I’m not sure how big a deal the liver risk is if you’re just dosing once every week or two with ketoconazole, but I think people might avoid it for the polypharmacy issues… the more drugs and supplements you take, the greater the risk of some unforeseen interactions. I try to keep my stack as simple as possible as a general policy.
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“Obviously this is the correct answer”- but what is the question? I see two of them.
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If I take Xmg rapa with and without GFJ, what will be the difference in my rapa blood level? (answer seems to be ~3x)
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If I take Xmg rapa with GFJ, what will my rapa blood level be? (answer was ~8x for me)
Two very different, but relevant questions. I may be a little biased, as I wrote the original post, but if I could only ask one question, it would be #2.
I wonder if that will work for all values of x. Is it a linear function? We have one point.
Not saying it’s not, I just don’t know. If you increase the amount in the gut, then more will get through to the blood. Even though the units are wrong, all things may cancel out and this could work.
Does anybody know of a paper that shows blood level graphed against dose taken? You would have to wait a couple weeks between replications to let it go away.
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My reasoning for stopping ketoconazole, which, like you I loved for its reliability, was that I got the impression from my reading that its inhibition of CYP3a4 was much longer lasting than that of grapefruit, significant for a week as I recall.
Not wanting to stop for more than a day the other drugs that interacted with ketoconazole, I switched back to grapefruit. If my reasoning can be shown to be in error, I would return to ketoconazole. The connection with liver damage was never a concern given the infrequent use.
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@bicep Agetron takes 2mg with GFJ and his blood level is ~8 (4x vs. my 8x with 4mg dose).
Could be a linear function or just that day, that time, that person…
I agree with Bicep’s post - rapa is so cheap from India that GFJ is likely an unnecessary confounder. I will do a blood test with 2mg and GFJ (enquiring minds like to know!), but not today (my rapa day). I just took 8mg sirolimus from Siroboon and will get a blood test at 2 hours post dosing. I’ve been using the Biocon, but Siroboon is a little cheaper. I’ll post the results tomorrow.
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@RapAdmin Ive been squawking a lot lately about the polypharmacy issue. My issue is only my personal feeling that I was making a mistake. I completely slipped down the slippery slope of wishful thinking. I was / am addicted. But I am in recovery now. I no longer take any sleep supplements (or anything in the evening), and my sleep is already better.
I’ve cut down to 10 chemicals that I take regularly but cycle out of at least 2 days each week. I feel much safer, and I’ve shifted my focus to lifestyle interventions. I’m learning a sleep / circadian rhythm daily schedule right now.
It’s a long term plan but so far so good.
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Is it possible for the CYP3A4 inhibition to be longer than the blood levels of ketoconazole?
How long does ketoconazole stay in your system? Ketoconazole has a half-life of 2 hours in the first 10 hours of taking the drug. From that point onwards, the half-life of the drug increases to 8 hours.
Source: Ketoconazole - Side Effects, Dosage, Precautions, Uses.
If you take a irreversible inhibitor of CYP3A4, body needs around 3-4 days to recover the function cytochrome P450-3A if I remember correctly. GFJ is irreversible inhibitor, but works in intestine only.
Ketoconazole is a reversible inhibitor with very short elimination, so probably the recovery of cytochrome P450-3A must be short too.
Yes, I understand that the the time it takes for CYP3a4 to return to normal levels is not the same as the time it takes to eliminate ketoconazole from the body.
Also, the mechanism of inhibition differs between GFJ and ketoconozole and the rate of regeneration of the enzyme differs between the two…
I dont know of any study that sheds light on how long it will take to normalize the enzyme after single dose of ketoconazole. I am assuming it is at least 3 days.
I’m inclined to agree with scta123 and now expect that normalization of CYP3a4 after ketoconazole could actually be faster than with GFJ.
If that’s the case, I may prefer ketoconazole. I have plenty left, just looking for corroboration if anyone can provide it.
If the multiplier is 8x at 2 hours then the cmax is close to 8x. But that’s if. Problem is, you don’t know if the multiplier is 8x at 2 hours if you measure with or without GFJ at 2 hours because you don’t know if you’re exactly as close to the peak in both cases. Trying to measure the peak and comparing it with or without GFJ is a very inaccurate way to estimate the multiplier. It’s far better to measure at 48 hours.
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I understand you hope it’s 3x, but you really have little idea unless you do blood tests to measure it.
Yes, the 3.5X is just the average. The variation is quite large. Some people have a lot more CYP3A4 in their intestines than other people. People can get anywhere from less than 2X to over 8X with GFJ. That is why I think anyone that is taking rapamycin with GFJ should take blood tests with or without it to see what their individual multiplier is. Otherwise they have very little idea of how much they are getting in their blood.
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@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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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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@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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@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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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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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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A reasonable suggestion. Does anyone know of a lab that offers this service in the UK?
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