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Journal of Pharmacognosy and Phytochemistry 2013; 2 (3): 55-60 ISSN 2278-4136
Natural Bioenhancers: An overview
ISSN 2349-8234
JPP 2013; 2 (3): 55-60 Deepthi V. Tatiraju,* Varsha B. Bagade, Priya J. Karambelkar, Varsha M. Jadhav,
2013 AkiNik Publications Vilasrao Kadam
Received: 19-7-2013 Accepted: 09-8-2013 ABSTRACT
Bioenhancers are chemical entities which promote and augment the bioavailability of the drugs which are mixed with them and do not exhibit synergistic effect with the drug. The need for bioenhancers arises due to drugs which are poorly available, administered for long periods, toxic and expensive. Bioenhancers can be classified based on their natural origin as well as based on the various mechanisms elicited by them when in combination with drugs to improve their bioavailability. The various bioenhancers available are piperine, garlic, Carum carvi, Cuminum cyminum, lysergol, naringin, quercetin, niaziridin, glycyrrhizin, stevia, cow urine distillate ginger. Deepthi V.Tatiraju
Out of these, Cuminum cyminum and niaziridin are the potential bioenhancers of future. Therefore, Bharati Vidyapeeth's College of the need of the hour is to carry out extensive research on these bioenhancers so that they could be Pharmacy, C.B.D Belapur, Navi utilised in the drug formulations. Mumbai, Maharashtra, India. Keywords: Bioenhancers, Classification, Piperine, Cuminum cyminum.
Varsha B. Bagade
Bharati Vidyapeeth's College of 1. Introduction
Pharmacy, C.B.D Belapur, Navi Mumbai, Maharashtra, India. Plant based medicines are used by a majority of the world's population. Our Ayurvedic texts have a mention of thousands of herbal drugs for various diseases including the rare ones. Priya J.Karambelkar
Almost 25% of modern pharmacopoeias too contain drugs of plant origin [1].
Bharati Vidyapeeth's College of Many synthetic and herbal drugs suffer from the problem of low bioavailability. Bioavailability Pharmacy, C.B.D Belapur, Navi is the rate and extent to which a substance enters systemic circulation and becomes available at Mumbai, Maharashtra, India. the required site of action [2].
Varsha M.Jadhav
Maximum bioavailability is attained by drugs administered via intravenous route, whereas Bharati Vidyapeeth's College of drugs administered orally are poorly bioavailable as they readily undergo first pass metabolism Pharmacy, C.B.D Belapur, Navi and incomplete absorption. Such unutilized drug in the body may lead to adverse effects and Mumbai, Maharashtra, India. also drug resistance. Thus, there is need of molecules which themselves have no same
Vilasrao Kadam
therapeutic activity but when combined with other drugs/molecules enhance their Bharati Vidyapeeth's College of bioavailability. Many natural compounds from medicinal plants have capacity to augment the Pharmacy, C.B.D Belapur, Navi bioavailability when co-administered with another drug. Thus bioenhancers are chemical Mumbai, Maharashtra, India. entities which promote and augment the bioavailability of the drugs which are mixed with them and do not exhibit synergistic effect with the drug [3.4].
Bioenhancers should have novel properties such as: Nontoxic to humans or animals, Should be effective at a very low concentration in a combination, Should be easy to formulate, and Most importantly, enhance uptake/absorption and activity of the drug molecules [5].
Following the use of bioenhancers, the dose of the drug is reduced and risk of drug resistance is minimized. It also reduces the dose-dependent toxicity of the drug, especially of anticancer 1.1 Drug Absorption Barriers
The drug must cross the epithelial barrier of the intestinal mucosa for its transportation from Correspondence:
Deepthi V.Tatiraju
the lumen of the gut into the systemic circulation and exert its biological actions. There are Bharati Vidyapeeth's College of many anatomical and biological barriers for the oral drug delivery system to penetrate the Pharmacy, C.B.D Belapur, Navi epithelial membrane [6, 7]. There are many structures in the intestinal epithelium which act as
Mumbai, Maharashtra, India. barriers to the transfer of drugs from the gastrointestinal track to the systemic circulation. The Tel: +91-9766904351
membranes around cells are lipid bilayers containing proteins such as receptors and carrier E-Mail: [email protected]
Journal of Pharmacognosy and Phytochemistry Drugs cross the lipid membrane by passive diffusion or carrier- and intestinal motility, mediated transport which involves the spending of energy. For the Modifications in GIT epithelial cell membrane passage of small water-soluble molecules such as ethanol there are aqueous channels within the proteins. The drug molecules larger Cholagogoue effect, than about 0.4 nm face difficulty in passing through these aqueous Bioenergetics and thermogenic properties channels [6].
Suppression of first pass metabolism and inhibition of drug metabolizing enzymes and stimulation of gamma Drug efflux pumps like Pgp have been proven to have a very glutamyl transpeptidase (GGT) activity which enhances important role in inhibiting efficient drug entry into the systemic uptake of amino acids [11].
circulation [8]. P-gp is a type of ATPase and an energy dependent
transmembrane drug efflux pump it belongs to members of ABC 3. Hurdles with Bioenhancers
transporters. It has a molecular weight of -170 kDa and has 1280 Although bio-enhancers in drug delivery have been successful, not amino acid residues [9]. A lot of bioenhancers work by inhibiting
all approaches have met with the same success. this efflux pump. New bio-enhancers being developed come with challenges which have to be surmounted. One of the challenges is to improve on 2. Mechanism of Action of Bioenhancers
properties of drug formulations such as long circulation in the The following are the chief mechanisms via which the various blood, increased functional surface area, protection of incorporated bioenhancers exert their bioavailability enhancing properties on the drug from degradation, crossing of biological barriers and site- specific targeting. 1. By enhancing the absorption of orally administered drugs Another challenge of research and development of herbal from gastrointestinal tract by increase in blood supply. bioenhancers is large scale production. There is always a need to 2. By modulating the active transporters located in various scale up laboratory or pilot technologies for eventual locations eg. P-glycoprotein (P-gp) is an efflux pump commercialization. The challenges of scaling up include low which pumps out drugs and prevent it from reaching the concentration of nanomaterials, agglomeration and the chemistry target site. Bioenhancers in such case act by inhibiting the process; it is easier to modify nanomaterials at laboratory scale for improved performance than at large scale. 3. Decreasing the elimination process thereby extending the Advances in herbal bio-enhancers also provide new challenges for sojourn of drug in the body. regulatory control. There is an increasing need to have regulations a.) Inhibiting the drug metabolizing enzymes like CYP 3A4, that would account for physicochemical and pharmacokinetic CYP1A1, CYP1B2, CYP2E1, in the liver, gut, lungs, and various properties of nano drug products, which are different from other locations. This will in addition help to overcome the first pass conventional drug products [11].
effect administered drugs. b.) Inhibiting the renal clearance by preventing glomerular Classification of Bioenhancers
filtration, active tubular secretion by inhibiting P-gp and facilitating The use of bioenhancers is familiar concept in Ayurveda as passive tubular reabsorption. Sometimes biliary clearance is also ‘Yogavahi' which was used to enhance bioavailability, tissue affected by inhibiting the UDP glucuronyl transferase enzyme distribution and efficacy of drugs especially those with poor which conjugates and inactivates the drug [10].
availability. One such example is ‘trikatu' which is a mixture of Piper longum (long pepper), Piper nigrum (black pepper) and In addition to the above mentioned mechanisms, few other Zingiber officinale (ginger). postulated theories for herbal bioenhancers are: Bose, in 1929, first reported the application of bioenhancer long Reduction in hydrochloric acid secretion and increase in pepper to increase the antiasthmatic effect of vasaka [12,13].
gastrointestinal blood supply, Bioenhancers can be classified based on origin and mechanism of Inhibition of gastrointestinal transit, gastric emptying time action (Table 1 and 2). Table 1: Classification of Bioenhancers Based on Origin
Journal of Pharmacognosy and Phytochemistry Table 2: Classification of Bioenhancers Based on Mechanism of Action
A detailed description of some of the bioenhancers based on the fumigatus and yeast Saccharomyces cerevisiae. Amphotericin B above classification system is as follows: when given along with Allicin exhibited enhanced antifungal activity against S. cerevisiae [11].
4.1 Piperine
Piperine (1-piperoyl piperidine) is an amide alkaloid found in 4.4 Naringin [5, 10, 21]
plants of Piperaceae family like Piper longum (long pepper), Piper Naringin is the major flavonoid glycoside found in grapefruit, nigrum (blackpepper). The bioenhancing property of piperine was apples, onions and tea. first utilized in the treatment of tuberculosis in human. Piperine was found to increase the bioavailability of rifampicin by about 60%
and hence reduce the dose from 450 to 200mg [14]. In human
medicine piperine is approved to be combined with antitubercular
drugs. Piperine also showed enhanced bioavailability when
combined with Nevirapine, a potent non-nucleoside inhibitor of
HIV-1 reverse transcriptase which is used in combination with
other antiretroviral agents for the treatment of HIV-1 infection.15
Piperine also increases the bioavailability of curcumin, the active
principle of Curcuma longa (turmeric). A 20 mg dose of piperine
can increase the bioavailability of curcumin by 20 fold in
humans.16Several animal studies on piperine have shown promising results in bioenhancing capacity of piperine for various drugs [13, 17,
4.4.1 Naringin
It exhibits pharmacological actions like anti-oxidant, anti-ulcer, 4.2 Turmeric
anti-allergic and blood lipid lowering. Naringin is capable of Turmeric (Curcuma longa) is a common household item used as inhibiting intestinal CYP3A4, CYP3A1, CYP3A2, P-gp and thus remedy for various ailments. Curcumin, a flavonoid from turmeric acts as a bioenhancer. Pretreatment with oral ingestion of naringin suppresses drug metabolizing enzymes like CYP3A4 in liver and is @ 3.3 and 10mg/kg improves the AUC for intravenous paclitaxel also capable of inducing change in drug transporter P-gp and thus (3 mg/kg) in a dose dependent manner [21]. Naringin at 3.3-10
increased the bioavailability of celiprolol and midazolam in rats [19].
mg/kg body weight dose enhances the bioavailability of paclitaxel. The bioenhancer nature of curcumin is similar to piperine [13].
Other drugs bioenhanced are diltiazem, verapamil, saquinavir and Curcumin suppresses UDP-glucuronyl transferase level in intestine and hepatic tissues [20]. It also modifies the physiological activity in
the gastrointestinal tract leading to better absorption of drugs. 4.5 Quercetin [5, 10, 21]
Quercetin is a flavonoid; an aglycone form of a number of other 4.3 Allicin
flavonoid glycosides found in citrus fruits. It exhibits anti-oxidant, It is an allyl sulphur compound obtained from garlic (Allium anti-inflammatory, anti-atherosclerotic sativum).Allicin enhances the fungicidal activity of Amphotericin activities. It works by inhibiting CYP3A4 and P-gp efflux pump. B against pathogenic fungi such as Candida albicans, Aspergillus Quercetin has been shown to increase bioavailability, blood levels

Journal of Pharmacognosy and Phytochemistry and efficacy of a number of drugs including diltiazem, digoxin, verapamil, etoposide, and paclitaxel. Sachin et al. studied the enhancement of rifampicin levels in rat plasma by 3', 5-dihydroxyflavone-7-O- -D-galactouronide-4'- - 4.6 Genistein [5, 10, 21]
O-D-glucopyranoside. The results obtained revealed that the Cmax Genistein is a phytoestrogen belongs to the isoflavone class of of rifampicin was enhanced by 35% and the AUC was enhanced by flavonoids found in a number of dietary plants like soyabean (Glycine max) and kudzu (Pueraria lobata). It is a P-gp and BCRP Apart from the above bioenhancing effects, black cumin also efflux pump inhibitor. The presence of genistein (10 mg/kg) causes enhances the bioavailability of anti-biotics (Cefadroxil – 90% and an increase in AUC by 54.7% and a decrease in total plasma Cloxacillin – 94%), anti-fungal (Fluconazole – 170%), anti-viral clearance by 35.2% after oral administration of paclitaxel at dose of (Zidovudine – 330%) and anti-cancer (5-fluorouracil – 335%) 4.7 Caraway [22]
4.9 Drumstick pods26
It contains niaziridin, a nitrile glycoside which is a powerful
bioenhancer. It regulates GIT functions to facilitate better
absorption. It enhances the bioavailability of rifampicin by 38.8
folds at 1.0
g/ml. It also enhances the bioavailability of Clotrimazole by 5-6 folds.
An in-vitro study of active fraction of M. oleifera pods against
Mycobacterium tuberculosis (H37Ra) exhibited no anti-
tuberculosis activity at the concentration at which it enhanced the
anti-tubercular activity of rifampicin [27].
Khanuja et al. performed a pre-clinical study to evaluate the
influence of M. oleifera (MoAF) on pharmacokinetic disposition of
rifampicin using HPLC-PDA method.26 They orally administered to Swiss albino mice a dose of 20 mg/kg body weight of rifampicin Caraway/cumin which is a P-gp efflux pump inhibitor consists of alongwith a dose of 0.1 mg/kg body weight of the active fraction of the dried ripe fruits of Carum carvi of family Umbelliferae. It M. oleifera (viz. Niaziridin). They observed the bioavailability shows anti-oxidant, anti-microbial, diuretic and carminative. The pattern shown in the following figure thereby proving the success main constituents are carvone and limonene. The effective dose of of Niaziridin as an effective bioenhancer for rifampicin [27].
the bioenhancer extract is in the range of 5-100 mg/kg body weight. Percentage enhancement of bioavailability for rifampicin is 110%, 4.10 Morning glory plant [10]
for cycloserine is 75%, for ethionamide is 68%. Apart from the above bioenhancing effects, caraway also enhances
the bioavailability of anti-biotics (Cefdinir – 89% and Cloxacillin –
100%), anti-fungal (Amphotericin B – 78%), anti-viral (Zidovudine
– 92%) and anti-cancer (5-fluorouracil – 90%) drugs at the dose of
1-55 mg/kg body weight.
4.8 Black cumin [23, 24]
Black cumin (Cuminum cyminum) is a carminative, estrogenic,
anti-nociceptive, anti-inflammatory, anti-oxidant and anti-
microbial. The Bioenhancer chemical constituent present in cumin
is 3', 5-dihydroxyflavone-7-O- -D-galactouronide-4'- -O-D-
glucopyranoside.

It is a source of lysergol that enhances the bioavailability of
rifampicin by 4.5-6 folds at 0.2 g/ml concentration. It also
enhances the bioavailability of antibiotics in the range of 2-12
folds. It's mechanism of bioenhancer action is not yet clearly
known.
4.11 Liquorice [28]
Liquorice consists of dried, peeled or unpeeled, root and stolon of
Glycyrrhiza glabra and exhibits anti-hepatotoxic, anti-fertility,
anti-inflammatory, expectorant and anti-oxidant activity. It The effective dose of the bioenhancer extract is in the range of 0.5- contains glycyrrhizin which enhances the bioavailability of 25 mg/kg body weight. Percentage enhancement of bioavailability rifampicin by 6.5 fold at the concentration of 1 g/ml. It also for rifampicin is 250%, for cycloserine is 89%, for ethionamide is enhances the bioavailability of taxol by 5 fold at the concentration Journal of Pharmacognosy and Phytochemistry 4.20 Ammoniac multiflora
4.12 Ginger [29]
The methanolic extract of Ammannia multiflora (Lythraceae) It contains Gingerol which facilitates better absorption by showed significant bioenhancing activity with the antibiotic regulating GI tract function. nalidixic acid. A. multiflora contains a novel compound ammonia The effective dose of the bioenhancer extract is in the range of 10- along with other compounds. The methanolic extract of Ammannia 30 mg/kg body weight. multiflora bioenhancing activity in combination with nalidixic acid It enhances the bioavailability of rifampicin by 65% and against the two strains, CA8000 and DH5a of Escherichia coli [39].
ethionamide by 56%. It also enhances the bioavailability of antibiotics (Azithromycin – 78%), anti-fungal (Ketoconazole – 4.21 Cow urine distillate: (Kamdhenu ark) [40]
125%), anti-viral (Zidovudine – 105%) and anti-cancer (5- Cow urine distillate is more effective as a bioenhancer than cow fluorouracil – 110%) drugs. urine. It enhances the transport of antibiotics like rifampicin, tetracycline and ampicillin across the gut wall by 2-7 folds [40]. It
4.13 Stevia (Honey leaf) [30]
also enhances the potency of taxol against MCF-7 cell lines [41]. It
Stevia is anti-hypertensive agent and also promotes insulin enhances the bioavailability of rifampicin by 80 fold in 0.05 g/ml secretion. The bioenhancing chemical constituent present in Stevia concentration, ampicillin by 11.6 fold in 0.05 g/ml concentration and clotrimazole by 5 fold in 0.88 g/ml concentration. Cow urine Though the mechanism of action is not known, it enhances the also has antitoxic activity against the cadmium chloride toxicity bioavailability of anti-tubercular, anti-leprotic, anti-cancer, anti- and it can be used as a bioenhancer of zinc [12]. The bioenhancing
fungal and anti-viral drugs. ability is by facilitating absorption of drugs across the cell The effective dose of the bioenhancer extract is in the range of 0.01-50 mg/kg body weight. 5. Reference:
4.14 Peppermint oil [31]
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