Piperine multiplies the strength of many supplements and drugs

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 â€” and yet even the well-designed studies often contradict each other. The field of dietary supplement research is thus a miasma of conflicting opinion.

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. In the U.S. piperine is sold under the trademark Bioperine®.

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. (See Table 1.)

Table 1. 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.

Table 2. Metabolizing enzymes inhibited or induced by piperine, and a few of the substances whose bioavailability is affected by these enzymes. Metabolizing Enzymes: CYP1A1, CYP1B1, CYP1B2, CYP2E1, CYP3A4 Drugs: acetaminophen, alfentanyl, amiodarone, amlodipine, astemizole, atorvastatin, barbiturates, benzodiazepines, buspirone, Cafergot, caffeine, carbamazepine, cerivastatin, chlorpheniramine, chlorzoxazone, cimetidine, ciprofloxacin, cisapride, clarithromycin, cocaine, codeine, cyclosporine, dapsone, dextromethorphan, diethyl-dithiocarbamate, diltiazem, disulfiram, efavirenz, enflurane, eplerenone, erythromycin, estradiol, ethanol, felodipine, fentanyl, finasteride, fluconazole, fluvoxamine, gestodene, Gleevec, glucocorticoids, haloperidol, halothane, hydrocortisone, indinavir, irinotecan, isoflurane, isoniazid, itraconazole, ketoconazole, LAAM, lercanidipine, lidocaine, lovastatin, methadone, methoxyflurane, mibefradil, mifepristone, modafinil, nefazodone, nelfinavir, nevirapine, nifedipine, nisoldipine, nitrendipine, norfloxacin, norfluoxetine, odanestron, phenobarbital, phenytoin, pimozide, pioglitazone, progesterone, propranolol, quinidine, quinine, rifabutin, rifampin, ritonavir, salmeterol, saquinavir, sevoflurane, sildenafil (Viagra), simvastatin, sirolimus, St. John’s wort, tamoxifen, taxol, terfenadine, testosterone, theophylline, trazodone, troglitazone, verapamil, vincristine, zaleplon, zolpidem

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.

Piperine and HIV

As mentioned above, the cells in some tissues have ‘pump’ proteins that expel substances from cells. One such protein is p-glycoprotein (Pgp) which is active in the intestines, where it prevents substances from being absorbed into the blood. Pgp is active against many drugs, among them most or all of the HIV protease inhibitors currently in use. Pgp activity in the intestines lowers the bioavailability of the protease inhibitors, and Pgp activity in other tissues lowers the effectiveness of the drug molecules that do manage to enter the body because it decreases the residence time of the drugs in the cells where they are needed.

Logic says that the effectiveness of HIV protease inhibitors would be increased if they were used in combination with inhibitors of Pgp. Indeed, this concept is supported by experiments with various Pgp inhibitors. In fact, Pgp inhibition has been shown to reduce HIV viral replication. Piperine itself has not been studied, but there is no reason to think that it would not behave similarly.

Certain other HIV drugs can cause an increase in the body’s production of P-glycoprotein, even though they are not themselves transported by Pgp. Nevirapine, for example, induces the production of Pgp which in turn interferes with the action of other drugs, such as the protease inhibitors. Here again, a Pgp inhibitor seems to be called for.

Piperine and Viagra

The drug sildenafil (Viagra®) is metabolized mainly by the enzyme CYP3A4, which is found in many tissues, including the small intestine and the liver. Consequently, when one takes a dose of this drug, some of the dose is destroyed before it reaches the bloodstream, and more of it is destroyed in the liver before it reaches the rest of the body. About 40% of the sildenafil successfully reaches the general circulation. Once there, half of it gets metabolized every 4 hours during passes through the liver and other tissues. Thus, out of a 100 mg dose, about 20 mg remains in circulation after 4 hours.

Piperine, as indicated above, is an inhibitor of the CYP3A4 enzyme. If a dose of piperine is taken shortly before a dose of sildenafil, the sildenafil will not have to ‘run the gauntlet’ of CYP3A4 metabolism on its way to the bloodstream. This will boost the efficiency of a dose of sildenafil – potentially by as much as a factor of 2.5. This means that a 100 mg dose taken with piperine could be equivalent to a 250 mg dose taken without it – a dose likely to produce unpleasant side effects at the very least. Piperine will also prolong the action of sildenafil, probably by about two hours, which is how long the inhibition of CYP3A4 lasts in the liver.

The gist of this discussion is that if you’re using piperine with Viagra, cut those Viagra pills in half for safety’s sake. And save some money in the process – Viagra is expensive!

Dosage

The usual recommended dose of piperine is 5-15 mg/day. It is absorbed quickly and well from the digestive tract. Effects on absorption of other substances begin around 15 minutes after dosing and last for an hour or two. Blood levels peak about 1-2 hours after dosing but effects on metabolic enzymes can last much longer – from one to many hours, depending upon the enzyme type.

Piperine dosing should therefore be coordinated with the dosing of the substances whose bioavailability one wants to enhance, since too long an interval between the piperine dose and the dose of another substance may result in the piperine effects having disappeared during the interim. Although this effect depends on which enzymes are responsible for metabolizing the substance in question, one may not know which enzymes these are or how long they are affected by piperine. The most reliable method for ensuring piperine’s effectiveness is to take a piperine dose about half an hour before taking the substance whose bioavailability one wants to enhance.

Theoretically, using piperine on a daily basis can put the body in a continuous state of altered metabolism for certain substances. (Since this phenomenon has received little research attention, the substances in question, if there are any, are unknown.) In this state, the body would produce higher-than-usual levels of metabolic enzymes that, on the one hand, deactivate toxic substances, and on the other, reduce the effectiveness of certain drugs one may be using. One would therefore be more resistant to some toxic pollutants, but might need to increase the dosage of certain medications.

In conclusion

Piperine is one of those delightful surprises that occasionally come to light in spite of there being no reason to expect them to exist at all. How remarkable that pepper plants should produce a substance that turns out to be so useful and versatile! Certainly the pepper plants didn’t invent piperine in order to please human beings â€” they have undoubtedly been producing this substance since long before human beings existed, and for reasons that we can only guess at. The fact that it is a bioavailability enhancer for our drugs and supplements seems to be a lucky coincidence.

We are also lucky that piperine is made by plants. If it were a purely man-made chemical our access to it would have been blocked by government bureaucrats, who would have run the development costs up so high that no company would have found it worthwhile to develop it as a product. We can only hope that there are lots more such substances waiting to be discovered in the biological world, and that we can continue to foil attempts by government agencies to strip away our rights to use them.