Turmeric absorption - A known issue...

The main component of Turmeric is CURCUMIN and its effectiveness has been demostrated in serveral clinical trials. Despite its effects, curcumin-based drugs -and diet supplements- are not readily available in the market because of their low bioavailability.
Bioavailability

Bioavailability

Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. In simple words, bioavailability means how much our body is capable of absorbe and take advantage of the benefits of certain drugs or supplements.



Causes of low bioavailability

  1. Size of the molecule - Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver; both are common sites of first-pass metabolism (metabolism that occurs before a drug reaches systemic circulation). Thus, many drugs may be metabolized before adequate plasma concentrations are reached. Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs.

  2. Insufficient time of absroption - Insufficient time for absorption in the gastrointestinal (GI) tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (eg, if it is highly ionized and polar), time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low.

  3. Chemical reactions - They include formation of a complex (eg, between tetracycline and polyvalent metal ions), hydrolysis by gastric acid or digestive enzymes (eg, penicillin and chloramphenicol palmitate hydrolysis), conjugation in the intestinal wall (eg, sulfoconjugation of isoproterenol), adsorption to other drugs (eg, digoxin to cholestyramine), and metabolism by luminal microflora.

  4. Poor water solubility - Curcumin is an oil soluble pigment, practically insoluble in water at acidic and neutral pH, soluble in alkali. It is stable at high temperatures and in acids, but unstable in alkaline conditions and in the presence of light.

  5. Other factors - Age, sex, physical activity, genetic phenotype, stress, disorders (eg, achlorhydria, malabsorption syndromes), or previous GI surgery (eg, bariatric surgery) can also affect drug bioavailability.

  6. Conclusion - According to The Nutraceutical Bioavailability Classification Scheme (NuBACS), physicochemical/physiological factors contributing to the poor bioavailability (BA) of bioactive compounds -such as curcumin- can be categorized in five classes:
    • Bioaccessibility (B*)
    • Absorption (A*)
    • Transformation (T*)
    • Distribution (D*)
    • Excretion (E*)
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Bioavailability

Milestones in curcumin bioavailability

Unformulated curcumin

In 1978 was reported for the first time poor amount of curcumin in blood plasma of rats after oral administration. Same type of experiments in humans revealed that curcumin was practically undetectable in blood stream. Intravenous administration was also tried showing better -but not significant- absorption rates.



Nanocurcumin

Trying to increase the bioavailability of curcumin different formulations were designed. Among them, nanoglobules based nanoemulsion formulation showed a hight release than suspension curcumin. Another study showed an encapsulating the curcumin into the hydrogel nanoparticles yielded a homogenous curcumin dispersion in aqueous solution compared to the free form of curcumin.

The pharmacokinetics of curcumin and another formulation nanoemulsion curcumin (NEC) containing up to 20% curcumin (w/w) showed a 10 fold increase in the area under the blood concentration-time curve (AUC) 24 hours and more than 40-fold increase in the C(max) in NEC compared to curcumin in mice.

Another curcumin-loaded apotransferrin nanoparticles (nano-curcumin), prepared by sol-oil chemistry, releases significant quantities of drug gradually over a fairly long period, ~50% of curcumin still remaining at 6 hours of time. In contrast, intracellular soluble curcumin (sol-curcumin) reaches a maximum at 2 hours followed by its complete elimination by 4 hours.

The colloidal nanoparticles, named as 'theracurmin' showed AUC after the oral administration more than 40-fold higher than that of curcumin powder in rats. In healthy human volunteers, theracurmin (30 mg) when administered orally resulted 27-fold higher AUC than that of curcumin powder.

The nanoparticle of curcumin prepared by Cheng et al. produced significantly higher curcumin concentration in plasma and six times higher AUC and mean residence time in mice brain than regular curcumin. Thus, nanocurcumin enhances bioavailability of curcumin in animals as well as in humans.



Polylactic-co-glycolic acid (PLGA)

To improve the pharmacokinetics of curcumin with enhancing its bioavailability other effective formulation PLGA encapsulated curcumin was prepared.

Intravenous administration of either curcumin or PLGA-curcumin (2.5 mg/kg), exhibited almost twice as high serum concentration of PLGA-curcumin than curcumin.

In support of previous study, it has been found that after oral administration of curcumin-PLGA-nanoparticles, the relative bioavailability was increased 5.6-fold and has a longer half-life compared with that of native curcumin. This improved oral bioavailability of curcumin found to be associated with improved water solubility, higher release rate in the intestinal juice, enhanced absorption by improved permeability, inhibition of P-glycoprotein-mediated efflux, and increased residence time in the intestinal cavity.



Liposomal encapsulation

Another formulation designed for improvement of bioavailability of curcumin is liposomal curcumin. Liposomes are considered as effective drug carriers because of their ability to solubilize hydrophobic compounds and to alter their pharmacokinetic properties.

In rat oral administration of liposome-encapsulated curcumin (LEC) showed high bioavailability of curcumin. In addition, a faster rate and better absorption of curcumin were observed as compared to the other forms. Oral LEC gave higher C(max) and shorter T(max) values, as well as a higher value for the AUC, at all time points.



Cyclodextrin (CD)

CD, cyclic oligosaccharides, has been also used in order to improve curcumin's delivery and bioavailability via its encapsulation with CD. It has been found that CD encapsulated curcumin (CDC) had a greater cellular uptake and longer half-life in the cancer cells compared with free curcumin indicating CDC has superior attributes compared with free curcumin for cellular uptake. In addition, the improvement of CUR permeability acrossed animal skin tissue was observed in CD encapsulated curcumin and was about 1.8-fold when compared with the free curcumin. Thus, these studies suggest that CDC has improved in vitro and in vivo bioavailability and chemotherapeutic efficacy compared to curcumin alone.



Piperine

Besides these natural compounds have been also used to increase the bioavailability of curcumin. One of them is piperine, a major component of black pepper, known as inhibitor of hepatic and intestinal glucuronidation and is also shown to increase the bioavailability of curcumin. This effect of piperine on the pharmacokinetics of curcumin has been shown to be much greater in humans than in rats. In humans, curcumin bioavailability was increased by 2,000% at 45 minutes after co-administering curcumin orally with piperine, whereas in rats, it has been found that concomitant administration of piperine 20 mg/kg with curcumin 2 g/kg increased the serum concentration of curcumin by 154% for a short period of 1-2 hours post drug. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.

In view of these findings, curcumin-piperine (Cu-Pi) nanoparticles has been prepared by various methods. The bioavailability, cellular uptake and biological effects of this nanoparticles are being tested.



Micellar curcumin

Although piperine boots absorption of curcumin it does not significantly delay its the elimination from the organism. Inhibiting curcumin metabolism by adjuvants (e.g. piperine) has small effect on circulating curcumin. Inhibiting phase II enzymes carries the additional risk of drug interactions.

Despite its widespread coverage on internet discussion boards and in marketing campaigns of some companies, inhibiting phase II enzymes is a poor strategy to enhance curcumin bioavailability.

The use of micelles as carriers dramatically increases the absorption of curcumin for the body. In consequence, curcumin remains in the body at higher concentrations for loger after a single dose. Repeated intake results in significant curcumin concentrations in fasting plasma that exceed the maximum concentration reported in many pharmacokinetic trials. Curcumin can be quantified in brain tumors when administered as micellar formulation. This solution carries no adverse effects.
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