Bioenhancers
- piperine and quercetin are considered bio-enhancers
- genistein
Piperine act by suppressing P-gp and cytochrome P450 enzymes, which counteract the metabolism of rifampicin via these proteins, thus enhancing the oral bioavailability of rifampicin. It also decreases the intestinal production of glucuronic acid, thus allowing more substances to enter the body in active form. It was found to increase the bioavailability of various drugs from 30% to 200%.[25]
Table 1: Published research on bioenhancer effect of piperine with various medicines
Drug Studied in Reference
Antimicrobial agents
Rifampicin In vitro Balakrishnan et al, 2001[11]
Isoniazid Rabbits Karan et al, 1998 [12]
Pefl oxacin Mountain Gaddi goats Madhukar et al, 2008[13]
Tetracycline Rats Atal et al, 1980[14]
Sulfadiazine Rats and dogs Atal et al, 1980[14]
Oxytetracycline Poultry birds Singh et al, 2005[15]
Ampicillin Rabbits Janakiraman and Manavalan, 2008[16]
Norfl oxacin Rabbits Janakiraman and Manavalan, 2008 [16]
Nevirapine Adult males Kasibhatta et al, 2007 [17]
Metronidazole In vitro Singh et al, 2010[18]
Analgesics
Diclofenac sodium Albino mice Pooja et al, 2007[19]
Pentazocine Albino mice Pooja et al, 2007[19]
Nimesulide Mice Gupta et al, 1998[20]
Antiepileptics
Carbamazepine In vitro Pattanaik et al, 2009 [21]
Phenytoin Human volunteers Bano et al, 1987[22]
Pentobarbitone Rats Majumdar et al, 1990[23]
Other drugs
Propranolol In vitro Bano et al, 1991 [24]
Theophylline In vitro Bano et al, 1991 [24]
Nutrients In vitro Pooja et al, 2007 [19
***Borneol
-Borneol is thought to temporarily open tight junctions between endothelial cells, enhancing drug penetration. It may also downregulate efflux transporters such as P-glycoprotein (P-gp), allowing higher intracellular concentrations of co-administered drugs.
-presence of urea (as a carrier) increased the aqueous solubility of capsaicin by 3.6-fold compared to pure capsaicin
Quercetin is found in citrus fruits and is a dual inhibitor of cytochrome P 3A4 (CYP3A4) and P-gp.
Table 2: Effect of quercetin pretreatment/co-treatment on pharmacokinetic parameters of different drugs
Drugs combined Increase in pharmacokinetic parametera
Cmax AUC ABA
Verapamil Two fold Two fold SH
Diltiazem SH SH Not known
Paclitaxel SH SH T wo fold
Digoxin 413% 170% Not known
Tamoxifen SH SH 59%
Compared to drug in question alone. Cmax, peak plasma concentration; AUC, area under the curve; ABA, absolute bioavailability; SH, significantly higher.
Another flavonoid, genistein belongs to the isoflavone class of flavonoids. It is a well-known phytoestrogen. The presence of genistein (10 mg/kg) caused an increase in AUC (54.7%) and a decrease in the total plasma clearance (35.2%) after oral administration of paclitaxel at a dose of 30 mg/kg in rats.[37]
Naringin is the major flavonoid glycoside found in grapefruit and makes grapefruit juice taste bitter. Oral naringin (3.3 and 10 mg/kg) was pretreated 30 min before and after intravenous administration of paclitaxel (3 mg/kg), the AUC was significantly improved (40.8% and 49.1% for naringin doses of 3.3 and 10 mg/kg, respectively).[38
Carum carvi/Cuminum cyminum ( Jeera)
Carum carvi seeds are a prized culinary herb. Extracts of its parts increased significantly (25%–300%), the bioavailability of a number of classes of drugs, such as antibiotics, antifungals, antivirals, anticancer, cardiovascular, anti-inflammatory/ antiarthritic, anti-TB, antileprosy, antihistaminic/respiratory disorders, corticosteroids, immunosuppressants, and antiulcers. Such extracts either in the presence or absence of piperine have been found to be highly selective in their bioavailability/bioefficacy-enhancing action.[40]
Capmul
One of the widely used bioenhancers is Capmul MCM C10, a glyceryl monocaprate, produced from edible fats and oils and is commonly used in lip products. In a study in rats, antibiotic ceftriaxone when given concomitantly with capmul, increased the bioavailability of ceftriaxone by 80%.[41]
Nitrile glycoside
Nitrite glycoside is a bioenhancer for drugs and nutrients. Novel bioactive nitrile glycosides, niaziridin and niazirin is obtained from the leaves, pods, and bark of Moringa oleifera. [42] An immunoenhancing polysaccharide and niaziminin, having structural requirement to inhibit tumor promoter-induced Epstein–Barr virus activation have been reported from the leaves of Moringa.[43,44] It enhances the bioactivity of commonly used antibiotics, such as rifampicin, tetracycline, and ampicillin, and also facilitate the absorption of drugs, vitamins, and nutrients through the gastrointestinal membrane, thus increasing their bioavailability. [41] Niazirin is another bioactive nitrile glycoside belonging to M. oleifera. [45,46] Process of isolation of nitrite glycoside from M. oleifera has been patented (US 6858588) by Khanuja et al in 2004–2005. [42
Mechanism of Action Of Bioenhancers
Bioavailability-enhancing activity of natural compounds from the medicinal plants may be attributed to various mechanisms, such as P-gp inhibition activity by flavone, quercetin, and genistein; [51]
inhibition of efflux transporters, such as P-gp and breast cancer resistance protein (BCRP),[52,53] by naringin and sinomenine thus preventing drug resistance; DNA receptor binding, modulation of cell signaling transduction, and inhibition of drug efflux pumps[54-56] ; by stimulating leucine amino peptidase and glycyl–glycine dipeptidase activity, thus modulating the cell membrane dynamics related to passive transport mechanism as seen with piperine [57] ; nonspecific mechanisms, such as increased blood supply to the gastrointestinal tract, decreased hydrochloric acid secretion, preventing breakdown of some drugs[6] ; and inhibition of metabolic enzymes participating in the biotransformation of drugs, thus preventing inactivation and elimination of drugs and thereby, increasing their bioavailability. [57-5]
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