Article Type : Research Article
Authors : Venkatesh S
Keywords : Natural bio enhancers; Bioavailability; Piperine; Naringin
Nowadays
herbs are increasingly being used worldwide as therapeutic agents or in
collaboration with minerals and vitamins in health supplements, teas etc. There
are many advantages of herbalism over modern or conventional medicine such as
the herbal/traditional systems of medicine causes lesser side effects than
modern medicine; herbal medicine along with lifestyle modification enhances its
potency by assisting and boosting the inborn self-healing mechanisms of the
patient. Thus, the chronic disorder is not only cured but the possibilities of
its recurrence are highly reduced. However, despite having great in-vitro
potential, herbs or herbal extracts have demonstrated very less in-vivo
activity due to insufficient lipid solubility and irregular molecular size.
Thus, this led to poor absorption and poor bioavailability. With the
advancement in science and technology, several trials are undergone to enhance
the bioavailability of drugs via novel drug delivery systems such as
microspheres, nanoparticles, liposomes, transferases, lipid-based systems, etc.
Besides these novel approaches, there are certain compounds that exist in
nature that are found to exhibit enhanced bioavailability rate such as
piperine, curcumin, naringin, quercetin, genistein, etc. The objective of this
review is to throw light on bioavailability enhancing effects of these natural
bio enhancers of herbal origin, their characteristic features and mechanisms of
action.
The utilization of plants for the medicinal objectives
is from time immemorial. India is one amongst the many ancient civilisations
which is famous for its rich heritage and also considered an abundant
repository of plants used for therapeutic purposes. About 80 per cent of the
population in the world still rely and use the plant-based medicines. About 25%
of the drugs used in pharmacopoeias belong to plant origin. Medicinal plants
are a major contribution towards traditional or alternative systems of
medicines. The application of herbal plants for medicinal purposes is since
pre-historic period. In the last century, studies on pharmacological and
chemical aspects of plant extracts are carried out to learn about their chemical
composition and to validate the manifestations of traditional medicine [1].
Although the pharmacological and phytochemical studies have been accepted for
the compositions, therapeutics and other health benefits of plant and plant
products, there is a necessity for the bioavailability enhancement of the most
of plants extracts and herbal drugs which have very less lipid solubility and
are hence less bioavailable [2]. Nowadays many herbs or herbal extracts have
good potential in in vitro but they are not successful as they fail to exhibit
significant in vivo activity due to poor absorption and bioavailability because of irregular molecular
size or poor lipid solubility [3].
Therefore,
to sum up most of the synthetic and herbal drugs have the disadvantage of low
bioavailability. The factors that contribute to low bioavailability are
decreased membrane permeability which is the major cause, lower lipophilicity,
ionic properties, poor water solubility or P-glycoprotein. When drugs are
administered via intravenous route of administration, the highest rate of
bioavailability is attained. On the other hand, the drugs that are administered
via oral route of administration are poorly bioavailable due to incomplete
absorption and first pass metabolism. Such unutilised fraction of the drug in
the body causes adverse effects and also drug resistance. Therefore, there is a
necessity of molecules which by themselves have no same therapeutic activity
but when given in combination of other drugs/molecules increase their bioavailability.
Mother Nature has provided several compounds from plant sources which when
co-administered with other drug have the capacity to increase the
bioavailability. Thus, bioenhancers are the chemical entities which boosts and
promotes the bioavailability of the drugs when administered concomitantly and
do not exhibit synergism [4,5]. “The phenomenon of total availability
increasing of any chemical entity in systematic circulation is called as
bioenhancement or biopotentionation and the secondary agents which causes this
augmentation of plasma concentration of principle ingredient are termed as
Biopotentiers or Bioavailability Enhancers [6]. The concept of bioavailability
enhancers is acquired from the traditional 5000-year-old Alternative System of Ayurvedic
Medicine. An Ayurvedic preparation, “Trikatu”, has been popularly used between
the period 700 BC and 600 AD. The term, “Trikatu” is a Sanskrit word which
means three acrids. The term refers to amalgamation of three herbal
ingredients, viz., Piper nigrum Linn.
(Black pepper), Piper longum Linn.
(Long pepper), and Zingiber officianale Rosc.
(Ginger). This preparation contains active principle piperine, which is
responsible for the enhancement of the bioavailability of drugs, and other
substances like vitamins and nutrients [7,8]. In 1929, the activity of
bioenhancers was first reported by Bose who illustrated that the action of Piper longum increased the
anti-histaminic properties of Adhatoda vasika leaves. The Scientists of India
at the Regional Research Laboratory, Jammu (RRL, now recognised as the Indian
Institute of Integrative Medicine) first coined the term, “Bioavailability
Enhancer” and in 1979, also discovered piperine and scientifically approved it
as the first bioavailability enhancer in the world [7].
Bio enhancers should have the following characteristic
features [9].
·
Should be non-toxic,
non-allergenic and non-irritating.
·
Should not exhibit its
own pharmacological effects.
·
Should be fast-acting
·
Should exhibit
reproducible and predictable activity.
·
Should be one-directional
in action.
·
Should be compatible with
the active pharmaceutical ingredient (APIs).
·
Should be stability with
time and environment.
·
Should be easily
formulated into different forms of dosage.
·
Should be easily
available.
·
Should be cost effective.
Drug
absorption barriers
For the drug to exhibit its biological action, it is
essential to cross the barrier of the intestinal mucosa made of epithelial
cells so that it can be delivered into the systemic circulation from the lumen
of the gut. The epithelial membrane has many barriers in terms of its anatomy
and physiology, hence, the drugs intended for the purpose of oral
administration must be able to pass through it [10,11]. The epithelial layer of
the intestine is composed of many structures that cause hindrance to the drug
transport from the lumen of gastrointestinal tract to the systemic circulation.
The potential obstacle to the mechanism of drug absorption is an aqueous
stationary layer overlying the apical membrane on account of its hydrophilic
nature. Besides these, the apical and basolateral membranes having less
permeability also act as possible barriers to the drug absorption. The cell
membranes are lipid-bilayers composed of proteins such as receptors and carrier
molecules. Drugs penetrate the cell membrane by means of passive diffusion or
carrier-mediated transport involving the dissipation of the energy. There are
aqueous channels within the protein molecules for the purpose of transport
of small water-soluble molecules like ethanol. The drug molecules which are
larger in size than 0.4nm cannot pass through these aqueous channels[11].
Mechanism
of action of bioenhancers
The principal mechanisms by which bioenhancers exert
their bioavailability enhancing property on the drugs are as follows:
· By increasing the supply
of blood which enhances the oral drug absorption from gastro-intestinal tract.
· By regulation of the
carrier molecules involved in the active transport mechanism. E.g. P-glycoprotein
(P-gp) which is an ATP-dependent efflux pump that pumps foreign substances and
drugs out of cells and block them from reaching the site of action. Thus, here
the bioenhancers exert their action by inhibition of the P-gp.
· By decreasing the
elimination time of drug, thus, increasing the residence time of drug in the
body.
· Inhibition of the enzymes
responsible for drug metabolism which include CYP 3A4, CYP 1A1, CYP 1B2,
CYP2E1, in the liver, gut, lungs and other parts of the body which also assist
in controlling the first pass metabolism of orally administered drugs.
· Inhibition of the renal
clearance by hindering glomerular filtration, active tubular secretion and
assisting passive tubular reabsorption.
Besides the above-mentioned mechanisms, the other
hypotheses for the action of bioenhancers include the following:
· Decrease in the secretion
of Hydrochloric Acid and increase in gastro-intestinal blood supply.
· Inhibition of GI transit,
gastric emptying time and intestinal motility.
· Regulation in
permeability of epithelial cell membrane of GI tract.
· Cholagogoue effect.
· Bioenergetics and
thermogenic properties.
· Prevention of first pass
metabolism and inhibition of drug metabolising enzymes.
· Activation of gamma
glutamyl trans peptidase (GGT) activity that promotes the
consumption of amino acids [12].
Bio enhancers can be
broadly classified based on their nature of origin and also based on their
mechanism of action as follows.
Classification of bio enhancers based on origin
Plant Origin: Piperine,
Curcumin, Naringin, Quercetin, Niaziridin, Carum carvi, Capsaicin, Cuminum
cyminum, Stevia, Lysergol, Glycyrrihizin, Ginger, Allicin, Aloe vera,
Simomenine, Genistein, Peppermint oil, Gallic acid, Ellagic acid, Ferulic acid,
5-hydroxy hydnocarpin, Ammannia multiflora.
Animal origin: Cow
urine distillate
Classification of Bio enhancers based on
mechanism of action
Inhibition of P-gp and other efflux pumps: e.g.
Carum carvi (Caraway), Genistein, Sinomenine, Cuminum cyminum
(Black cumin), Naringin, Quercetin.
Suppression of CYP-450 enzyme and its isoenzymes: e.g.
Piperine, Naringin, Gallic acid and its esters, Quercetin.
Modulators of GI tract function to enhance absorption:
e.g. Aloe vera (Aloe), Niaziridin
(Drumstick pods), Zingiber officinale (Ginger), Glycyrrhizin (Liquorice)
[13-15].
Inhibition of P-gp
The objective of the inhibition of efflux pump is to
enhance the transport of drugs. Generally, inhibition of P-gp occurs by three
different mechanisms:
Classification of P-gp inhibitors
P-gp inhibitors based on their specificity, affinity,
and toxicity are classified into three generations.
First generation inhibitors
They are non-selective and have low binding
affinities.
Examples: Reserpine, verapamil, quinidine, cyclosporin
A, tamoxifen, yohimbine, and toremifene. First generation inhibitors are
pharmacologically active. They are therapeutically employed for specific type
of treatments but can also inhibit P-gp. Their use is limited on account of
their high serum concentrations [24]. They also act as substrates to other
transporters and enzyme systems that lead to pharmacokinetic interactions.
Second generation inhibitors
They exhibit higher specificity than first generation
inhibitors but have the disadvantage of interaction with other systems.
Examples: Dexniguldipine, dexverapamil, valspodar (PSC 833), and Dofequidar
fumarate (MS-209)
Second generation inhibitors do not exhibit
pharmacological actions but have higher P-gp affinity. They cause inhibition of
the CYPA4 enzyme and other ABC transporters. Hence, metabolizing rate decreases
and inhibition of two or more ABC transporters resulting in complicated
pharmacokinetic interactions.
Third generation inhibitors
They exhibit highest specificity as they specifically
and efficiently inhibit P-gp efflux.
Examples:
Cyclopropyldibenzo suberane zosuquidar (LY335979), laniquidar (r101933),
mitotane (NSC-38721), biricodar (vX-710), elacridar (GF120918/GG918), ONT-093,
tariquidar (Xr9576), and hM30181
Third generation P-gp inhibitors are under clinical
development phase with the objective to inhibit P-gp with higher specificity
and lower toxicity. They are established using structure activity relationships
(SARs). Most of them were known to be very specific and potent against P-gp
with minimal toxicity [25,26].
Suppression of CYP 450 enzyme and its
isoenzymes
Herbal medicines are polyherbal formulations which
consist of combination of biologically active compounds. The metabolism of
these compounds may take place with the similar mechanism of the administered
drug, thereby leading to interaction and eventually inhibition/increase of free
drug metabolizing enzymes or transporters. The alteration in the expression of
these proteins, or physical/chemical/pharmacological competition, eventually
effects the free drug/metabolite concentration and the pharmacokinetic
parameters resulting in the altered pharmacological effects. Many herbs were
found to interact with the cytochrome P450, the major microsomal enzyme for
drug metabolism/detoxi?cation, which has high polymorphisms in both human and
companion animals. As the enzymes CYP and UDPs are essential for phase I
metabolism of several substances such as drugs, nutrients, endogenous
substances, and environmental toxins, the regulation of their expression
contributes a great deal in the efficacy of the therapy or the progress of the
toxicity [27,28].
Inhibition will
result in lesser drug molecules to be metabolized with an increased
concentration of unchanged drug passing from gastro-intestinal tract into the
systemic circulation. The important isoenzymes of CYPs which are responsible
for the metabolism of drugs in humans are CYP3A4, 2D6 and 2C9 family.
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