Since the early 1980s there has been a tremendous increase in the
use and appreciation of herbal medicine in North America. I have
termed this process the Herbal Renaissance. The key fuel for this
increased popularity of herbal medicine has been scientific research.
During the last 20 to 30 years there has been a virtual explosion
of scientific information concerning the medicinal use of plants.
Through science we now have a better understanding of how a particular
herb might work to promote health. We also now know how to grow
a plant for highest medicinal effect, when to harvest it and how
to concentrate the medicinal components in extracts.
One area of herbal medicine that is still in its relative infancy
is the field of pharmacokinetics - the study of the absorption of
compounds by the body and their biotransformation, distribution,
metabolism, and elimination from the body. The same scientific methods
used to determine the pharmacokinetics of drugs have been applied
to some of the more popular herbal medicines as well as other natural
products.
Pharmacokinetic studies can provide the answer as to what is the
best delivery vehicle for a substance. For example, some compounds
need to be protected from the harsh secretions of the stomach by
incorporating them into specially coated capsules or tablets that
can withstand gastric acids while other compounds may be required
to be administered in a soft-gelatin capsule with other lipid (fatty)
substances for maximum absorption.
The alpha-lipoic acid example
One of my favorite examples in pharmacokinetics is immediate-release
alpha-lipoic acid vs. timed-release alpha-lipoic acid. Alpha-lipoic
acid is a vitamin-like substance that is often described as “nature’s
perfect antioxidant.” The primary clinical use of alpha-lipoic
acid has been for the treatment of diabetic neuropathy. In fact,
it has been successfully used in Germany for over thirty years as
an approved drug for this condition. Detailed absorption studies
have shown that immediate-release alpha-lipoic acid is quickly absorbed
with dosage proportionality – meaning that roughly the same
percentage is absorbed whether the dosage is 50 or 600 mg with about
30% of the actual dosage getting into the bloodstream before it
is broken down by the liver.1
While we know a great deal about how immediate-release alpha-lipoic
acid is handled by the body and its clinical effectiveness, there
has been only one study with a timed released preparation –
it was a pharmacokinetic study that concluded that the timed-released
formula was associated with an approximately 40% reduction in overall
bioavailability compared to the immediate-release product.2
While the timed-release product was absorbed more slowly over time,
it did not produce as high of peak value as the immediate release
nor was the area under the curve (AUC) as high as the immediate
release. The AUC is often used to show the total absorption of compound
over time. In this case, the AUC for the immediate release alpha-lipoic
acid was 4,466 ng/ml compared to 2,621 ng/ml. Based upon the clinical
research over the last 30 years and the pharmacokinetics of immediate-release
alpha-lipoic acid, it appears to be obviously superior to the timed-release
product.
I like this example because it suggests that the key to the effectiveness
of immediate-release alpha-lipoic acid may be in achieving higher
peak values vs. trying to achieve a steady state in the blood.
Steady state vs. high peaks
For many drugs, nutrients, and herbs the idea has been that multiple
dosing or utilizing pharmaceutical technology to produce timed-released
absorption for a more steady state in blood levels was the best
way to go. However, many drugs that were once given in multiple
doses throughout the day are now being given once a day, once a
week, or even once a month dosages. Why? Well the easy answer to
this question is that clinical results or pharmacokinetic studies
have indicated that the compound was absorbed, distributed, and
eliminated in such a manner that multiple dosing was simply not
necessary.
Let me offer a couple examples of popular drugs that require a
steady state or constant blood level in order to produce their benefit:
lithium, digitalis (digoxin), and anti-seizure medications like
Dilantin. Many chemotherapy drugs also require a constant blood
level.
In contrast to these sorts of agents, some compounds work better
therapeutically if there is a rapid rise in blood levels. The reason
has everything to do with one of two processes: diffusion and active
transport. Diffusion refers to the transfer of molecules from an
area of high concentration to an area of low concentration. There
are many factors that determine the diffusion rate of a substance
across cell membranes, but from a simplistic view it is much easier
if the concentration on one side of the cell is substantially larger
than the other.
Diffusion, however, is not the only way molecules enter the cells.
Cells are also equipped with transport mechanisms to actively carry
molecules across the cell membranes. Again, it is often easier for
these transport sites to do their jobs when there is an increased
concentration in the external environment of the compounding needing
to be transported. The point I am trying to make here is that by
rapidly raising the concentration in the blood with some compounds,
it makes it easier for these molecules to get into the cells where
they produce their beneficial effects.
It may eventually turn out that even better results will be obtained
with single daily dosage compared to multiple doses with some herbs
just like what has been observed with some drugs and natural products.
Here is something to think about; in a study in beagle dogs repeated
oral administration of the main polyphenols found in green tea (epigallocatechin
gallate or EGCG) during the day resulted in significantly lower
blood levels compared to the concentration following a single dose.3
In a human study, single daily dosages of EGCG were shown to produce
a >60% increase in blood EGCG values over a 4-week period compared
to the same dosage given as a twice daily dose.4
The researchers concluded that the twice daily dosage “did
not result in significant changes in the AUC (area under the curve)
of free EGCG.” The reason seems to be the fact that absorption
of EGCG is mediated by a transporter in the intestinal tract.5
Again, an immediate higher concentration of a substance makes it
easier for some transporters to do their job. These results indicate
that the benefits of green tea extract may best be achieved if a
larger single dose is given all at once rather than being split
into multiple doses.
The problem with generalizations
Generalizations about what is the best form, delivery vehicle,
or dosage protocol for herbal medicines are even more inaccurate
than those made about single ingredient drugs or natural products.
Let me give you an example of what I am referring to with a common
generalization that I have heard about the timing of taking herbal
products. I have heard it said that it is best to take herbal medicines
on an empty stomach away from foods. While that is certainly true
for some herbal products, it is not true for many others. It is
simply too general of a statement that does not hold up.
I want to be clear here that I am not making a generalization here
that all herbal products are best taken in single daily dosages.
The point that I am trying to make is that for some herbal products
it appears to be the best route. The answer to the question about
the best form, delivery vehicle, or dosage protocol must be based
upon the existing scientific understanding. Hopefully, part of that
includes results from clinical and/or pharmacokinetic studies.
Single, daily dosage herbal products
Recently, Natural Factors launched a several herbal products with
an “All You Need is One” label. These products include
CranMax®, Saw Palmetto Extract, Black Cohosh Extract, L-theanine,
Rhodiola Extract, and Green Tea Extract. These natural compounds
were selected based upon the scientific understanding of the pharmacokinetics
or clinical response indicating single daily dosages are at least
equally effective as multiple dosages during the day, or as given
above with the EGCG example perhaps even more effective.
To illustrate this point further, let’s take a look at saw
palmetto extract, perhaps the botanical medicine with the greatest
acceptance and clinical documentation of effectiveness. Numerous
double-blind studies have shown the fat-soluble saw palmetto berry
extracts standardized to contain 85-95% fatty acids and sterols
can significantly improve the signs and symptoms of benign prostatic
hyperplasia (BPH). The typical dosage has been 160 mg twice daily,
however a one-year study demonstrated no difference in therapeutic
efficacy or safety comparing this dosage with a single dosage of
320 mg daily.6
Both dosage schedules produced significant improvements in signs
and symptoms of BPH.
A similar result was found with CranMax®, an all natural proprietary
product manufactured from the whole cranberry (not just the juice).
In the case of CranMax®, although it is a single daily dosage
it does utilize an exclusive delivery technology that allows the
product to be effectively time released over a 12-16 hour period
while also protecting the key active nutrients from the acidic environment
of the gut. It also is important to point out that CranMax®
is extremely concentrated – it takes 34 pounds of whole fresh
cranberries to produce one pound of Cran-Max®.
As well as being more beneficial, a single daily dosage recommendation
results is much more convenient.
Final Comment
The study of herbal medicine spans the breadth of the scientific
field of pharmacology: the study of the history, source, physical
and chemical properties, mechanisms of action, absorption, distribution,
biotransformation, excretion, interactions, and therapeutic uses
of “drugs”. In many respects, the pharmacological investigation
of herbal medicine is just beginning. It is an exciting time.
Key References:
- Teichert J, Kern J, Tritschler
HJ, Ulrich H, Preiss R. Investigations on the pharmacokinetics of
alpha-lipoic acid in healthy volunteers. Int J Clin Pharmacol Ther
1998;36(12):625-8
- Evans JL, Heymann CJ, Goldfine ID, Gavin LA. Pharmacokinetics,
tolerability, and fructosamine-lowering effect of a novel, controlled-release
formulation of alpha-lipoic acid. Endocr Pract 2002;8(1):29-35.
- Swezey RR, Aldridge DE, LeValley SE, et al. Absorption, tissue
distribution and elimination of 4-[(3)h]-epigallocatechin gallate
in beagle dogs. Int J Toxicol 2003;22(3):187-93.
- Chow HH, Cai Y, Hakim IA, Crowell JA, et al. Pharmacokinetics
and safety of green tea polyphenols after multiple-dose administration
of epigallocatechin gallate and polyphenon E in healthy individuals.
Clin Cancer Res. 2003;9(9):3312-9.
- Vaidyanathan JB, Walle T. Cellular uptake and efflux of the tea
flavonoid (-)epicatechin-3-gallate in the human intestinal cell
line Caco-2. J Pharmacol Exp Ther. 2003;307(2):745-52.
- Braeckman J, Bruhwyler J, Vandekerckhove K, et al. Efficacy and
safety of the extract of Serenoa repens in the treatment of benign
prostatic hyperplasia: therapeutic equivalence between twice and
once daily dosage forms. Phytotherapy Res 1997; 11: 558-563.
Michael T. Murray, N.D., is widely regarded as one of world's leading authorities on natural medicine. A prolific author, Dr. Murray has written over 20 books on health and nutrition including the best-selling Encyclopedia of Natural Medicine and his latest book The Encyclopedia of Healing Foods. Dr. Murray is also Director of Product Development and Education for Natural Factors one of the leading manufacturers of natural products.
