Appraisal of Bioenhancers in Improving Oral Bioavailability: Applications to Herbal Medicinal Products

Journal of Pharmaceutical Research International

24(4): 1-23, 2018; Article no.JPRI.45330 ISSN: 2456-9119 (Past name: British Journal of Pharmaceutical Research, Past ISSN: 2231-2919, NLM ID: 101631759)

Francis A. Oladimeji1, Adebanjo J. Adegbola2 and Cyprian O. Onyeji2*

1Department of Pharmaceutics, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria. 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.

Authors’ contributions

This work was carried out in collaboration between all authors. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/JPRI/2018/45330 Editor(s): (1) Dr. Barkat Ali Khan, Department of Pharmaceutics, Gomal University, Dera Ismail Khan, Pakistan. Reviewers: (1) Emelia Oppong Bekoe, University of Ghana, Ghana. (2) Selma Sahin, Hacettepe University, Turkey. Complete Peer review History: http://www.sciencedomain.org/review-history/27486

Received 15 September 2018 Accepted 22 November 2018 Review Article Published 29 November 2018

ABSTRACT

The oral route of administration is associated with some challenges such as poor aqueous solubility and low intestinal permeability of many active pharmaceutical ingredients resulting in decreased drug absorption and subsequent poor bioavailability. In recent years, research on bioenhancers has started receiving increased attention and this approach can complement the traditional methods of solubility enhancement. Bioenhancers boost the bioavailability of drugs when co-administered at low doses with the drug. A large variety of compounds have been clearly demonstrated to possess significant bioenhancing activity with different mechanisms of action. Some compounds considered as bioenhancers isolated from plants include piperine, gallic acid, niaziridine, sinomenine, genistein, and lysergol. There are several reports of herbal medicinal products (HMPs) that require large doses to be therapeutically effective and some studies have identified that the active compounds in such products have poor bioavailability. Thus, there is every need to optimise dosage formulations of HMPs. The application of the concept of bio-enhancement and knowledge of their mechanism of action can lead to the selective use of suitable bioenhancers

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*Corresponding author: E-mail: [email protected], [email protected];

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resulting in reduction in therapeutic dose of the HMP, thus reducing the possibilities of toxicity. This review was aimed at updating knowledge on different natural bioenhancers and also provides an overview of currently marketed HMPs containing bioenhancers. The article highlights different strategies that can be employed to improve the bioavailability of HMPs. The bioactive constituents of the HMP were identified and facts on their physicochemical properties, metabolic fate, as well as factors that impact on their gastrointestinal absorption, were examined with a view to providing information to serve as a guide in developing suitable bioavailability enhancement strategies for other HMPs.

Keywords: Bioavailability improvement; bioenhancers; herbal medicinal products.

1. INTRODUCTION the measurements of the rate of the mass transfer across the intestinal membranes in vitro 1.1 Bioavailability and Biopharmaceutic or by using in vivo models. A drug substance is Classification Systems (BCS) considered to be highly permeable when the systemic bioavailability or the extent of For a drug to undergo absorption, it must be absorption in humans is determined to be 85 available as an aqueous solution at the site of percent or more of an administered dose based absorption. This implies that aqueous solubility on a mass balance determination (along with and dissolution rate are very important properties evidence showing stability of the drug in the GI of any drug and impact on its oral bioavailability tract) or in comparison to an intravenous [1]. A major challenge in the development of reference dose [7]. formulations of poorly water-soluble drugs is how to increase their bioavailability and it is reported The BCS class 1 (high solubility/high that about 70% of all new chemical entities permeability) usually do not have bioavailability (NCE) have poor water solubility and fail to have problems since their absorption is neither commercial viability due to their limited dissolution nor permeability rate-limited. bioavailability [2]. The drug molecules have to However, Active Pharmaceutical Ingredients traverse biological membrane at the absorption (APIs) in this BCS class can only enjoy site to enter the systemic circulation. Hence, the bioavailability waiver if they satisfy all the gastrointestinal permeability of the drug is also a requirements of high solubility, high permeability fundamental factor that contributes to and rapid dissolution [7]. Examples of drug determining the rate and extent of drug substances in this class include diltiazem, absorption and its bioavailability [3]. The metoprolol, paracetamol, propranolol etc [8]. The importance of solubility and permeability in BCS class II drugs have low aqueous solubility controlling bioavailability has been demonstrated and high permeability, hence, dissolution process in their being used to construct the is the rate-limiting step in the drug absorption Biopharmaceutic Classification Systems (BCS). process. Bioavailability of this class of drugs can BCS is a scientific framework for classifying a be enhanced by using techniques that increase drug substance based on its solubility and the solubility and dissolution rates of the intestinal permeability and they have been found compound. Studies from our laboratories and by useful in combination with dissolution rate data to several other investigators indicate that different predict absorption profile of drug products [4-6]. It methods are used for the improvement of the is important to consider the BCS class of a drug solubility of poorly water-soluble drugs and these substance to be able to make an informed include micronisation, crystal form modification, judgment on the best approach to follow when salt formation, use of surfactant, complexation improvement of bioavailability of a drug is with cyclodextrin and other complexing agents, desired. According to United States Food and solid dispersion, and others [3,9-12]. With the Drug Administration (USFDA) BCS guidance, a advancement in technology, novel techniques drug substance is considered highly soluble such as cryogenic technology, nano-suspension, when the highest dose strength is soluble in 250 and supercritical processing have also been mL or less of aqueous media over the pH range developed for solubility enhancement [1,13-16]. It of 1- 6.8 at 37 ± 1°C [7]. The drug permeability is noteworthy that several researches on may be determined directly from the extent of solubility enhancement have been focused on intestinal absorption of a drug substance in the BCS class II drugs [17,18]. For the BCS class humans. It can also be estimated indirectly from III drugs (High solubility/low permeability), there

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can be bioavailability waivers for the APIs that Products (HMPs) as part of Complementary and have high solubility and rapid dissolution rate. In Alternative Medicines is very widespread in large addition, the test product formulation should be sections of the population in developing countries qualitatively the same and quantitatively very [24,25]. Also, as complementary and alternative similar [7]. However, since the absorption of medicines are now becoming popular in some APIs in this class can be limited by its rate developed countries [26,27], reports show that of intestinal permeability, the use of absorption over the past two decades, there has been an enhancers or bioenhancers which can improve increased prevalence in use of HMPs in these their permeability has the potential of enhancing countries [28,29]. The revival of interest in HMPs bioavailability of the drug. In the case of BCS has been ascribed to a number of factors such class IV compounds (low solubility/low as the perception that herbal products are safer permeability), the drug absorption is both because they are natural in origin. Other reasons dissolution and intestinal permeability rate- include the cost-effectiveness and the belief that limited. The bioavailability of this class of drug herbal medicines might be effective in the substances may be achieved through treatment of certain diseases where conventional enhancement of solubility and dissolution rate in therapies have proven to be ineffective [27,30, addition to the use of absorption enhancers. 31]. In spite of their significant therapeutic effects Examples of drugs in this class include ritonavir, and less adverse effects profiles, there are saquinavir, taxol, cyclosporine A and several numerous cases of herbal products with others [8]. remarkable in vitro activities but with disappointingly poor in vivo efficacy. These are 1.2 Bioavailability with Bioenhancers revealed through animal and clinical trial studies conducted on HMPs indicating that the herbal It is evident from the BCS that the classes III and drugs have poor bioavailability [32,33]. Thus, IV drugs have low intestinal permeability, thus, several plant extracts and phytoconstituents approaches that can increase the permeability of demonstrate reduced in vivo actions due to the these compounds are likely to enhance their inappropriate molecular size, poor aqueous bioavailability. The use of bioenhancers can be solubility and/or poor intestinal permeability of regarded as an innovative concept. the bioactive constituents resulting in decreased Bioenhancers are agents or substances that absorption and consequently poor bioavailability. boost the bioavailability of drugs when co- For example, extract of the plant Azadirachta administered at low doses with the drug. An ideal indica, which is widely used in indigenous bioenhancer should be safe, effective, readily medicine for the treatment of malaria exhibits available and economical. In addition, it should high in vitro activity against various strains of not produce its own pharmacological effects at Plasmodium falciparum but required very high the dose used, should be rapid-acting with doses (e.g. 800 mg/kg body weight) to exhibit predictable and reproducible activity and should significant in vivo activity [34,35]. Similarly, be compatible with other APIs [19,20]. When Silybum marianum commonly known as milk used in a judicious manner bioenhancers can thistle has Silymarin as the major bioactive lead to reductions in drug dosages due to compound isolated from its seed which has enhanced bioavailability, with resultant numerous applications including use for the oral decreases in drug treatment cost, toxicity and therapy of chronic liver disorder. But, its efficacy adverse effect profiles [21]. From historical is limited by poor aqueous solubility, resulting in viewpoint, bio-enhancement originated from poor bioavailability [36]. In addition to other Ayurvedic medicine as reported by Bose in 1929 techniques used for improving solubility and who first described the use of a condiment, long bioavailability of APIs, it has been demonstrated pepper, to improve the antiasthmatic effect of the that the efficacy of HMPs with poor in vivo leave of Adhatodavasica species [22]. activity can be improved by formulating the product with a herbal bioenhancer [37]. The need 1.3 Bioavailability and Herbal Medicinal for bioenhancers is especially applicable when Products the bioactive constituents have limited intestinal permeability. In essence, a better understanding From time immemorial, phytomedicine has been of the physicochemical characteristics of the playing an important role in pharmacotherapy bioactive constituents of HMPs will assist in and presently, about 50 percent of useful drugs designing a formulation with optimal are obtained from natural sources [23]. Several bioavailability. reports indicate that the use of Herbal Medicinal

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The objective of this review was to update 2.1.1 Inhibitors of cytochrome P450 and P-gp knowledge on different natural agents being used as bioenhancers and to discuss their possible Piperine (1-piperoyl piperidine) is an alkaloidal mechanisms of action with the overall aim of component of Black pepper (Piper nigrum) and providing an insight into how these long pepper (Piper longum). The fruits of these pharmacological advances can be applied in two herbs generally contain volatile oil (1 – 2.5%) optimization of bioavailability of formulations of and total alkaloids (5 – 9%) with the major HMPs. Also, the article highlights different other alkaloids consisting of piperine, piperidine, and strategies that can be employed to improve the piperetine. It has been documented that most of bioavailability of HMPs. Since herbal medicine is the pharmacological properties of the fruits are increasingly playing a significant role in the credited to the piperine [43]. healthcare industry, it is appropriate that the Ethnopharmacological survey indicates that products also receive due attention to the piperine/pepper is commonly used as orthodox medicines. antirheumatic, analgesic, diuretic, antispasmodic and antiseptic [44] or a preservative and a 2. ROLE OF BIOENHANCERS perfume in some climes. However, when used as a bioenhancer, these pharmacological effects are not relevant. 2.1 Classification of Bioenhancers Studies have established piperine to be useful as A large variety of both natural and synthetic a bioenhancer at a low dose of 10-15 mg [45]. compounds have been clearly demonstrated to This property was first utilized to enhance the possess significant bioenhancing activity and bioavailability of rifampicin by more than 50% in they have different mechanisms of action [38- an antitubercular regimen [46]. Thus, studies 40]. Bioenhancers are categorized either based have shown that piperine increases the on their origins (natural-from plants and animals; bioavailability and efficacy of numerous drugs and synthetic), chemical classes or mechanism including phenytoin, sulfadiazine, propranolol, of actions. Some compounds considered as carbamazepine, fexofenadine, ampicillin bioenhancers isolated from plants include Trihydrate, nevirapine, metronidazole, piperine, gallic acid, niaziridine, sinomenine, omeprazole and many other drugs. It was genistein, and lysergol. Apart from the isolated concluded that piperine significantly enhanced molecules, whole plant or parts of the plant are the oral bioavailability of these drugs, possibly by also used as bioenhancers. Examples of parts of decreasing the elimination and/or by increasing plants used as bioenhancers include the its absorption through the inhibition of P- rhizomes of Zingiber officinale and the seeds of glycoprotein (P-gp) at the gut and kidneys, in Carum carvi [16]. Piperine is the world's first addition to inhibition of CYP3A4 and other drug- bioavailability enhancer first reported in 1979 and metabolizing enzymes especially UDP- there are currently several reports on its glucuronosyl transferase (UGT) in the gut [47- bioavailability enhancement of various drugs and 53]. Piperine also mediates bioavailability nutraceuticals [39,40]. Since bioenhancers have enhancement by enhancing the blood supply in different mechanisms of bioavailability the enteric vessel due to its local vasodilatory improvement, it is pertinent to clarify that the effect [54], improvement of lipid solubility through term ‘absorption enhancers’ is used for a class of increase in the secretion of bile acid and bioenhancers that promote bioavailability by modification of intestinal epithelial cells [45]. specifically enhancing the intestinal permeability Other herbal bioenhancers that have similar of the drug [41]. Based on their mechanisms of bioenhancing mechanisms of action like piperine action, there are three major classes of include: bioenhancers [38,42] and these include: (a) Naringin: Naringin is a CYP3A4 inhibitor (a) Regulators of GIT functions: Aloe vera, [55]. It is the major flavonoid glycoside Niaziridin, Zingiber officinale (Ginger), found in grapefruit, apples and onions. Due Glycyrrhizin (from Liquorice). to its ability to inhibit intestinal CYP3A4 (b) Inhibitors of cytochrome P450: Piperine, and P-gp, it has been found to enhance Naringin, Gallic acid and its esters. the bioavailability of a number of CYP3A4 (c) Inhibitors of P-glycoprotein (P-gp) and and P-gp substrates such as paclitaxel, other efflux pumps: Piperine, Carum carvi, diltiazem, verapamil, saquinavir and Genistein, Sinomenine, Naringin. cyclosporine A [56,57].

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(b) Gallic acid: Gallic acid is a CYP3A4 The extracts of ginger have been found to be inhibitor [58] and its esters like propyl selective in their abilities to enhance gallate, octyl gallate and lauryl gallate have bioavailability of a wide range of drugs of been demonstrated to increase the different therapeutic classes and the bioavailability of orally administered enhancement can vary from 20% to 200% [67, pharmaceutical compounds which are 68]. These drugs include azithromycin, substrates of CYP3A4 [57,58]. ketoconazole, erythromycin, cefadroxil, (c) Sinomenine: Sinomenine, a monoterpene amoxycillin, cloxacillin, rifampicin, ethionamide, glucose alkaloid extracted from zidovudine and fluorouracil [47]. These drugs are Sinomenium acutum is known to be a P-gp not necessarily substrates of particular drug inhibitor [59]. Co-administration of metabolising enzymes or drug transporter sinomenine markedly increased the oral systems. Therefore, unlike piperine and other absorption of paeoniflorin through a bioenhancers which are inhibitors of CYP3A4 decrease in the efflux transport of the drug and P-gp, and whose bioavailability by P-gp in the small intestine [59]. enhancement are manifested on drugs that are Paeoniflorin, used in the treatment of substrates of these systems, the bioenhancing inflammation and arthritic conditions, has a effect of ginger extract is not predictable. very low oral bioavailability which is in the range of 3 – 4% [60]. Other herbal Bioenhancers with action on GIT (d) Genistein: Genistein, an isoflavone found membrane similar to the effect of ginger include: in a number of dietary plants like soyabean (Glycine max) and kudzu (Pueraria lobata), (a) Aloe Vera Extract: The gel and whole leaf is known to be a P-gp inhibitor [40,61]. extracts of Aloe vera have been The intestinal absorption of paclitaxel, a demonstrated to enhance the oral substrate of P-glycoprotein, was absorption of vitamin C and vitamin E [69]. significantly augmented when co- The bioenhancing mechanism of action of administered with genistein [61]. these products is thought to be attributed (e) Carum carvi: Carum carvi (family – to their polysaccharides constituents. Apiaceae) also called Caraway/cumin has Polysaccharides of natural origin such as carvone as its major constituent which is chitosan act as penetration enhancers obtained from the dried and crushed through a process of a transient opening of seeds. At a dose in the range of 5 – 100 the tight junctions between adjacent mg/kg body weight, this extract epithelial cells. Thus, they are capable of significantly enhanced bioavailability of a enhancing the intestinal absorption of wide range of drugs of various therapeutic concurrently administered drugs. It has classes including antimicrobial, antileprosy, been shown that the Aloe vera gel and anti-inflammatory, anti-arthritic, whole leaf extract significantly increased cardiovascular, antihistaminics, CNS the transport of the macromolecular drugs, antiulcers, nutraceuticals and herbal peptide drug, insulin, across the Caco-2 formulations. Its mode of action is by cell monolayers [70]. Limited information is inhibition of P-gp efflux pump [38,40,62]. currently available on the drug absorption enhancement activities of A. vera extracts. 2.1.2 Regulators of GIT functions (b) Liquorice: Liquorice is the name given to the root of the plant Glycyrrhiza glabra. Ginger, the rhizome of Zingiber officinale, has a The extract of this plant contains a long history of medicinal use for conditions such phytoconstituent, Glycyrrhizin, that has as diarrhoea, nausea, and stomach ache, in been established to have bioenhancing addition to a range of other pharmacological activity. The compound is reported to activities [63,64]. Ginger contains numerous cause a 2 to 6 fold enhancement in GIT constituents but the major is gingerols which can absorption of various drugs such as be converted to shogaols, zingerone, and rifampicin, tetracycline, nalidixic acid, paradol [65]. These compounds along with the ampicillin and vitamins B1 and B12 [71]. In volatile oil constituents have strong effects on a study to elucidate the molecular GIT mucous membrane resulting in regulating mechanism of bioenhancing action of the intestinal function to facilitate absorption [42]. glycyrrhizin, the influence of the compound Ginger is used in the range of 10-30 mg/kg body on the functional properties of weight as bioenhancer [66]. biomembranes was investigated using a

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model system of human erythrocytes. HMPs with intrinsic poor bioavailability of its Glycyrrhizin produced about 60% increase active constituents. There are numerous reports in the permeability and decreased elasticity of decreased absorption and subsequent poor modulus of cell membranes even in bioavailability resulting in reduced in vivo micromolar concentrations [72]. activities of several medicinal plant extracts and Structurally, glycyrrizin is a saponin and phytoconstituents. The factors contributing to saponins have surfactant properties that decreased gastric absorption and subsequent can act on the paracellular route [73]. The poor bioavailability include the nature of absorption enhancing effect of glycyrrhizin physicochemical properties of the active is further enhanced in the presence of constituents such as poor aqueous solubility, other enhancers [74]. large molecular weight, excessively high (c) Nitrile glycosides: Niaziridin and niazirin aqueous solubility, instability in the GIT fluid as are nitrile glycosides isolated from the well as metabolism at the gut epithelial cells and pods of Moringa oleifera (Family - activities of drug transporters [34-36]. Moringaceae). They have been found to increase the bioavailability of commonly 3.1 HMPs with Piperine (and Other used antibiotics (eg rifampicin, tetracycline Bioavailability Improvement and ampicillin), vitamins, and nutrients by Approaches) facilitating their absorption through the gastrointestinal membrane [47,75]. For 3.1.1 Curcumin example, in a study on the influence of active fraction isolated from pods of Curcumin, commonly called diferuloyl methane, Moringa oleifera on pharmacokinetic has been identified as the active principle derived disposition of rifampicin, the results from the rhizome (called turmeric) of the herb revealed that co-administration of the Curcuma longa. It is a hydrophobic compound extract resulted in significantly increased that has been used traditionally in the rifampicin plasma concentrations [76]. management of a variety of ailments due to its wide spectrum of pharmacological activities [78]. 3. HERBAL MEDICINAL PRODUCTS Curcumin has structurally related compounds WITH BIOENHANCERS which are all curcuminoids but are often referred to simply as curcumin and their chemical Applications of novel techniques for improvement structures are presented in Fig. 1. Commercially of bioavailability of drugs have been extended to available curcumin generally contains three HMPs and these include herbal liposomal major curcuminoids: curcumin (77%), formulations, microspheres, nanoparticles, demethoxycurcumin (7%) and bisdemethoxy- transferosomes, lipid-based herbal formulations, curcumin (3%) [78]. and other herbal vesicular formulations [77]. In addition, there are studies reporting clear Early studies of the pharmacokinetics of evidence of improvement of oral absorption and curcumin in animal models have shown that it is bioavailability of HMPs by concomitant use of poorly absorbed from intestine after oral bioenhancers. The literature is replete with administration of different doses of the studies indicating bioavailability enhancement of compound [79]. The hydrophobicity of the orthodox medicines by bioenhancers [16] but an compound results in its poor aqueous solubility extensive review of the literature revealed and this class of compounds in the BCS is comparatively limited data on the deliberate associated with reduced bioavailability. In a study application of this technique in HMPs with poor to determine whether curcumin is a substrate of bioavailability. P-gp and CYP3A isozymes, the compound was co-administered with drugs (celiprolol and The emphasis of this review is to focus more on midazolam) that are known substrates of these the enhancement of bioavailability of HMPs. The systems in a rat model. Results indicated that the bioactive phytoconstituents of the HMP are plasma blood levels of celiprolol (a P-gp identified and information on their substrate) and midazolam (substrate of CYP3A) physicochemical properties, metabolic fate as were significantly increased by curcumin, well as factors that impact on their confirming that curcumin is a substrate for both gastrointestinal absorption are examined. These P-gp and CYP3A4 [80]. Since the mechanisms can serve as guide for the application of the by which piperine acts as a bioenhancer is by bioavailability enhancement technique to other reducing drug metabolism in the gut through

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Fig. 1. Chemical structures of Curcumin and its derivatives, and Rutin inhibition of CYP3A activity in gut epithelial cells 3.1.2 Rutin and also by inhibiting P-gp transport system [52], inhibition of these two systems by piperine in gut Rutin also known as quercetin-3-rutinosoid or epithelial cells is expected to lead to increasing in sophori is a flavonol glycoside comprising curcumin absorption. This hypothesis was quercetin (a flavanol) and a disaccharide called validated in a study on the effect of piperine on rutinose (α-L-rhamnopyranosyl-(1→6)-β-D- the bioavailability of curcumin in which it was glucopyranose). The chemical structure is demonstrated that concomitant administration of presented in Fig. 1. It is found in a wide variety of piperine significantly increased the extent of plants including many citrus fruits and is often absorption and bioavailability of curcumin in both sold as an herbal supplement. Quercetin, the rats and humans with no adverse effects. In active moiety of rutin has been reported to exert humans, the increase in bioavailability was as numerous pharmacological activities including high as 2000% [81]. Also, there was a antidiabetic, anti-inflammatory, antioxidant, potentiation of curcumin antidepressant activity cardiovascular, and it has been used following concomitant administration of this HMP therapeutically to decrease capillary fragility and with piperine. This approach has been found for management of many chronic diseases [84- useful in the management of depression [82,83]. 86]. It is reasonable to project that a poorly absorbed HMP with constituents having similar Considering the size and polarity of flavonoids, physicochemical characteristics as curcumin and some medicinal chemistry rules would predict are also substrates of P-gp and CYP3A4 can be difficulty in their ability to cross bio-membranes. made more bioavailable by concurrent use with Thus, generally, flavonoids are poorly absorbed piperine. from the small intestine. The high molecular

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weight of rutin (664.58) also limits the intestinal medicinal use for a variety of conditions permeability of the compound. Studies have especially in the prevention and treatment of shown that trans-epithelial transport of rutin is upper respiratory tract infections attributed to the poor and mainly by passive diffusion [87,88]. For immunostimulatory and anti-inflammatory this class of compounds, techniques that properties of the HMP. The fresh or dried enhance solubility and intestinal permeability are underground parts (roots, rhizomes) of these promising approaches to bioavailability species are used and the marketed echinacea improvement. The oral bioavailability of rutin in products may contain one or more of these three human studies showed that the compound is species [98-100]. The major constituents that are poorly orally absorbed with only 20 – 30% of the responsible for the bioactivities of this HMP are dose absorbed [89]. There are numerous reports hydrophilic components which include caffeic on studies aimed at improving the bioavailability acid derivatives (cichoric acid, echinacoside, and by applying various excipients and techniques chlorogenic acid) and lipophilic components including use of cyclodextrin complexation, which are alklyamides [98]. Their chemical surfactants, nano-phytosomes, chitosan, and structures are presented in Fig. 2. nanoemulsion [20,90-92]. Studies to enhance the bioavailability of A contribution to the poor oral absorption of rutin echinacea constituents have been reported. Due is the metabolism of the compound in the gut. to the hydrophilicity of caffeic acid derivatives, The microflora in lower gut hydrolyzes rutin to their intestinal permeability has been shown to quercetin and isoquercetin [93]. But, the enzyme be poor while the lipophilic alklyamides diffuse Uridine Diphosphate-Glucoronosyl-Transferase rapidly [101]. Echinacoside, representing caffeic (UGT) conjugates the part of the free quercetin acid derivatives is a substrate of P-gp and with glucuronide producing a bulky and inert inhibition of this transporter by verapamil resulted adduct which is un-absorbable, hence, reducing in the oral bioavailability enhancement of the the extent of absorption of quercetin [94]. Since compound [102]. Also, the essential oils in clove piperine has been shown to be an inhibitor of oil acting as absorption enhancers augmented UGT [51], this bioenhancer was demonstrated to the intestinal absorption of echinacoside [102]. improve the neurocognitive efficacy of quercetin Since these caffeic acid derivatives are in mice [95] and this is an indication of enhanced substrates of P-gp and CYP3A4 [102,103], it is bioavailability of quercetin by piperine. Studies expected that absorption of these compounds have also shown that piperine can enhance the may be enhanced by piperine which inhibits the antioxidant and anti-inflammatory properties of activities of this transporter and isozyme at the quercetin, and quercetin exhibited stronger gut epithelial. This assumption was validated by neuroprotective effects when given in studies indicating augmentation of bioavailability combination with piperine [96]. An in vitro study of echinacea extract by concurrent administration demonstrated that piperine enhanced antioxidant of piperine [42]. effect of rutin and the authors suggested that the findings provide more insight into the mechanism 3.1.4 Boswellia of the hepato-protective action of rutin [97]. It is not likely that piperine enhanced bioavailability Boswellia serrata (Family: Burseraceae) is a and hence the efficacy of rutin or quercetin deciduous middle sized tree mostly concentrated through modulating P-gp activity because rutin in parts of Asia and Africa. The dried exudate and related compounds have been shown not to from the bark of this tree is an oleo-gum-resin be substrates for efflux transporters [89]. From which has a wide range of pharmacological the foregoing, the bioavailability of HMPs activities and is reported to be useful in the containing phytoconstituents with similar treatment of bronchitis, asthma, cough, physicochemical properties and metabolic fate as inflammatory conditions and various intestinal rutin might be expected to be enhanced when problems [104-106]. The major fraction of the co-administered with piperine. gum-resin consists of terpenoids of which the biologically active phytoconstituent is boswellic 3.1.3 Echinacea acid which is a pentacyclic triterpene acid [107]. α- and β-Boswellic acids were the first to be Preparations from the genus Echinacea which isolated followed by several other of its are from Echinacea species (Echinacea derivatives such as 3-acetyl-α-boswellic acid, 3- angustifolia, Echinacea pallida and Echinacea acetyl-β-boswellic acid, 11-keto- β-boswellic acid purpurea) are among the most widely used and 3-acetyl-11-keto- β-boswellic acid [106]. herbal medicines and have a long history of Some of these structures are presented in Fig. 3.

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Dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (A1); Dodeca-2E,4E-dienoic acid isobutylamide (A2); Undeca-2E-en-8,10-diynoic acid isobutylamide (A3)

Fig. 2. Chemical structures of some of the bioactive constituents of Echinacea

Being pentacyclic triperpenes, boswellic acid and Studies indicate that CYP3A4 plays a its derivatives are lipophilic and the poor predominant role in the hydroxylation reaction of aqueous solubility results in low oral Keto-boswellic acid in the GIT of humans [111] bioavailability of these compounds. In addition, and this contributes to a reduction in drug the keto derivatives of boswellic acid undergo absorption. Coadministration with piperine has extensive first pass metabolism and this the potential to improve the bioavailability of contributes to the low oral bioavailability [108, keto-boswellic acid as it is an inhibitor of 109]. Many attempts have been made to produce CYP3A4. It has been demonstrated that piperine drug delivery systems with improved absorption significantly enhanced the bioavailability of such as loading boswellic acids into liposomes, boswellia extracts when concurrently solid lipid nanoparticles as well as delivery administered [112]. This observation can also be as niosomes, phytosomes and nano-micelles applied to other HMPs containing [110]. phytoconstituents with similar metabolic fate.

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α-boswellic acid β-boswellic acid 3-acetyl-β-boswellic acid

3-acetyl- α-boswellic acid acetyl-11-keto-ß-boswellic Acid (AKBA) 11-keto-β-boswellic acid

Fig. 3. Chemical structures of the six major bioactive constituents of Boswellia serrata extracts

3.1.5 Ginkgo Biloba phospholipid complexes and solid dispersions [117]. The major pathway of metabolism of Ginkgo biloba is a large tree originally native to flavonoids in humans is hydrolysis in the China but it is now cultivated worldwide. The intestinal microflora followed by phase II leave extract has been used in traditional conjugation reaction where UGTs are the major medicine for centuries to treat circulatory contributors [118]. Based on the knowledge of disorders, asthma, tinnitus, vertigo, and cognitive mechanisms of bioenhancing activity of piperine, problems, and it is one of the most commonly being an inhibitor of UGT, a concurrent taken phytomedicines globally [113,114]. The administration with piperine is expected to pharmacological properties of this HMP are enhance the oral absorption of the Ginkgo attributed to its constituents of terpenoids, flavanols. In addition, studies have shown that flavonoids and proanthocyanidins [115]. These Ginkgo flavonols quercetin, kaempferol and active components have been identified as isorhamnetin are substrates of P‐gp. This efflux bilobalide, ginkgolides A, B, C, quercetin, pump contributes to limiting the bioavailability of kaempferol, rutin hydrate, and isorhamnetin the flavanols [119]. Since piperine also acts by [116]. Their chemical structures are depicted in inhibiting activity of P-gp, this is an additional Fig. 4. pathway through which it can enhance bioavailability of Ginkgo flavanols. These As earlier highlighted with quercetin, flavanoids expectations have been validated in studies have poor oral absorption. Thus, different which demonstrated that piperine significantly approaches have been investigated for enhanced the bioavailability of Ginkgo extracts improvement of the bioavailability of Ginkgo when concurrently administered [112]. extract and these included the use of

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Ginkgolides A, B and C Kaempferol R1 R2 R3

A OH H H B OH OH H C OH OH OH

Isorhamnetin Bilobalide

Fig. 4. Chemical structures of the major bioactive constituents of Gingo biloba extracts

The physicochemical properties and metabolic (Genistein, Naringin, Sinomenine, Carum carvi) fate of the Ginkgo terpene lactones (bilobalide might be expected to also augment oral and ginkgolides) are different from those of the absorption of phytoconstituents that are flavanols. The intestinal absorption of the terpene substrates of CYP3A4, UGT and P-gp. It will be lactones is dictated by their intermediate worthwhile to subject this proposition to further membrane permeability and they are not research. substrates of CYP3A4, UGT and P-gp at the gut [120-121]. Thus, augmentation of the oral 3.2 HMPs with Ginger (and Other absorption of these terpene lactones by piperine Bioavailability Improvement could plausibly be through the non-specific Approaches) mechanism of enhancing the blood supply in the enteric vessel due to the local vasodilatory effect 3.2.1 Andrographis paniculata of piperine [54]. Andrographis paniculata belongs to the family 3.1.6 Other Bioenhancers with action as Acanthaceae and is an important medicinal plant Piperine widely used around the world [122]. The aerial part of this herb is most commonly used and has Other herbal bioenhancers that have similar been reported to have a broad range of bioenhancing mechanisms of action like piperine pharmacological effects including anticancer,

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antihepatitis, antihyperglycemic, immunomodula- bioavailability. Several strategies have been tory, antibacterial, anti-inflammatory, antioxidant used to improve the bioavailability of and antimalarial [123-125]. The phytochemicals andrographolide from the herbal extract [130] extracted from this herb consist of diterpenoids, and these include cyclodextrin complexation flavonoids, quinicacids, xanthones, [131], preparation as herbosome [132,133], andandrographoloid with its derivatives [126, niosome formulation [134], nanoemulsion 127]. The major bioactive compounds are the formulation [135], liquid and solid self- andrographoloids which are diterpene lactones microemulsifying drug delivery systems [136], [125]. The chemical structures of some bioactive pH-sensitive nanoparticle delivery system [129], phytoconstituents isolated from Andrographis and solid lipid nanoparticle formulation [137]. paniculata are presented in Fig. 5. In addition to these approaches, the Andrographis paniculata extracts are incorporation of ginger, acting as a bioenhancer, standardized using andrographolide contents. significantly enhanced the bioavailability of Andrographolide has poor aqueous solubility and Andrographis paniculata extract by up to 55%, its oral bioavailability at therapeutic doses is very through regulation of intestinal function to low [127-129]. The poor oral absorption of the facilitate absorption [42,67,68]. Addition of product at the clinically useful dose necessitated piperine further increased the bioavailability to reformulation of the extract to enhance its 70%, which suggests that the oral absorption

Andrographolide 14-deoxyandrographolide 14-Deoxy -11,12-dide- hydroandrographolide

Neoandrographolide 14-deoxy-12(R)-sulfoandrographolide Andrographanin

Fig. 5. Chemical structures of some bioactive phytoconstituents of Andrographis paniculata

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can be bioenhanced through other mechanisms. use of this herb for treatment of anxiety, cognitive Reports indicate that andrographolide is a and neurological disorders, inflammation, substrate of P-gp [138], hence, inhibition of hyperlipidemia and Parkinson’s disease [140]. It intestinal P-gp by piperine has the potential of has several other pharmacological activities potentiating the bioavailability of the compound including immunomodulatory, aphrodisiac and [39]. Thus, the poor oral bioavailability of sedative properties [141]. The roots extracts of andrographolide is attributed to not only its poor Withania somnifera consist mainly of steroidal aqueous solubility but also to its rapid gut lactones known as withanolides, which the biotransformation and efflux by P-gp [139]. medicinal properties of the herbal product are attributed to [142,143]. The major withanolides 3.2.2 Withania somnifera are withanolide A and D, and Withaferin A with their derivatives. Their chemical structures are Withania somnifera (family Solanaceae) also presented in Fig. 6. Other biologically active known as ashwagandha or Indian ginseng has chemical constituents are alkaloids of which been an important herb in the ancient system of withanine is the main constituent with other minor Indian traditional medicine. The main parts of the alkaloids such as somniferine, cuscohygrine, plant used therapeutically are the roots. Results isopelletierine, anaferine andanahydrine [144]. from animal studies and clinical trials support the

Fig. 6. Chemical Structures of some bioactive phytoconstituents of Withania somnifera

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Steroidal lactones including withanolides Ginger extract was found to significantly generally have poor aqueous solubility and increase the bioavailability of Picrorhiza kurroa hence have bioavailability problems. Several product by as much as 56 % and this was approaches have been investigated aimed at increased further to 87% when piperine was enhancing the solubility and bioavailability, and added to the formulation [67,68]. Both are thus increase the pharmacological activity of this bioenhancers acting through different HMP. These include formulation of polymeric mechanisms [42]. nanoparticles [145], phytosomes [146,147], and preparation of enteric coated dosage form of the 3.2.4 Tinospora cordifolia herbal extract which protects the composition from hydrolysis in the acidic medium of the Tinospora cordifolia (family Menispermaceae) stomach, thus enhancing the absorption [148]. grows throughout tropical Asia and its extracts have a broad range of pharmacological activities Incorporation of ginger into Withania somnifera notable of which are anti-diabetic, anti- extract increases its absorption by up to 64% spasmodic, anti-inflammatory, anti-oxidant, anti- [42]. This action is mediated via the established malarial, hepatoprotective, immunomodulatory activity of ginger as a potent bioavailability and anti-neoplastic activities [157]. A variety of enhancer which operates by regulation of phytoconstituents isolated from the root, stem intestinal function resulting in increased GIT drug and whole plant have been identified to belong to absorption [42,67,68]. different chemical classes, and the major group of compounds considered as the bioactive 3.2.3 Picrorhiza kurroa constituents are protoberberine alkaloids (egberberine, tembetarine, isocolumbin); Picrorhiza kurroa (family scrophulariaceae), also diterpenoid lactones (eg furanolactone, commonly known as Kutki (Nepali language), is tinosporon, tinosporide); steroids (eg β – an important alpine herb that grows in limited sitosterol, δ-sitosterol,ecdysterone, giloinsterol) regions and altitude and found especially in the and glycosides (egcordifolioside, cordioside, Himalaya region. The roots and rhizomes of this tinocordiside, syringin) [157,158]. The chemical plant are used in traditional medicine for structures of some of these bioactive treatment disorders of liver and upper respiratory constituents are shown in Fig. 7. tract, dyspepsia, diarrhea, and dysentery, among other ailments [149]. The HMP has also been It is apparent from the chemical structures of the shown to possess other pharmacological various bioactive constituents of T. cordifolia that activities including antioxidant and anti- they have different degrees of hydrophilicity or inflammatory [150,151]. The major bioactive lipophilicity. For example, steroids are lipophilic constituents which its therapeutic effects are and generally have poor aqueous solubility while attributed to are irioid glycosides called picroside glycosides are hydrophilic and are associated I and picroside II [152]. The chemical structures with poor intestinal permeability. This entails that are presented in Fig. 7. formulation modalities which can improve aqueous solubility and/or GIT permeability have Like most irioid glycosides, the picrosides have the potential of enhancing the bioavailability of poor intestinal permeability attributable to their some constituents of this HMP. Few studies are high hydrophilic nature. Also, the glycosides reported on the bioavailability improvement of T. undergo hydrolysis in the GIT and the released cordifolia extract. Using an everted gut model, aglycones have poor bioavailabilty due to their when compared to control, about a 4-fold limited aqueous solubility [153]. As a result of the enhancement in permeability coefficient of T. poor bioavailability, this herbal product is cordifolia extract was obtained with recommended to be administered in higher nanoemulsion formulation of this HMP [159]. The quantities resulting in increased treatment cost authors concluded that the nanoemulsion [154]. Review of the literature shows that limited formulation will result in enhancement of strategies have been developed to improve therapeutic efficacy through improved bioavailability of these biomolecules and these permeation of the active constituents across the include a nano-encapsulation formulation of the GIT [159]. In another study, a significant plant extract [155]. Another study is an invention enhancement of bioavailability of T. cordifolia which reports on formulation of phytosomes of product was observed when Carum carvi picroside II with phospholipid which significantly extracts was incorporated into the product [62]. improves the bioavailability of picroside II [156]. Carum carvi extract has been reported to

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enhance the bioavailability of several synthetic Ginger extract was found to significantly increase and other herbal drugs and this bioavailability the bioavailability of T. cordifolia product by up to enhancing activity was found to be consistent 67% and this was increased further to 112% from 5 to100 mg/kg body weight irrespective of when piperine was added to the formulation [67, the amount of the drug(s) present in the 68]. As earlier stated, ginger has a strong effect formulation [62]. The mode of bioavailability on GIT mucous membrane leading to regulation enhancement action is thought to be by inhibition of intestinal function to facilitate absorption [42]. of P-gp mediated efflux of the absorbed Piperine, being a P-gp inhibitor just like Carum compounds back into the GIT [38,40] since some carvi extract [38,39] could have potentiated the constituents of T. cordifolia extract are substrates bioavailability by inhibition of P-gp efflux of T. of P-gp [159]. cordifolia constituents.

Fig. 7. Chemical Structures of bioactive phytoconstituents of Picrorhiza kurroa and Tinospora cordifolia

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