During the past few years, paralleling the public’s increasing interest in using nutritional supplements, there has been an increasing interest on the part of governmental agencies and so-called ‘consumer advocate’ groups to eliminate the public’s right to buy them. This conflict has given rise to a surge of research to determine the efficacy of various supplements. Some of the research is politically motivated and is designed to find no efficacy, some is sloppily designed and produces answers contrary to those found by other studies, and some is well-designed and gives answers we should be able rely on — and yet even the well-designed studies often contradict each other. The field of dietary supplement research is thus a miasma of conflicting claims.
This lack of consistency, in my opinion, usually stems from the failure of researchers to control the bioavailability of the substances they are studying. A given substance acts somewhat differently in different individuals, and in the same individual at different times. Absorption from the digestive tract varies; the residency time in the body varies; the ability to enter and remain inside of cells varies; competition from other substances varies. Controlling all these variables would be a difficult and expensive task — so much so, that researchers make only feeble attempts at it.
Although we supplement users find this situation frustrating insofar as we are unable to get firm answers to questions about efficacy, we can draw one valuable conclusion from it: unless we take special action to ensure the bioavailability of the supplements we use, whatever potential benefits they might have can be lost due to poor absorption, poor residency time, etc. That brings us to the subject of a bioavailability enhancer that I’ve become rather enthusiastic about: piperine.
What is piperine?
Piperine is a pungent substance found in plants of the Piperaceae family — including Piper nigrum (black pepper) and Piper longum (long pepper). These peppers have been used in Ayurvedic medicine for the treatment of various diseases and discomforts. Recent research has provided support for some of these uses and has uncovered the probable mechanism responsible for them.
Let us look at what is known about the piperine’s mechanism of action in the body.
How the body controls access to its cells
The body has several major mechanisms for controlling the exposure of its cells to nutritional and other substances. Four of these mechanisms are of interest with regard to piperine: metabolic conversion, assisted absorption, assisted exclusion, and solubilizer attachment.
Metabolic conversion involves the use of enzymes to chemically convert substances to different substances that may be less active and, in any case, are more easily carried in blood to the kidneys for excretion. The original substances are called ‘substrates’ of the enzymes; after conversion they are called ‘metabolites’. For example, an enzyme called ‘aromatase’ converts the substance testosterone into estradiol. Testosterone is a substrate of the aromatase enzyme; estradiol is a metabolite of testosterone. Although estradiol is itself an important hormone in the body, it also serves as an excretable form of testosterone. Other enzymes convert estradiol into even more easily excreted forms, such as estriol.
Assisted absorption, the second method for controlling the exposure of cells to substances, involves the use of transporter proteins in the cells of the digestive tract. These proteins actively transport substances into cells of the intestinal lining; from there they can be transferred to the blood. Assisted absorption is particularly important for ensuring that essential amino acids are available in adequate amounts.
Assisted exclusion involves the use of transporter proteins that ‘pump’ certain substances out of cells, whereupon they can be taken away by the blood. While the activities of these pumps can protect cells from toxic overloads of many substances, they can also spoil the efficacy of otherwise beneficial drugs and supplements by pumping these substances out of the cells before they can act. One of the most important such ‘pump’ proteins is p-glycoprotein, which is found in the membranes of cells in the intestines, brain, liver, pancrease, kidneys, and other tissues.
Solubilizer attachment prevents substances from entering cells by linking them chemically to a highly water-soluble substance. Not only does this alter the biological activities of the substances in question, it also makes them unable to diffuse through cell membranes. One of the important solubilizers found in the body is glucuronic acid. Substances bound to this solubilizer are usually excreted either into the urine or into the small intestine, depending upon the nature of the substance.
How piperine increases the bioavailability of many substances
Piperine has the remarkable ability to manipulate all four of these mechanisms. It inhibits a number of enzymes responsible for metabolizing drugs and nutritional substances; it stimulates the activity of amino-acid transporters in the intestinal lining; it inhibits p-glycoprotein, the ‘pump’ protein that removes substances from cells; and it decreases the intestinal production of glucuronic acid, thereby permitting more of the substances to enter the body in active form. Consequently, some of these substances are able to reach, enter, and remain within their target cells for longer periods of time than would otherwise be the case. Of course, this can be a mixed blessing — if one is using a drug for which the therapeutic level is not substantially lower than the toxic level, piperine supplementation might raise the bioavailability of the drug until its intracellular concentration exceeds the toxic threshold. On the other hand, piperine supplementation can sometimes turn a marginally effective therapeutic substance into a highly effective one simply by increasing its bioavailability and intracellular residency time. A good example of this latter phenomenon is the use of piperine to increase the bioavailability of curcumin, a supplement with broad activity against cancers, inflammation and infections. A 20 mg dose of piperine can increase curcumin’s bioavailability twentyfold.
Piperine may reduce bioavailability of some substances
While piperine’s most noted effect is to inhibit the metabolic enzymes that would otherwise deactivate many substances, it also has the ability to induce the body’s production of certain of these enzymes. The net effect in some cases would be to increase, rather than decrease, the rate at which certain substances get metabolized in the body, thereby decreasing their bioavailability. Furthermore, in cases where the metabolizing of a substance converts it into a more active (rather than less active) form — for example, a prodrug that gets converted into an active form in the body — piperine may increase the bioavailability of the original substance by slowing its conversion to its metabolite and thus decrease the amount of the active metabolite. In effect, piperine would be reducing the availability of the desired substance. Consequently, the activities of piperine are complex and cannot always be predicted in advance. Piperine users whose drug or supplement regimens employ numerous or unusual substances should be on the lookout for undesired side effects resulting from piperine’s alteration of the bioavailability of these other substances. Presumably most such side effects can be eliminated by adjusting the dosages of these other substances. On the other hand, most users simply rely on the fact that piperine has been consumed for thousands of years as a component of black pepper, apparently without causing significant problems.
Biovailabilities affected by piperine
As indicated above, it is not yet possible to predict on theoretical grounds the effects piperine will have on any chosen dietary substance or drug. However, some categories of substances have been directly tested and found to have increased bioavailability when consumed with piperine. Substances for which piperine has been directly shown to increase bioavailability. barbiturates, beta-carotene, coenzyme Q10 (CoQ10), curcumin (extract from turmeric), dapsone, ethambutol, isoniazid, nalorphine, phenytoin, propranolol, pyrazinamide, rifampicin, selenium (from selenomethionine), sulfadiazene, theophylline, vitamin B-6 (pyridoxine), glucose (absorption increased), amino acids (absorption increased).
A far larger list could be compiled of substances (including drugs and dietary substances) whose bioavailability is assumed to be altered by piperine due to the known effects of piperine on proteins that metabolize or transport these substances. Table 2 lists some of the drugs that fall into this category. It would be useful to have an analogous list for dietary substances, but in most cases the data do not exist.
Other actions of piperine Aside from its effects on bioavailability, piperine has a number of other actions in the body. (It is suspected, but not proven, that some of these actions result from piperine’s effects on the bioavailability of other substances.) These actions include:
* Increasing the brain’s production of beta-endorphins
* Pain relief * Increasing the brain’s production of serotonin
* Anticonvulsant, anti-epileptic action
* Increasing the adrenal glands’ production of epinephrine (adrenaline)
* Altering contractions in the upper and lower digestive tract
* Reducing the stomach’s production of acid (for about 1 hour)
* Decreasing ulceration of the stomach
* Increasing the pancreas’s production of digestive enzymes (amylase, lipase, trypsin and chymotrypsin) * Stimulating production of melanin
* Reducing inflammation due to irritation or allergy
* Relieving asthma symptoms These actions have been deduced from lab experiments, not clinical studies, and so the dosages required to achieve them are not known.