with Milk thistle, please keep in mind that :

" Taking milk thistle might decrease how well the liver breaks down sirolimus. This might increase the effects and side effects of sirolimus."

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#308

I don’t have time to look into this in any detail, but this quote suggests that milk thistle won’t reach high enough concentrations to influence rapamycin metabolism in humans unless perhaps in those that suffer from liver damage:

" Both SLM and GLZ formulations, taken by a relatively large number of patients (15 and 19, respectively), were shown to reduce sirolimus CL/F significantly by about 34%. Silymarin, a flavonolignan from the ‘milk thistle’ plant, has been used almost exclusively for hepatoprotection for hundreds of years all over the world [56]. It is a complex mixture of four flavonolignan isomers, namely silybin, isosilybin, silydianin and silychristin [56]. In vitro studies have shown that silymarin, in higher concentrations, has a strong inhibitory effect on both P450 3A4 [56–58] and P-gp [59–61]. The concentration tested in vitro exceeded physiologically attainable levels [56–58, 60, 61] and hence previous studies in vivo have shown no to mild inhibition effects when co-administered with ranitidine [62], nifedipine [63], midazolam [64] and indinavir [65, 66] in healthy volunteers. Recently, Schrieber et al. reported that AUC0–24 h for the sum of total silymarin flavonolignans was 2.4-, 3.3- and 4.7-fold higher for hepatitis C virus (HCV) noncirrhosis, non-alcoholic fatty liver disease, and HCV cirrhosis cohorts, respectively, compared with healthy volunteers [67]. It is a common practice in China as well as in the current study that SLM or GLZ is added by clinicians when patients have abnormal liver function indices. Therefore, the remarkable inhibition effect of SLM on sirolimus CL/F could be explained by accumulated high concentrations of SLM in these patients with hepatic impairment."

Quote is from here: Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients - PubMed

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#309

Hi

I get my testing done in the UK at the Nuffield ( Labs) with my blood draw at the Chandlers Ford Hospital - all very relaxed - results by email with 48hrs - £50 last time around - do it once a year - get confused by units - State side are different to here but can convert between

I arrange it direct with the labs and am happy to share a prior email to give contact details

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#310

Hi

How do you reply to a specific individual posing a question?

Thanks

#311

hit the reply button in the lower right hand part of their post. It’s not blue.

#312

A 200 ml glass of grapefruit juice increases the effect of 2 mg of rapamycin on average by how many times?

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#313

I think it’s 3 or 4 times.

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#314

It is difficult to say because it also depends upon when you take the grapefruit juice. 200ml is not that much grapefruit juice and may fall into the territory of not enough to fully inhibit the enzymes.

My own approach on this and I have used Pomelos, Pomegranates and Grapefruits is that I look at the outcome in terms of biomarker changes (and sleep disruption) and I make a simplistic assumption of a single compartment half life of 60 hours.

My last dosage assuming 16x3 (and maybe a bit)=50mg does fit with this. I have also worn a GCM whilst taking Rapamycin and that did show a shift in glucose processing.

However, in terms of Rapamycin users I am in the minority as I take it far less frequently than others. I think the peak serum level (or interstitial fluid level) is the most important thing for the positive effects, but I wish it to be out of my system most of the time to minimise negative effects.

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#315

Yeah, sorry I didn’t see the 200 ml part because I drink a pint and start an hour before I swallow the pills. I had to google how much is 200 ml in pints.

#316

Its hard to say even with a pint. It is likely to vary. However, I agree that if you take enough and get the timing right you can get an increase beyond 3 times.

In the end, however, dosing remains an inexact science where we don’t yet know what the best thing to do is.

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