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Piperine multiplies the strength of many

supplements and drugs
by Russell Mills

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. 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
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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.

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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 isoniazid selenium (from selenomethionine)
beta-carotene nalorphine sulfadiazene
coenzyme Q10 (CoQ10) phenytoin theophylline
curcumin (extract from turmeric) propranolol vitamin B-6 (pyridoxine)
dapsone pyrazinamide glucose (absorption increased)
ethambutol rifampicin 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
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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 point 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.
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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 — 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.

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