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by Aftab J. Ahmed, Ph.D.
NUTRACEUTICALS
Absorption and Bioavailability
The challenge common to both
pharmaceuticals and nutraceuticals
is the maximal absorption of
a therapeutic/corrective agent
and its optimal availability in the
bloodstream upon oral intake. The unspoken
assumption is that the bulk of an orallyadministered
agent is absorbed efficiently over
the gastrointestinal (GI) tract and becomes
bioavailable in the requisite amounts, preferably
in the targeted tissue, to exert its therapeutic
effects. While that is true by and large in the
case of pharmaceuticals, thanks primarily to
extensive research in their development, it is
not always a given insofar as nutraceuticals
and nutritional supplements (henceforth
referred to as corrective agents) are concerned.
Nutraceuticals have begun to be studied only of
late, albeit in a circumscribed manner, and
many questions must be addressed regarding
their absorption, bioavailability and indeed, in
some instances their beneficial effects. This
communication elaborates, in general terms,
concepts underlying absorption and factors that
contribute to increased availability of corrective
agents.
Therapeutic and corrective agents are dispensed
by a variety of routes, including oral,
buccal, sublingual, parenteral, topical and
among others, inhalation. The properties of
such agents, their formulation and the route of
administration play a critical role in absorption.
A prerequisite to absorption over the gastrointestinal
(GI) tract is that an agent be able to enter
into a solution. Therefore a solid formulation in
the form of a tablet must first disintegrate and
disaggregate and its active ingredients must
undergo dissolution before it can be absorbed.
The active ingredient, then, must cross several
semi-permeable cell membranes before reaching
the general circulation. After the so-called firstpass
metabolism in the liver, the active principle
reaches systemic circulation. Finally it is targeted
to various tissues and organs in the body
where it exerts its beneficial effects and is finally
cleared, either by renal or biliary excretion. This
sequence of events is generally codified as the
ADME canon in pharmacology of a drug or
nutrient. That is, a corrective agent must first be
absorbed (A), then distributed (D) systemically,
metabolized (M) in and eventually eliminated
(E) from the body. Thus, oral intake of a
corrective agent is a far more complex process
than is normally appreciated. Any one of these
steps can become a bottleneck, which could
pose serious health issues. To give but one
example, when a drug is absorbed too quickly, it
may become toxic. In general, drug
administration is not unlike chemical
warfare in the body, albeit with the
explicit purpose of restoring biological
harmony intact. Increasingly, that
appears to be the implicit objective of
nutritional therapy as well.
Nutraceuticals have assumed center
stage not only in preventive but also
in corrective health care for a vast
majority of Americans and indeed,
populations worldwide. There is a
tendency to presume that a nutritional
supplement will be absorbed and
circulate in the blood quite like the
nutrients harnessed from breakdown
of ingested foods. Numerous instances
poignantly demonstrate that such is
not necessarily the case, for efficient
uptake of a nutraceutical depends both
on amounts and mode of its formulation. In
multi-component nutritional supplements, the
formulation is of central importance, as disintegration
of the tablet and disaggregation of
individual components determine the amounts
of each nutrient absorbed.
Insofar as the effect of formulation on
absorption is concerned, the example of chondroitin
and glucosamine sulfates would be in
order. Together chondroitin sulfate (CS) and
glucosamine sulfate (GS) help reverse damage to
the deteriorating joints due to the ability of GS
to stimulate the synthesis of glycosaminoglycans
and hyaluronic acid backbone for fresh cartilage
formation.1 Any formulation containing CS
and GS must therefore not only disintegrate
promptly but also disaggregate the actives sufficiently in order for them to function in
concert with each other. Even though such
considerations are not given due weight, the
absorption, and in the end effectiveness, of a
multi-component nutritional supplement
depends on how it is formulated.2
Broader availability and in fact popularity of
corrective agents has given rise to an urban
legend that the so-called “mega doses” of nutritional
supplements are either more effective or pack greater punch to deliver amplified health
benefits. That is at best an oversimplification. To
begin with, it is not always that large amounts of
a given nutrient would be efficiently absorbed.
Even if it is absorbed in reasonably large
amounts, it will be more often than not
degraded in the liver by first-pass metabolism.
Any orally ingested corrective agent has a doseresponse
profile. That is, as the dose
of a corrective agent is increased, so does the
amplitude or extent of its effectiveness—up to a
point. If sufficient amounts are absorbed, a saturation
effect ensues, with the result that the
effectiveness plateaus off. Once this plateau is
reached, the amounts ingested have no effect on
therapeutic outcome. This underscores an
entirely relevant premise in therapy that whereas small amounts of a corrective will not be beneficial,
larger amounts are equally ineffective. This
was yet again corroborated recently in
the case of CoQ10 Whereas small doses are ineffective,
in larger amounts it actually increases
the oxidative load, which decreases life span in
earthworms.3 That is, over-consumption of
corrective agents may be, in fact, quite harmful.
An evocative example of that is provided by
the amino acid arginine. Arginine has become
quite a market dynamo by virtue of its ability to
induce the neurotransmitter nitric oxide (NO).
A myriad of beneficial effects have been attributed
to (NO), including its ability to promote
blood circulation and to act as a growth hormone
(GH) inducer. In order for arginine to be
beneficial, however, it must be ingested in rather
substantial amounts. Intake of amino acids in
large amounts is inefficient, because amino
acids compete fiercely with each other for the
same generic transporters along the intestinal
wall for uptake into the bloodstream. Adequate
amounts of amino acids from foods do get
absorbed. That is precisely the reason that ingestion
of amino acids as a corrective modality is
recommended on a relatively empty stomach.
Irrespective of that, if an amino acid does enter
circulation in large enough amounts, it can
overwhelm the first-pass metabolism and is
therefore promptly degraded to circumvent the
potential for liver toxicity. That in fact, is the
fate of large amounts of orally ingested arginine.
Upon entering hepatic circulation, most of arginine is degraded.4
More important, however,
are the findings that citrulline,
a specialized
amino acid found in the
body and a precursor of
arginine, is a better source
for plasma arginine.
Inasmuch as citrulline
increases plasma arginine
by as much as 30 percent
in healthy individuals, it
does so in a much smaller
dose.5
This demonstrates that
availability of plasma arginine
is significantly higher
with citrulline, if equivalent
doses of arginine and
citrulline are taken.
Parenthetically, another
advantage of citrulline as
an alternative to arginine
is that citrulline and arginine
cycle upon each
other. That is, if orally
ingested citrulline produces more arginine than
is metabolically warranted, arginine is cycled
back to citrulline, which is then stored until its
mobilization becomes necessary again. As such,
citrulline serves as a depot for arginine and, in
turn, nitric oxide.
These examples illustrate that efficient
absorption and bioavailability is less a role of
dice and more a well considered balance among
various factors, including the properties of
active ingredients and contemplated therapeutic
outcome. In addition, since the human body is
not a passive recipient of corrective agents, how
it affects the dispensed dosages must also be
taken into consideration. For example, body
weight is a critical factor in determining the
effective dosage. On the other hand, age per se
does not justify excessive intake of supplemental
nutrients. Occasionally, excessive intake in
advanced age is rationalized by alluding to
malabsorption syndrome(s). That however, begs
the question. If absorption is compromised to
begin with, excessive amounts to replenish a
deficiency are unlikely to alleviate it and in fact,
may be counter-productive. Absent of frank
clinical malabsorption, any nutrient deficiency
as a result of decreased absorption is best offset
by analyzing the properties of given nutrients.
Accordingly, with advancing years, when the
ratio of fat to lean tissue increases, adjusted
dosages of fat-soluble vitamins/correctives
might be the only variable to consider, as
fat-soluble substances tend to be deposited more readily in the fatty tissue. These considerations
underscore the complexity of absorption of
nutrients and their bioavailability and, to an
extent, explain the r aft of reports of late that show
adverse interactions not only of various herbs but
also between herbs and pharmaceuticals.
Mass media give considerable coverage to
adverse drug events and justifiably so, as
between 75,000 and 135,000 hospitalized
patients suffer fatal drug interactions.6 With the
increase in self-medication with nutraceuticals,
and concomitant use of prescription drugs, in
some cases without the knowledge of the primary
healthcare providers, preventive regimens
are coming under increasing scrutiny as well.
Adverse events are at least partially due to either
increased or decreased absorption of various
nutrients and herbal formulations. In an ideal
world, intake of nutrients would be as straightforward
as ingesting a meal. The incontrovertible
fact, however, is that even the nutrients
derived from foodstuffs go through a complex
cascade of events in order for the nutrients to
become bioavailable. In a sense, absorption can
be likened to the Russian doll, in which each
doll contains a smaller one inside. In other
words, each of the steps is dependent upon
another step and yet another in the absorption
process. That does not mean, however, that
intake of nutrients should become a game of
roulette. After all, the express purpose of preventive
regimens is to promote health and
well-being in a progressively aging population.
As the industry matures, though, deliberate
approaches to the manufacture and dispensation
of nutraceuticals is expected to be more
the norm.
Aftab J. Ahmed, Ph.D., is the COO of Bio-Aging Inc., Phoenix, Arizona.
E-mail:
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Selected References
- Reginster, J., Deroisy, R., Rovati, L., Lee, R., Lejeune, E., Bruyere, O., Giacovelli, G., Henrotin, Y., Dacre, J. And Gossett, C. “Long-Term Effects Of Glucosamine Sulphate On Osteoarthritis Progression: A Randomized, Placebo-Controlled Clinical Trial.” The Lancet: 357, 251, 2001.
- Vaithiyalingam, S., Agarwal, V., Reddy, I., Ashraf, M And Khan, M. “Formulation Development And Stability Evaluation Of A Multi-Component Nutritional Supplement.” Pharm. Tech.: 25, 38, 2001.
- Anonymous, “Coenzyme Q Shortens Life Span Of Worms Substantially.” www.Sciencedaily.com/Releases/2002/01/020108075801.Htm
- Featherson, W., Rogers, Q. and Freedland, R. “Relative Importance of Kidney and Liver in the Synthesis of Arginine by the Rat.” Am. J. Physiol.: 224, 127, 1973.
- Windmueller, H. and Spaeth, A. “Source and Fate of Circulating Citrulline.” ibid., 241, E473, 1981.
- 6. Lazarou, J., Pomeranz, B. and Corey, P. “Incidence of Adverse Drug Interactions in Hospitalized Patients.” J. Am. Med. Assoc.: 279, 1200, 1998.
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