Bioavailability Woes of Curcumin

Curcumin suffers from notoriously poor oral bioavailability. In pharmacology, bioavailability is:

The fraction of a drug that enters the bloodstream when introduced into the body.

This is the fraction of drug that is able to have an active, biological effect. When a drug is consumed it can be transformed into an inactive compound or excreted unchanged too quickly to have an effect.

In practice, poor bioavailability means that you can ingest a lot of curcumin, but little of it makes it into circulation without being degraded by the liver and excreted.

What happens if you take a large dose of curcumin? You’ll see a spike in curcumin blood levels that lasts maybe 15 minutes - but then it will drop off to zero. The top of this spike is the Cmax, the maximum drug concentration observed.

In order to realize the health benefits of curcumin, you need a sustained increase in circulating curcumin.

The major biliary metabolites of curcumin are glucuronides of tetrahydrocurcumin (THC) and hexahydrocurcumin (HHC). The minor metabolites are dihydroferulic acid and ferulic acid.

Orally administered curcumin is absorbed from the alimentary tract and present in the bloodstream after being metabolized to glucuronide/sulphate conjugates.

Bioavailability != Absorption

Dr. Easton says it best:

There is a lot of confusion about curcumin bioavailability versus absorption. Curcumin is absorbed, but not necessarily bioavailable. Further GI and liver glucuronidation or sulfation "tagged curcumin" which interfere with bioavailability it some tissues also leadds to its rapid removal by the kidneys. Unliked tagged curcumin, free curcumin readily crossed the blood brain barrier and is relatively stable.

Enhancing Curcumin’s Bioavailability

Curcumin is rapidly glucuronidated and sulphonated in the liver (called hepatic first-pass effect). The glucuronidated curcumin is an inactive metabolite so it doesn't contribute to curcumin's beneficial effects.

Nutraceutical companies have tried to tackle curcumin’s bioavailability issues through a few strategies. The original approach is adding piperine (derived from pepper) to curcumin. If you look on Amazon, the vast majority of the curcumin products will be a simple combination of piperine (often as bioperine) with curcumin.

How Does Piperine Improve Bioavailability?

Piperine inhibits the enzyme that metabolizes curcumin, CYP3A4. If you co-ingest curcumin with piperine (or pepper), you prolong the effect of curcumin and enhance its bioavailability.

Which Curcumin Supplement Should You Get?

In many cases, brand doesn't really matter. You can pay a lot of money for a fancy bottled water, but it’s probably no better than tap water.

But with curcumin, brand matters! That's because how curcumin is formulated markedly affects bioavailability and absorption. Curcumin brands adopt different drug delivery technologies to enhance the bioavailability (and therefore potential health benefits) of curcumin.

Comparing Curcumin Supplements

There's a great 2011 study by Munjal et. al. that compares seven different curcumin formulations. You can read it here: Comparative oral bioavailability advantage from curcumin formulations (2011).

Specifically, the authors evaluate these formulations:

Aqueous suspension (AS) . This is like the control group - it's curcumin mixed with water. Curcumin isn't water soluble which is why this strategy is ineffective.

. This is like the control group - it's curcumin mixed with water. Curcumin isn't water soluble which is why this strategy is ineffective. Micronized suspension (MS) .

. Nanosuspension (NS) , e.g., Theracumin.

, e.g., Theracumin. Amorphous solid dispersion (ASD) .

. Hydroxypropyl-β-cyclodextrin inclusion complex (HIC) .

. Combination with piperine (WP) .

. Curcumin–milk composite (MC) .

All of these approaches work by protecting curcumin from degradation so that it has time to diffuse into tissues throughout the body. To my knowledge, no company has combined these strategies. It is only natural for people to want to hedge their bets, so it would be an interesting to add piperine to liposomal curcumin, for example.

Munjal's Comparative Study of Curcumin Oral Bioavailability

Munjal's paper concludes:

The aim of the present study was to study the oral bioavailability of seven different formulations of curcumin (CRM)...

Aqueous suspension provided a Cmax and AUC(0−t) of 28.9 ng/ml and 26.9 ng h/ml, respectively.

In comparison, statistically significant increase in the oral bioavailability was obtained with the nanosuspension, HP-β-CD inclusion complex, and amorphous solid dispersion with 251%, 567%, and 446% increase in terms of AUC(0−t) and 405%, 415%, and 270% in terms of Cmax.

However, no significant increase in AUC(0−t) and Cmax was observed with piperine and micronized suspension. The milk composite reduced the oral bioavailability of CRM (10% and 37% in terms of AUC(0−t) and Cmax).

A statistically significant increase in the Tmax was observed with piperine and in HP-β-CD complex, while the Tmax was reduced for nanosuspension. The results provide interesting insights into the role of solubility enhancement and metabolism inhibition, for improving the oral bioavailability of CRM.

Formulations

Curcumin inherently is poorly absorbed when ingested alone [^12]. 8 grams of curcumin fails to increase serum levels.[^13] Thus, biomedical science has attempted to invent methods to enhance the amount of curcumin that reaches circulation.

Curcumin plus piperidine from black pepper extract (inhibitor of glucuronidation) increases the bioavailability of curcumin 20-fold when 20mg piperidine is used alongside 2,000mg curcumin.[^16]

Theracumin emulsions (nanoparticles) possesses a 40-fold higher AUC (area under the curve) when compared with basic curcumin power in rats, and a 27-fold higher AUC in individuals.[^20]

Although another study found just a 10-fold increase in AUC and a 40-fold increase in Cmax in rodents.[^21] This increased bioavailability is, in part, due to increased water-solubility.[^22] Nanoparticles can be used up to 210mg without any ceiling effects. Nanoparticles increase Cmax to 275 /-67ng/mL, an AUC of 3,649 /-430 ng/ml/h, and a half-life of 13 /-3.3 hours.[^22]

Benefits of Curcumin Supplementation

Curcumin boasts beneficial effects on the nervous and cardiovascular systems. It has anti-inflammatory, anti-cancer, and neuroprotective properties, to name a few [^ref1]. The curcumin in curries may even explain the lower incidence of neurodegenerative disease in India ^ref2. Here’s a laundry list of the documented health benefits of curcumin (with citations):

Pronounced anti-inflammatory effects

Antioxidative, anti-lipofusinogenesic, and anti-aging effects in the brain of animals [^ref28]

Increased expression or activity of antioxidant enzymes like superoxide dismutase (SOD) [^ref29]

Decreased beta-amyloid, the protein implicated in the pathogenesis of Alzheimer’s disease [^ref30]

Neuroprotective effects mediated by decreased microglial activation, metal chelation, and suppression of inflammatory mediators

Enhanced hippocampal neurogenesis [^ref31](the process by which new neurons are integrated into the adult mammalian CNS)

Decreased risk of neurodegenerative disease ^ref32

References

[^13]: Lao CD, Ruffin MT, Normolle D, et al. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. 2006;6:10.

[^12]: Sharma RA, Mclelland HR, Hill KA, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res. 2001;7(7):1894-900.

[^16]: Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64(4):353-6.

[^20]: Sasaki H, Sunagawa Y, Takahashi K, et al. Innovative preparation of curcumin for improved oral bioavailability. Biol Pharm Bull. 2011;34(5):660-5.

[^21]: Zhongfa L, Chiu M, Wang J, et al. Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice. Cancer Chemother Pharmacol. 2012;69(3):679-89.

[^22]: Kanai M, Imaizumi A, Otsuka Y, et al. Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol. 2012;69(1):65-70.

[^ref1]: "Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn’s disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis."

[^ref40]: Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as "Curecumin": from kitchen to clinic. Biochem Pharmacol. 2008;75(4):787-809.

[^ref28]: Bala K, Tripathy BC, Sharma D. Neuroprotective and anti­ageing effects of curcumin in aged rat brain regions . Biogerontology. 2006;7(2):81­9.

[^ref29]: Kalpravidh RW, Siritanaratkul N, Insain P, et al. Improvement in oxidative stress and antioxidant parameters in beta­thalassemia/Hb E patients treated with curcuminoids . Clin Biochem. 2010;43(4­5):424­9. [ref30] Mishra S, Palanivelu K. The effect of curcumin (turmeric) on Alzheimer's disease: An overview. Ann Indian Acad Neurol . 2008;11(1):13­9.

[^ref30]: Mishra S, Palanivelu K. The effect of curcumin (turmeric) on Alzheimer's disease: An overview. Ann Indian Acad Neurol . 2008;11(1):13­9.

[^ref31]: Kim SJ, Son TG, Park HR, et al. Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus . J Biol Chem. 2008;283(21):14497­505.

[^18]: Jurenka JS Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev. (2009).

[^20]: Sasaki H, et al. Innovative preparation of curcumin for improved oral bioavailability . Biol Pharm Bull. (2011)

[^21]: Zhongfa L, et al Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice . Cancer Chemother Pharmacol. (2012)

[^22]: Kanai M, et al Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol. (2012)

[^23]: Karin M, Liu Z, Zandi E AP-1 function and regulation. Curr Opin Cell Biol. (1997)

[^24]: Angel P, et al Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. (1987)

Further reading: Comparative oral bioavailability advantage from curcumin formulations (2011).