Ketoconazole timing for enhanced Rapamycin absorption

I know ketoconazole has known hepatotoxicity, but enhances rapa absorption by 5-6 times vs. 3 times with grapefruit juice. I’m willing to do it due to taking only 3 pills per month (my current rapa dosing is 7mg every 10 days).

Any idea of when the ketoconazole should be taken when taking rapa? Right now I’m taking the keto 1/2 hour prior to the rapamycin.

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It sounds like we would want to take it 1 to 2 hours prior to taking the rapamycin.

Here is what the FDA insert has to say:

Mean peak plasma concentrations of approximately 3.5 μg/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Oral bioavailability is maximal when the tablets are taken with a meal.

Elimination from plasma is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter .


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Thanks. A typical useful, data-driven, thoughtful answer. Should have thought of the FDA insert.

FYI, I got 180 tablets of 200mg each for $193 from AllDayChemist.

The original paper shows a 5x effect with Ketoconazole versus a 3.5x effect with grapefruit juice. On further reflection, it probably makes more sense to stay with grapefruit juice, given its low toxicity.


Yes - I really like the idea of ketoconazole because the result is so consistent, and its so cost-effective for raising effective rapamycin doses. I also suspect that if you are only using it a few times a month, the downsides/risks are infinitesimally small.

It’s very hard to find grapefruit because it is not in season now.
I may consider to introduce ketoconazole in my rapamycin regime later.

Beside the potential hepatotoxicity of ketoconazole, what else should we pay attention to?

Unlike grapefruit that inhibits cyp3a4 most in GI tract, I guess ketoconazole acts most on liver
Will it cause prolongation of elimination half-life of rapamycin?

In this paper, they recommend the following dose of ketoconazole

one-eighth to onefourth of the recommended dose of sirolimus (0.25–0.5mg) with 100 to 200 mg of ketoconazole.

What’s the optimal dose of ketoconazole with rapamycin in your opinion ?

Sorry that I haven’t studied pharmacokinetics, so I am asking for the opinions of ketoconazole
I should study pharmacokinetics when I have spare time in future anyway :smile:

I agree that the chances of hepatic injury are minimal. It appears that Ketoconazole causes liver injury following long dosing periods. Typically, patients would exhibit asymptomatic, reversible liver function test abnormalities in approximately 0.1 to 1.0%. Liver abnormalities were not associated with the size of the dose but with the duration, i.e., long dosing periods. So it should be safe to take 3 or 4 pills a month.


Interestingly, I read that Ketoconazole is a CYP3A substrate (meaning that the CYP3A enzyme degrades it), leading to warnings that grapefruit juice can slow down the degradation of Ketoconazole, and so should be avoided when taking Ketoconazole.

Which brings up the interesting question of whether CYP3A-inhibitor Ketoconazole inhibits it’s own enzymatic degradation. I assume yes.

Also, as an aside, I read that grapefruit juice reaches maximum potency in CYP3A inhibition one hour after taking. So if you’re using grapefruit juice to enhance Rapamycin absorption, you should wait one hour after drinking an 8-oz glass of grapefruit juice before taking the rapa.