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:
- Either competitive,
non-competitive or allosteric inhibition of binding site of the drugs;
- Interference with
hydrolysis of ATP; and
- Modification of the
integrity of the lipids in the cell membrane [16-23].
Classification of P-gp inhibitors
P-gp inhibitors based on their specificity, affinity,
and toxicity are classified into three generations.
- First Generation
Inhibitors
- Second Generation
Inhibitors
- Third Generation
Inhibitors
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.