Curcumin Does Not Appear to Meaningfully Inhibit CYP3A4

The evidence for this appears to be mostly in vitro studies on intestinal cells or recombinant enzyme, with a small amount of supportive animal data. Human studies do not appear to support it:

A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). …

Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 μM and 0.6 μM, respectively).

Conclusion: The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes.
Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers - PubMed

Dextromethorphan (DEX) was used as common probe for CYP2D6 and CYP3A4 enzymes. Metabolic activity of CYP2D6 and CYP3A4 was evaluated through in vitro study; where microsomes were incubated with NADPH in presence and absence of Curcuma extract. In clinical study phase-I, six healthy human subjects received a single dose (30 mg) of DEX syrup, and in phase-II DEX syrup was administered with Curcuma powder. The enzyme CYP2D6 and CYP3A4 mediated O- and N-demethylation of dextromethorphan into dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. Curcuma extract significantly inhibited the formation of DOR and 3-MM, in a dose-dependent and linear fashion. The 100 μg/ml dose of curcuma extract produced highest inhibition, which was about 70 % for DOR and 80 % for 3-MM. [This is the in vitro result: see the full text].

Therefore, the clinical study was conducted to confirm the results obtained from in vitro investigations. To determine in vivo inhibitory effects, the urinary metabolic ratio of DEX/DOR and DEX/3-MM as well as the amounts of DOR and 3-MM excreted in urine was used to assess the metabolic activities of CYP2D6 and CYP3A4, respectively. …

The inhibitory effect of curcuma on the formation of 3-MM was weak (about 28 % inhibition was recorded), as indicated by insignificant changes in urinary metabolic ratio of DEX/3- MM (Table 1). … C. longa remarkably reduced the level of DOR and 3-MM metabolites excreted in urine and enhanced DEX/ DOR at statistically significant level, while the increased in DEX/3-MM metabolic ratios was statistically insignificant

Present findings suggested that curcuma significantly inhibits the activity of CYP2D6 in in vitro as well as in vivo; which indicates that curcuma has potential to interact with CYP2D6 substrates.
Effect of Curcuma longa on CYP2D6- and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human subjects - PubMed

It’s a bit odd that they describe the effect on 3-MM (28% inhibition) as “weak” but also say that it “remarkably reduced the level of DOR and 3-MM metabolites”. A 28% inhibition does sound meaningful, but, they clearly think the effect on DYP2D6 is important and the effect on CYP3A4 as not. The ratios for DEX alone vs. DEX with curcuma extract are 5.959 and 8.290, respectively. The other caveat is that this is anethanolic extract not standardized for curcumin, so it’s not clear how much this one reflects a standard 95% curcumin extract.

In Vitro metabolism of imatinib and bosutinib were investigated in pooled human liver microsomes and recombinant CYP3A4 enzyme in the presence and absence of curcumin and curcumin glucuronide…The potential effects of curcumin coadministration on systemic exposures of imatinib and bosutinib were predicted in silico using PBPK simulations.

PBPK model simulations of curcumin pharmacokinetics given as a single oral dose (SLN formulation containing 160 mg of curcumin) was performed to replicate trial designs (number of people, age range, proportion of male to female) matched to the corresponding published clinical studies (Table 2). A total of 100 virtual trials were carried out. The clinical pharmacokinetic data were taken from a study in healthy people of Indian geographic ancestry receiving the SLN formulation of curcumin [PMID 20092313 — Longvida curcumin nanoparticle]

Results: Curcumin demonstrated potent reversible inhibition of cytochrome P450 (CYP)3A4-mediated N-demethylation of imatinib and bosutinib and CYP2C8-mediated metabolism of imatinib with inhibitory constants (ki,u) of ≤1.5 μmol. L-1… PBPK model simulations predicted that at recommended dosing regimens of SLN curcumin, coadministration would result in an increase in systemic exposures of imatinib and bosutinib of up to only 10%.

Although curcumin possesses a strong In Vitro inhibitory activity towards CYP3A4 and CYP2C8 enzymes, its interactions with imatinib and bosutinib were unlikely to be of clinical importance due to curcumin’s poor bioavailability.
Physiologically-Based Pharmacokinetic Predictions of the Effect of Curcumin on Metabolism of Imatinib and Bosutinib: In Vitro and In Vivo Disconnect - PubMed

This last is only a model, but it’s a much better model than the typical crude 1:1 extrapolation and is recognized by FDA. And the dose is lower than standard curcumin extract, though it’s of a high-bioavailability formulation.

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Its valuable to recognize that the interaction between curcumin and CYP3A4 isnt yet completely understood.

Here is the 2014 study that demonstrated the effect of curcumin on pharmacokinetics of everolimus: https://sci-hub.se/10.1038/srep06587

Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies

Effect of curcumin on EVL pharmacokinetics in rats. The results showed that 50 and 100 mg/kg of curcumin both significantly decreased the Cmax of EVL by 76.7%, and reduced the AUC0-540 by 70.6% and 71.5%, respectively.

However, this 2022 study again raises some issues: https://bijps.uobaghdad.edu.iq/index.php/bijps/article/view/1514

Effect of Curcumin at Various Doses on the Pharmacokinetic Profile of Tacrolimus in Healthy Rabbits

Our results revealed that the differences for the three groups in PK parameters as Cmax, tmax, ke, AUC0-6 and AUC0-? were statistically insignificant (P>0.05). In conclusion, it has been found that CUR at the experimented doses does not affect the PK of TAC. Further confirmation of our findings is required before these results can be applied in patient care.

So until there is clarity on the interaction issue, as much as I appreciate the potential benefits of curcumin, I put a higher weight on the potential benefits of ameliorating senescence. I can omit it for a few days prior to and after dosing my rapamycin and D&Q&F.

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Right — but both of these studies are in animals. I posted two studies in vivo in humans, plus a modeling study using PK data taken from a human trial.

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I find the effect of curcumin kind of confusing because studies have shown that curcumin is both an inducer and an inhibitor of CYP3A4

Our interest in curcumin is for its role as an inducer of the enzymes CYP3A4 that metabolizes rapamycin before its uptake as an anti-senescent.

You cite fairly compelling evidence that curcumin does not inhibit CYP3A4. My concern, as I mentioned, is not with the inhibiting effects but the inducing effects. I don’t want to induce an enzyme that enhances the elimination of rapamycin. I want to inhibit it, thus the use of grapefruit or ketoconazole.

From the 2014 rat study, I still am of the opinion that curcumin probably reduces the effective AUC of rapamycin, probably by inducing CYP3A4.

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Yes. I’m guessing that that’s because it’s actually a bit of a wash :wink: .

We’re interested in both, of course. If it’s an inhibitor (like grapefruit juice), then it could increase the bioavailability of drugs (like rapa) that are metabolized by it; many people on this forum use it for that purpose. If it’s an inducer, then it could reduce bioavailability, which most people would find undesirable and want to avoid.

The human studies I’ve cited find that the net effect of curcumin on PK of drugs metabolized by CYP3A4 is very small.

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Curcumine maybe doesn’t but I Piperine, which is added to many Curcumine supplements, does.

I once did measure in TDM a 2x plasma level increase of Guanfacine (metabolized via CYP3A4) when I took Curcumine+Piperine extract daily. (each 5mg of Piperine)

So I regard Curcumine/Piperine-Extracts as very interesting supplement to boost Rapamycin levels by CYP3A4 inhibition.

It would be nice, though, to measure it scientifically. So if anyone has the means to measure Rapamycin levels with and without Curcumine/Piperine, that would be great.

See also:
Cui, T., Wang, Q., Tian, X., Zhang, K., Peng, Y., & Zheng, J. (2020). Piperine Is a Mechanism-Based Inactivator of CYP3A. Drug metabolism and disposition: the biological fate of chemicals, 48(2), 123–134. https://doi.org/10.1124/dmd.119.088955

Curcumin inhibits the activity and induces apoptosis of activated hepatic stellate cell by suppressing autophagy

Curcumin, a kind of natural compound, has been previously proven to inhibit the autophagy in hepatic stellate cells (HSCs) and induce their apoptosis. However, it is not clear whether the enhanced apoptosis of activated HSCs (aHSCs) caused by curcumin depends on autophagy inhibition. We aim to verify this hypothesis and explore the potential mechanisms in this study. Immortalized human HSC line LX-2 was used as an experimental specimen and pretreated with transforming growth factor β1(TGF-β1) for 24 h to activate it before drug application. The levels of autophagy, apoptosis, cell activity, lipid metabolism, and the activity of the PI3K/Akt/mTOR signal pathway were evaluated by multiple methods, such as Western blotting, mcherry-EGFP-LC3B adenoviruses transfection, immunofluorescence, Nile Red staining, flow cytometry among others. Our results showed that rapamycin, an autophagy activator, could partly offset the effects of curcumin on autophagy and apoptosis of LX-2 cells, while 3-Methyladenine (3-MA), an autophagy inhibitor, could enhance these effects. Furthermore, curcumin could promote the activity of the PI3K/Akt/mTOR signal pathway in LX-2 cells, while PI3K inhibitor could partly offset this effect and increase the autophagy level. Overall, we demonstrated that curcumin could inhibit the activity and promote LX-2 cells apoptosis by suppressing autophagy by activating the PI3K/Akt/mTOR signal pathway. In addition, lipid recovery and energy deprivation due to autophagy inhibition may be the exact mechanism by which curcumin attenuates the pro-fibrotic activity of LX-2.