Article

Piperine-mediated inhibition of glucuronidation activity in isolated epithelial cells of the guinea-pig small intestine: evidence that piperine lowers the endogeneous UDP-glucuronic acid content

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Modulation of the factors affecting EGCG bioavailability might increase plasma and tissue levels of this compound as well as its cancer preventive activity. Piperine ( Fig. 1), an alkaloid derived from black pepper (Piper spp.), has been reported to inhibit glucuronidation activity in rats and guinea pigs (7,8). Singh et al. (7) reported that piperine inhibited rat hepatocyte-mediated glucuronidation of 3-hydroxybenzo[a]pyrene with an IC 50 of 50 mol/L. ...
... Piperine ( Fig. 1), an alkaloid derived from black pepper (Piper spp.), has been reported to inhibit glucuronidation activity in rats and guinea pigs (7,8). Singh et al. (7) reported that piperine inhibited rat hepatocyte-mediated glucuronidation of 3-hydroxybenzo[a]pyrene with an IC 50 of 50 mol/L. It was reported that coadministration of piperine and curcumin to humans and rats enhanced the bioavailability of curcumin by 2000% and 154%, respectively (9). ...
... In the present study, we sought to determine whether the black pepper alkaloid, piperine, could serve as a potential dietary modulator of the bioavailability of the green tea catechin, EGCG, in mice. Previously, piperine was shown to inhibit the glucuronidation of 3-hydroxybenzo[a]pyrene by small intestinal and hepatic microsomes (7,13). Moreover, coadministration of piperine and curcumin substantially enhanced the bioavailability of curcumin in humans and rats compared to treatment with curcumin only (9). ...
Article
(-)-Epigallocatechin-3-gallate (EGCG), from green tea (Camellia sinensis), has demonstrated chemopreventive activity in animal models of carcinogenesis. Previously, we reported the bioavailability of EGCG in rats (1.6%) and mice (26.5%). Here, we report that cotreatment with a second dietary component, piperine (from black pepper), enhanced the bioavailability of EGCG in mice. Intragastric coadministration of 163.8 mumol/kg EGCG and 70.2 mumol/kg piperine to male CF-1 mice increased the plasma C,a and area under the curve (AUC) by 1.3-fold compared to mice treated with EGCG only. Piperine appeared to increase EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit. Piperine (100 mumol/L) inhibited EGCG glucuronidation in mouse small intestine (by 40%) but not in hepatic microsomes. Piperine (20 mumol/L) also inhibited production of EGCG-3"-glucuronide in human HT-29 colon adenocarcinoma cells. Small intestinal EGCG levels in CF-1 mice following treatment with EGCG alone had a C-max = 37.50 +/- 22.50 nmol/g at 60 min that then decreased to 5.14 +/- 1.65 nmol/g at 90 min; however, cotreatment with piperine resulted in a C-max = 31.60 +/- 15.08 nmol/g at 90 min, and levels were maintained above 20 nmol/g until 180 min. This resulted in a significant increase in the small intestine EGCG AUC (4621.80 +/- 1958.72 vs. 1686.50 +/- 757.07 (nmol/g(.)min)). EGCG appearance in the colon and the feces of piperine-cotreated mice was slower than in mice treated with EGCG alone. The present study demonstrates the modulation of the EGCG bioavailablity by a second dietary component and illustrates a mechanism for interactions between dietary chemicals.
... The spiciness of black pepper is because of the MDP-containing phytochemical, piperine, and related pungent alkaloids known as piperamides [454] (Fig. 16.12). These compounds function as insecticides in the pepper plant [457][458][459], but in mammalian systems they are inhibitors of various XMEs [460][461][462][463][464][465][466][467][468][469][470][471] and transporters [186,187,[472][473][474][475]. While inhibition is clearly the most prevalent finding, especially on acute exposure, several animal studies report upregulation of GSTs [476], certain CYPs [477,478], and ABCs [186,472,474] with long-term exposure to piperine, a finding in line with other studies examining chronic feeding of MDP-PSMs. ...
... In addition, piperine increased the pharmacodynamic effects of hexobarbital and zoxazolamine in a dose-dependent manner [460]. Follow-up studies by Atal's group observed that piperine administration was a noncompetitive inhibitor of various murine hepatic monoxygenases as well as UGTs [461]. Subsequent studies confirmed piperine's effect on murine XMEs [462][463][464][465][466][467]470] and also found that it and other piperamides were selective inhibitors of human CYP3A4, CYP2D6, and ABCB1 in vitro [187,468,469,471]. ...
... Piperine is endowed with numerous pharmacological activities but the most important being the enhancement of bioavailability [11,12] inhibition of cytochrome P450 as well as mammalian pglycoprotein [16]. On the basis of above mentioned pharmacological actions of piperine Indian Institute of Integrative Medicine, Jammu has developed an anti-TB formulation called 'Risorine', being marketed in India by Cadila Pharmaceutical Ltd. ...
... However, there was no effect on Th-2 cytokines such as IL-4. The Th-1 cytokines are associated with the generation of cellmediated immunity and resistance to intracellular parasites, whereas Th-2 cytokines favour the induction of humoral immunity and resistance to extracellular parasites [19,16]. IL-2 stimulates NKcell proliferation and activation for the production of IFN-g [20]. ...
... Piperine is one of the first purified natural molecules with bioenhancer properties [6] . It increases the bioavailability of drugs by inhibiting the biotransformation processes occurring in liver and intestine, due to its ability to inhibit the activity of various metabolizing enzymes [6,7,8] . ...
... Piperine is endowed with numerous pharmacological activities but the most important being the enhancement of bioavailability inhibition of cytochrome P450 as well as mammalian p-glycoprotein. Its potential immune-modulatory activity has also been reported [6,7,26,27] . Piperine content in fruits of five Piper species namely, P. nigrum, P. longum, P. retrofractum Vahl, P. cubea Hunter, P. betle and also in processed P. nigrum (white pepper) was estimated by high performance thin layer chromatography method by Rajopadhye et al. [28] . ...
... Adult male Swiss albino mice were daily administered Piperine at a dose of 2.50 mg/kg for 15 days, after that time serum levels of both the thyroid hormones, thyroxin (T4) and triiodothyronine (T3) as well as glucose concentrations were lowered [83]. Other study showed that its ingestion canmodulate the levels of apolipoprotein and insulin resistance in rat [86,87]. ...
... Piperine induced a noncompetitive inhibition of hepatic microsomal UDP-glucuronyltransferase with a Ki value of 70 M. The studies demonstrate that Piperine modifies the rate of glucuronidation by lowering the endogeneous UDP-glucuronic acid content and also by inhibiting the transferase activity [87]. Piperine has previously been shown to inhibit several cytochrome P450-mediated pathways and phase II reactions in animal models [88]. ...
Article
Full-text available
Objective: Piper has been used for long timelike condiment and food, but also in traditional medicine around of the world. This work resumes the available and up to date work done on members of the Piperaceae family and their uses for therapeutic purposes. Methods: Information on Piper genus was gathered via internet using scientific databases such as Scirus, Google Scholar, CAB-abstracts, MedlinePlus, Pubmed, SciFinder, Scopus and Web of Science. Results: The largeleafed perennial plant Piper is used for its spicy aromatic scent and flavor. It has an important presence in the cuisine of different cultures. Another quality of these plants is their known medicinal properties. It has been used as emollient, antirheumatic, diuretic, stimulant, abortifacient, anti-inflammatory, antibacterial, antifungal and antidermatophytic. A survey of the literature shows that the genus Piper is mainly known for its alkaloids with cytotoxic, chemopreventive, antimetastatic and antitumor properties in several types of cancer. Studies of its alkaloids highlight the existence of various potential leads to develop new anti-cancer agents. Modern pharmacology studies have demonstrated that its crude extracts and active compounds possess wide pharmacological activities, especially asantioxidant, anti-depressive, hepatoprotective, antimicrobial, anti-obesity, neuropharmacological, to treat cognitive disorders, anti-hyperlipidemic, anti-feedant, cardioactive, immuno-enhancing, and anti-inflamatory. All this evidence supporting its traditional uses. Aim of the review: This review summarizes the up-to-date and comprehensive information concerning the botany, traditional use, phytochemistry and pharmacology of Piper together with its toxicology, and discusses the possible trend and scope for further research on Piper in the future.
... These observations suggest that piperine is a potent inhibitor of drug metabolism. The mechanism of inhibition of glucuronidation by piperine has been explored by examining the rate of glucuronidation of 3-OH-BP and UDP-glucuronic acid (UDPGA) concentration in isolated epithelial cells of the guinea pig small intestine [9], and it was found that glucuronidation of 3-OH-BP was dependent on duration of incubation, cellular protein, and endogenous UDPGA concentration. Piperine caused a concentrationrelated decrease in UDPGA content and the rate of glucuronidation in these cells. ...
... A study of the modulation of benzo(a-)pyrene metabolism and regulation of cytochrome CYP1A1 gene expression by piperine in 5 L cells in culture revealed that piperine-mediated inhibition of AHH activity and consequent suppression of the procarcinogen activation results from direct interaction of piperine with [8] (b) Decreased UDP-glucuronic acid concentration and rate of glucuronidation in isolated epithelial cells of guinea pig small intestine by piperine [9] (c) Inhibition of aryl hydroxylase and O-deethylase activities by piperine in vitro in pulmonary microsomes [10] (d) Suppression of aryl hydroxylation in cell culture is mediated by direct interaction of piperine with cytochrome P 450 and not by downregulation of its gene expression [11] (e) Piperine decreased the activities of liver microsomal aryl hydroxylase, N-demethylase and UDP-glucuronosyl transferase, and cytochrome P 450 [12] Rats (a) Lower aryl hydroxylase and UDP-glucuronyl transferase activities, prolonged hexobarbital sleeping time in piperine-treated rats [8] (b) Inhibition of aryl hydroxylase and O-deethylase activities by piperine in vivo in pulmonary microsomes [10] (c) Decreased activities of hepatic microsomal cytochrome P 450 , Ndemethylase, aryl hydroxylase by intragastric/intraperitoneal piperine [13] (d) Inhibition of UDP-glucose dehydrogenase and UDP-glucuronyl transferase in liver and intestine by piperine [14] (e) Lowered activity of N-demethylase, UDP-glucuronosyl transferase, and NADPH-cytochrome-C reductase as a result of piperine feeding [12] Guinea pig (a) Inhibition of UDP-glucose dehydrogenase and UDP-glucuronyl transferase in liver and intestine by piperine [14] cytochrome P 450 1A1-protein and not because of downregulation of its gene expression [11]. Piperine was evaluated for beneficial effects in Alzheimer's disease by studying the potential for herb-drug interactions involving cytochrome P 450 , UDPglucuronosyl transferase, and sulfotransferase enzymes. ...
Chapter
Full-text available
The distinct biting quality of black pepper (Piper nigrum) widely used in human dietary is attributed to the alkaloid piperine. Black pepper is also used as a food preservative and as a vital component in traditional medicines in India and China. Several physiological effects of black pepper and its bioactive alkaloid piperine have been reported in recent decades. By stimulating the digestive enzymes of pancreas, piperine enhances the digestive capacity. Piperine has been documented to enhance the bioavailability of a number of therapeutic drugs as well as phytochemicals by its inhibitory influence on drug transformation reactions in liver and intestine. It strongly inhibits hepatic and intestinal aryl hydrocarbon hydroxylase and glucuronyl transferase. Piperine’s bioavailability enhancing property is also partly attributed to increased absorption as a result of its effect on the ultrastructure of intestinal brush border. Piperine has been evidenced to have antidiarrheal property and an effect on intestinal motility and on the ultrastructure of intestinal microvilli improving absorbability of micronutrients. Piperine has been demonstrated in in vitro studies to protect against oxidative damage by inhibiting or quenching reactive oxygen species. Piperine treatment also lowers lipid peroxidation in vivo and beneficially influences antioxidant status in situations of oxidative stress. Piperine has been found to possess antimutagenic and antitumor influences.
... Dose dependent inhibition of ethyl morphine-Ndemethylation, arylhydrocarbon hydroxylation, 3-hydroxybenzo (a) pyreneglucuronidation and 7-ethoxycoumarin-Odeethylation in rat post mitochondrial supernatant was observed in an in vitro study [48]. A study conducted on the effect of piperine on glucuronidation activity in epithelial cells of guinea pig small intestine confirms that piperine also inhibits the rat hepatic monooxygenase and glucuronidation by lowering the UDP-glucuronicacid and UDP-glucuronyltransferase activity [49]. Three studies conducted between 1991-1996 explore the inhibitory effects of piperine on cytochrome P-450 activities [50]. ...
Article
Natural products, especially foods and extracts from plant origin have been successful in treating various disorders in traditional medicine. Piperine, a versatile bioactive compound is found in almost 2000 varieties of piper species from piper genus. The plants containing piperine, particularly, Piper nigrum (black pepper) and Piper longum (long pepper), are widely used in the traditional as well as alternative therapies for both human and domestic illnesses. Effect of piperine on gastrointestinal system, drug metabolizing enzymes, P-glycoprotein and alteration of bioavailability of other drugs are the major area of research. Particularly, bio-enhancing properties of piperine is of clinical importance, as co-administration with drugs for the treatment of human immunodeficiency virus (HIV) infections, pancreatitis, tuberculosis, hyperlipidemia, bronchial asthma and epileptic disorders, resulted in enhanced bioavailability of these drugs. Also investigations are being carried out to elucidate the underlying mechanism of action for the anti-fertility and anti-cancer effects of piperine. Comprehensive data regarding the in silico, safety, pre-clinical pharmacology, clinical studies of piperine and its derivatives are compiled in this review, to act as a guide for future drug development.
... Measured hepatic UDPGA concentrations in mammals were in the range of 120 to 500 M (Zhivkov et al., 1975;Cappiello et al., 1991;Goon and Klaassen, 1992) and in fish were 21 M (carp) and 115 M (trout) (Zhivkov et al., 1975). The rate of glucuronidation of 3-hydroxybenzo[a]pyrene in guinea pig intestinal epithelial cells was found to be dependent on the endogenous level of UDPGA (Singh et al., 1986), as was glucuronidation of 7-hydroxycoumarin in rat liver (Conway et al., 1988). The efficacy of glucuronidation of a xenobiotic could be overestimated because the maximal rate determined by conventional kinetic experiments may be greater than the maximal rate that is possible in vivo. ...
Article
Full-text available
Polychlorinated biphenylols (OH-PCBs) are potentially toxic poly-chlorinated biphenyl metabolites that can be eliminated by glucu-ronidation, catalyzed by UDP-glucuronosyltransferases (UGTs). OH-PCBs with a 3,5-dichloro-4-hydroxy substitution pattern have been detected in blood from humans and wildlife, suggesting slow elimination. In this study we assessed the glucuronidation of 4-OH-PCBs with zero, one, or two chlorine atoms flanking the 4-hydroxyl group and zero to four chlorine atoms in the aphenolic ring in microsomes from channel catfish liver and proximal intestine. Product formation was quantitated with [ 14 C]UDP-glucuronic acid (UDPGA). Physiological concentrations of UDPGA were measured in preparations of liver and intestine. When the OH-PCB concentrations were varied in the presence of saturating UDPGA concentrations , glucuronidation V max values were higher in hepatic than in intestinal microsomes (0.40–3.4 and 0.12–0.78 nmol/min/mg of protein, respectively), whereas the K m values were generally lower for intestine (0.042–0.47 mM) than for liver (0.11–1.64 mM). In both tissues V max values with 3,5-dichloro-4-OH-PCBs were lower than with the corresponding 3-chloro-4-OH-PCBs. Varying the UDPGA concentrations in the presence of saturating concentrations of OH-PCB showed that the K m for UDPGA was lower in intestine (27 M) than in liver (690 M). The measured concentration of UDPGA in catfish liver (246–377 nmol/g) was lower than the K m for UDPGA, suggesting that in vivo rates of glucuronidation may be suboptimal, whereas in intestine the measured UDPGA concentration (71–258 nmol/g) was higher than the K m for UDPGA. Although liver has a greater glucuronidation capacity than proximal intestine, the properties of intestinal UGTs in channel catfish enable them to efficiently glucuronidate low concentrations of OH-PCBs.
... It has been shown to inhibit arylhydrocarbon hydroxylation, ethylmorphine-N-demethylation, and 7-ethoxycoumarin-o-deethylation and 3hydroxybenzopyrene glucuronidation in a nonspecific and noncompetitive manner in vitro. It appears that the Trikatu group of drugs increases bioavailability either by promoting rapid absorption from the gastrointestinal tract, or by protecting the drug from being metabolized /oxidized in its first passage through the liver after being absorbed, or by a combination of these two mechanisms [20,21,8] . Antioxidant Activity: In vitro antioxidant activity of petroleum ether, benzene, chloroform, ethyl acetate, 70% ethanol and aqueous extract of Trikatu was performed. ...
Article
Full-text available
Trikatu is a very well known ‘Rasayana’ in Ayurveda and widely used as a polyherbal ayurvedicformulation in India. It consists of three well known plants, viz., Piper longum Linn., Piper nigrum Linn. And Zingiber officinale Rosc. in equal ratio. It is mentioned in the ancient books of Ayurveda used for thetreatment of fever, asthma, cold and cough, diabetes, nasal diseases, obesity, anorexia, digestive, respiratorysystem and normal urinary tract function. Phytochemical investigations indicate that 3 compounds reported from the polyherbal formulation and also it contains various chemical category viz. alkaloids, phytosterol, triterpenes, flavonoids and various other phenolic compounds. Pharmacological activities of Trikatu reported include hepatoprotective, antioxidant, analgesic, anti-anorectic, anti-inflammatory, antimicrobial, antifungal, anthelminitic, anti-arthritic, adaptogenic, antihyperlipidemic and antitumor activity. In the present review the literature data on the phytochemical and biological investigations on the Trikatu are summarized up to March 2015
... It has been shown to inhibit arylhydrocarbon hydroxylation, ethylmorphine-N-demethylation, and 7-ethoxycoumarin-o-deethylation and 3hydroxybenzopyrene glucuronidation in a nonspecific and noncompetitive manner in vitro. It appears that the Trikatu group of drugs increases bioavailability either by promoting rapid absorption from the gastrointestinal tract, or by protecting the drug from being metabolized /oxidized in its first passage through the liver after being absorbed, or by a combination of these two mechanisms [20,21,8] . Antioxidant Activity: In vitro antioxidant activity of petroleum ether, benzene, chloroform, ethyl acetate, 70% ethanol and aqueous extract of Trikatu was performed. ...
Conference Paper
Full-text available
Trikatu is a very well known 'Rasayana' in Ayurveda and widely used as a polyherbal ayurvedic formulation in India. It consists of three well known plants, viz., Piper longum Linn., Piper nigrum Linn. and Zingiber officinale Rosc. in equal ratio. It is mentioned in the ancient books of Ayurveda used for the treatment of fever, asthma, cold and cough, diabetes, nasal diseases, obesity, anorexia, digestive, respiratory system and normal urinary tract function. Phytochemical investigations indicate that 3 compounds reported from the polyherbal formulation and also it contains various chemical category viz. alkaloids, phytosterol, triterpenes, flavonoids and various other phenolic compounds. Pharmacological activities of Trikatu reported include hepatoprotective, antioxidant, analgesic, anti-anorectic, anti-inflammatory, antimicrobial, antifungal, anthelminitic, anti-arthritic, adaptogenic, antihyperlipidemic and antitumor activity. In the present review the literature data on the phytochemical and biological investigations on the Trikatu are summarized up to March 2015.
... To overcome such barriers on effectiveness of flavonoids in a body, bioenhancers that can modulate hepatic metabolism of flavonoids have been introduced. Piperine strongly inhibited the UGT activities [15] and modified the rate of glucuronidation by lowering the endogenous UDP-glucuronic acid content and also by inhibiting the transferase activity [16]. Currently, resveratrol is a dietary chemical under development for its numerous health benefits. ...
Article
Full-text available
The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E₂ (PGE₂), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Ki value of 7.782 μM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body.
... Piperine is a drug potentiator that Review inhibits the human P-glycoprotein, 77 particularly cytochrome P450-mediated pathways, and mediates inhibition of glucuronidation activity in animal models. 78 Piperine is used commercially as an inhibitor of enzymes that are important both in drug metabolism and in the transport of metabolites and xenobiotics. It simultaneously increases the bioavailability of various compounds and reduces the efficacy of some medications. ...
Article
Full-text available
The emergence of drug resistance continues to plague TB control, with a global increase in the prevalence of MDR-TB. This acts as a gateway to XDR-TB and thus emphasizes the urgency for drug development and optimal treatment options. Bedaquiline is the first new anti-TB drug approved by the FDA in 40 years and has been shown to be an effective treatment option for MDR Mycobacterium tuberculosis infection. Bedaquiline has also recently been included in clinical trials for new regimens with the aim of improving and shortening treatment periods. Alarmingly, efflux-mediated bedaquiline resistance, as well as efflux-mediated cross-resistance to clofazimine, has been identified in treatment failures. This mechanism of resistance results in efflux of a variety of anti-TB drugs from the bacterial cell, thereby decreasing the intracellular drug concentration. In doing so, the bacillus is able to render the antibiotic treatment ineffective. Recent studies have explored strategies to reverse the resistance phenotype conferred by efflux pump activation. It was observed that the addition of efflux pump inhibitors partially restored drug susceptibility in vitro and in vivo. This has significant clinical implications, especially in MDR-TB management where treatment options are extremely limited. This review aims to highlight the current efflux pump inhibitors effective against M. tuberculosis, the effect of efflux pump inhibitors on mycobacterial growth and the clinical promise of treatment with efflux pump inhibitors and standard anti-TB therapy.
... Piperine has always been a center of attraction in research due to its potential of being an enhancer of bioavailability of drugs through the inhibition of CYP3A4 and human P-glycoprotein, particularly cytochrome P450-mediated pathways. 85,86 In tuberculosis treatment, piperine acts as an inhibitor of bacterial efflux pumps and an immunomodulatory compound. 87 Piperine is efficient against the multidrug-resistant strains along with eliminating drug-sensitive strains. ...
Article
Full-text available
Eastern countries are a major source of medicinal plants, which set up a rich source of ethnopharmacologically known medicines used in the treatment of various diseases. These traditional medicines have been known as complementary, alternative, or nonconventional therapy across globe for ages. Tuberculosis (TB) poses a huge global burden and leads to maximum number of deaths due to an infectious agent. Treatment of TB using Directly Observed Treatment Short‐course (DOTS) therapy comprises multiple antibiotics is quite lengthy and causes serious side‐effects in different organs. The length of the TB treatment leads to withdrawal from the patients, which paves the way for the emergence of drug resistance in the bacterial population. These concerns related to therapy need serious and immediate interventions. Traditional medicines using phytochemicals has shown to provide tremendous potential in TB treatment, mainly in the eradication of Mycobacterium tuberculosis (M.tb), increasing natural immunity, and managing the side effects of anti‐TB drugs. This review describes the antituberculosis potential of selected ethnopharmacologically important phytochemicals as potential immune‐modulator and as an adjunct‐therapy in TB. This review will be a useful reference for researchers working on ethnopharmacology and will open the door for the discovery of novel agents as an adjunct‐therapy to tuberculosis. The different modes of action of phytochemicals in adjunct therapy for the treatment of TB.
... The basis of inhibition of glucuronidation by piperine has been explored by examining the rate of glucuronidation of 3-OH-BP and UDP-glucuronic acid (UDPGA) content in the intact isolated epithelial cells of the guinea-pig small intestine. 29 It was found that glucuronidation of 3-OH-BP was dependent on duration of incubation, cellular protein and endogenous UDPGA concentration. ...
Chapter
Full-text available
Black pepper (Piper nigrum), an Indian native spice, has been widely used in human diet for several thousands of years. It is valued for its characteristic sharp and stinging qualities attributed to the alkaloid piperine. While it is used primarily as a food adjunct, black pepper is also used as a food preservative and as an essential component in traditional medicines in India and China. Since the discovery of black pepper's active ingredient, piperine, the use of black pepper has caught the interest of modern medical researchers. Many physiological effects of black pepper, its extracts or its bioactive compound, piperine, have been reported in recent decades. By stimulating the digestive enzymes of the pancreas, piperine enhances digestive capacity and significantly reduces gastrointestinal food transit time. Piperine has been documented to enhance the bioavailability of a number of therapeutic drugs as well as phytochemicals through its inhibitory influence on enzymatic drug biotransforming reactions in liver and intestine. It strongly inhibits hepatic and intestinal aryl hydrocarbon hydroxylase and glucuronyl transferase. Most of the clinical studies on piperine have focused on its effect on drug metabolism. Piperine's bioavailability enhancing property is also partly attributed to increased absorption as a result of its effect on the ultrastructure of the intestinal brush border. Piperine has been demonstrated in in vitro studies to protect against oxidative damage by inhibiting or quenching reactive oxygen species. Black pepper or piperine treatment has also been evidenced to lower lipid peroxidation in vivo and beneficially influence antioxidant status in a number of experimental situations of oxidative stress. Piperine has also been found to possess anti-mutagenic and anti-tumor influences. Clinical studies are limited, but several have reported the beneficial therapeutic effects of black pepper in the treatment of smoking cessation and dysphagia. © 2009 by World Scientific Publishing Co. Pte. Ltd. All rights reserved.
... 3-O-Acetyl-11-keto-b-boswellic acid (AK) is a pentacyclic triterpene obtained from gum resin of Boswellia serrata plant. Boswellia has a long history for being used in traditional Ayurvedic medicines for the treatment of inflammatory diseases (Safayhi et al., 1992;Singh et al., 1986), crohn disease, ulcerative colitis and arthritis (Gerhardt et al., 2001;Gupta et al., 2003;Kiela et al., 2005;Safayhi et al., 1991). Moreover, studies have also advocated the efficacy of AK in a variety of tumor cell lines (Liu et al., 2002;Park et al., 2002;Syrovets et al., 2005;Winking et al., 2000;Zhao et al., 2003). ...
Article
The present study was planned to see whether 3-O-Acetyl-11- keto-?-boswellic acid has any protective effects against benzo(a)pyrene (BaP) induced toxicity or not. In vitro studies show concentration dependent linear association of radical scavenging activity of AK which is comparable to ascorbic acid taken as reference compound. For in vivo studies, the animals were divided randomly into five groups which included a) normal control, b) vehicle treated (olive oil), c) BaP treated, d) AK treated and e) AK?+?BaP (combined treated). BaP was administered at a dose of 50mg/kg in olive oil twice a week orally for 4 weeks and AK (50mg/kg) was given in olive oil thrice a week for 4 weeks before and after BaP exposure. BaP treated animals showed a significant increase (p?<?0.001) in lipid peroxidation (LPO) and protein carbonyl contents (PCC) in hepatic tissue. Further, a significant increase (p?<?0.001) in the liver marker enzymes as well as citrulline and nitric oxide levels in the hepatic tissue was also observed. Interestingly, AK when supplemented to BaP treated animals ameliorated the above said biochemical indices appreciately. The histopathological observations also showed appreciable improvement when BaP treated animals were supplemented with AK, thus emphasing the protective potential of AK.
... Piperine, an alkaloid isolated from Piper nigrum fruits, is one of the first purified natural molecules with bioenhancer properties [22]. Piperine increases the bioavailability of drugs by inhibiting the biotransformation processes occurring in liver and intestine, due to its ability to inhibit the activity of various metabolizing enzymes, such as hepatic monooxygenases, aryl hydroxylases, N-demethylases, and UDP-glucuronyltransferases [22][23][24]. Piperine also inhibits cytochrome P450 3A4 (CYP3A4), a major enzyme participating in the first pass drug metabolism, and the P-glycoprotein transporter, which has been involved in the rapid efflux (systemic elimination) of drugs [25]. ...
Article
Full-text available
Knowing that curcumin has low bioavailability when administered orally, and that piperine has bioenhancer activity by inhibition of hepatic and intestinal biotransformation processes, the aim of this study was to investigate the antidiabetic and antioxidant activities of curcumin (90 mg/kg) and piperine (20 or 40 mg/kg), alone or co-administered, incorporated in yoghurt, in streptozotocin (STZ)-diabetic rats. The treatment for 45 days of STZ-diabetic rats with curcumin-enriched yoghurt improved all parameters altered in this experimental model of diabetes: the body weight was increased in association with the weight of skeletal muscles and white adipose tissues; the progressive increase in the glycemia levels was avoided, as well as in the glycosuria, urinary urea, dyslipidemia, and markers of liver (alanine and aspartate aminotransferases and alkaline phosphatase) and kidney (urinary protein) dysfunction; the hepatic oxidative stress was decreased, since the activities of the antioxidant enzymes superoxide dismutase, catalase and gluthatione peroxidase were increased, and the levels of malondialdehyde and protein carbonyl groups were reduced. The dose of 20 mg/kg piperine also showed antidiabetic and antioxidant activities. The treatment of STZ-diabetic rats with both curcumin and 20 mg/kg piperine in yoghurt did not change the antidiabetic and antioxidant activities of curcumin; notably, the treatment with both curcumin and 40 mg/kg piperine abrogated the beneficial effects of curcumin. In addition, the alanine aminotransferase levels were further increased in diabetic rats treated with curcumin and 40 mg/kg piperine in comparison with untreated diabetic rats. These findings support that the co-administration of curcumin with a bioenhancer did not bring any advantage to the curcumin effects, at least about the antidiabetic and antioxidant activities, which could be related to changes on its biotransformation.
... Indirect determination of UDPGA concentrations is based on the normally linear relationship between glucuronide formation and UDPGA concentration. The determination of glucuronide formation, whether via radiochemical detection (Schiller et al., 1982;Watkins and Klaasen, 1982;Hjelle et al., 1985;Cappiello et al., 1991), fluorometry (Singh et al., 1986) or reverse-phase HPLC (Yamamura et al., 2000), can then be used to down-extrapolate the UDPGA level via a standard curve. Since this method assumes that the linear relationship holds at low UDPGA physiological concentrations, determination of this co-substrate in tissues with lower levels (such as intestine) may be more subject to inaccuracies. ...
... All the drugs metabolized by these enzymes are inuenced by bio-enhancer piperine. 57 All categories of drugs like cardiovascular, respiratory, CNS, GIT, anticancer, immunomodulatory drugs, antibiotics, several other classes of drugs and nutraceuticals are greatly inuenced by piperine. It is interesting to note that piperine brings about its bioenhancing effect at a dose of 10 mg in all formulations irrespective of the dose of combination drug. ...
Article
Full-text available
Piperine, the main alkaloid of black pepper, Piper nigrum Linn., is an important Indian spice used in traditional food and medicine in India. In the present study, we investigated the antioxidant activities of piperine against copper-ascorbate induced toxic injury to mitochondria obtained from a goat heart, in vitro. Incubation of isolated cardiac mitochondria with copper-ascorbate resulted in elevated levels of lipid peroxidation and protein carbonylation of the mitochondrial membrane, a reduced level of mitochondrial GSH and altered status of antioxidant enzymes as well as decreased activities of pyruvate dehydrogenase and the Kreb's cycle enzymes, altered mitochondrial morphology, mitochondrial swelling, di-tyrosine level and mitochondrial DNA damage. All these changes were found to be ameliorated when the cardiac mitochondria were co-incubated with copper-ascorbate and piperine, in vitro. Piperine, in our in vitro experiments, was found to scavenge hydrogen peroxide, superoxide anion free radicals, hydroxyl radicals and DPPH radicals, in a chemically defined system, indicating that this compound may provide protection to cardiac mitochondria against copper-ascorbate induced toxic injury through its antioxidant activities. The results of this study suggest that piperine may be considered as a future therapeutic antioxidant and may be used singly or as a co-therapeutic in the treatment of diseases associated with mitochondrial oxidative stress.
... Piperine is an isolated alkaloid of black pepper [7] that belongs to capsaicin like family [8]. Animal studies have previously demonstrated that piperine inhibits several enzymatic pathways involving P450, as well as phase II metabolism [9,10]. ...
Article
Full-text available
Some studies showed that piperine (the alkaloid of piper nigrum) can change the activities of microsomal enzymes. Midazolam concentration is applied as a probe to determine the CYP3A enzyme activity. This study was done to determine piperine pretreatment role on midazolam plasma concentration. Twenty healthy volunteers (14 men and 6 women) received oral dose of piperine (15 mg) or placebo for three days as pretreatment and midazolam (10 mg) on fourth day of study and the blood samples were taken at 0.5, 2.5 and 5 h after midazolam administration. The midazolam plasma levels were assayed using HPLC method (C18 analytical column, 75:25 methanol:water as mobile phase, UV detector at 242 nm wavelength and diazepam as internal standard). Data were fit in a “one-compartment PK model” using P-Pharm 1.5 software and analyzed under statistical tests. The mean ±SD of the age and body mass index were 24.3 ± 1.83 years (range: 21–28 years) and 23.46± 2.85, respectively. The duration of sedation in piperine receiving group was greater that the placebo group (188±59 vs. 102±43 min, p<0.0001). Half-life and clearance of midazolam were higher in piperine pretreatment group compared to placebo [1.88±0.03 vs. 1.71± 0.04 h (p<0.0001) and 33.62 ± 0.4 vs. 37.09 ± 1.07 ml/min (p<0.0001), respectively]. According to the results, piperine can significantly increases half-life and decreases clearance of midazolam compared to placebo. It is suggested that piperine can demonstrate those effects by inhibition CYP3A4 enzyme activity in liver microsomal system.
... Piperine inhibits number of enzymes responsible for metabolism of drugs as well as nutrients. The studies suggested that piperine nonspecifically inhibited many Cytochrome P 450 isoforms -CYP3A4 (main drug metabolizing microsomal enzyme) hepatic arylhydrocarbon hydroxylse, UDP-glucuronyltransferase and other enzymes involved in biotransformation of drugs and other xenobiotics (Atal et al., 1985;Singh et al., 1986;Bhardwaj et al., 2002). Moreover, piperine administration in rats resulted in 50% decrease of total Cytochrome P 450 content indicating a suicide inhibition by piperine (Dalvi, 1991). ...
Article
Black pepper (family Piperaceae), is called king of spices because it is one of the oldest spice and alone accounts for about 35% of the world's total spice trade. The pepper is used in Ayurvedic medicine for the treatment of various ailments particularly neurological, broncho-pulmonary and gastrointestinal disorders. Pepper has also been reported to have various pharmacological actions but recently, it is highlighted as a bioavailability enhancer. This results in higher plasma concentration of drugs, nutrients, ions and other xenobiotics, rendering them more bioavailable for physiological as well as pharmacological actions in the body. Numerous scientific studies reported that piperine; a main bioactive compound of pepper, is responsible for its bioavailability enhancing property. It's a well known fact that pepper enhances bioavailability by inhibition of microsomal enzyme system but other mechanisms are also responsible to acts as a bioavailability enhancer. The brief overview of the mechanism of action of pepper as well as its applications as bioavailability enhancer is given in the present article.
... P. nigrum is the next frequent species which is found to be present in the traditional preparations. Earlier studies have demonstrated that piperine, obtained from P. nigrum inhibits several constitutive and inducible cytochrome P450 (CYP) activities in in vitro and in vivo studies (Atal et al. 1985;Singh et al. 1986Singh et al. , 1994Reen and Singh 1981;Reen et al. 1993Reen et al. , 1996Koul et al. 2000). The use of piper species in most of the traditional medicinal formulations is most likely to be because it leads to an enhancement of the drug bioavailability of the other drugs used in the formulation. ...
Article
Full-text available
An ethno-medicinal survey among the Tai-Ahom community of Assam was undertaken to gather knowledge on different medicinal formulations that are prepared and administered by their bejes/bejinis (medicine men/women). In this study, treatments mentioned in ancestral manuscripts, their methods of preparation, formulations and their applications in different diseases have been described. Ways of diagnosing the diseases, precautions to be maintained while on treatment, adverse effects, and follow up treatments have also been mentioned. The objective was to search for novel plants having medicinal value and to understand the importance of their traditional medicinal preparations and their relevance in the modern era. Besides providing information about the properties of some uncommon plants the data offers new insight to the usage of some of these medicinal preparations and reinforces the need for safeguarding these methods for further assessment.
... In particular, all the results summarized in Fig. 4 and Table 2 confirm the essential role of piperine in the pharmacokinetic profile of curcumin, in agreement with previous works related to the co-administration of unformulated curcumin and piperine [11,39]. In fact, as reported in Fig. 4, which describes the ratios of metabolites (glucuronide, C and sulphate, E) to parent curcumin AUCs, the presence of piperine determined beneficial changes in curcumin metabolism with the various treatments. ...
Article
Although nanocarriers can enhance the bioavailability of free curcumin in the blood, a systematic study on the parameters that affect such enhancement is still missing. In this work we focused the attention on a nanocarrier represented by an oil in water nano-emulsion coated with a thiol modified chitosan and carried out a comprehensive study on the effects that parameters such as size, co-delivery of piperine and degree of chitosan modification can exert on curcumin bioavailability and quantified their impact. We obtained an unprecedented pharmacokinetic profile of curcumin with the best formulation, represented by a combination of a small nano-emulsion size (110 nm), co-delivery of curcumin and piperine (weight ratio 100:1) and a high degree of chitosan thiolation (14–15%). Then, we assessed its anti-inflammatory properties after oral administration in rats at low doses (≤ 0.1 times the volume administered in the pharmacokinetic study). Furthermore, the proposed food grade nano-emulsions loaded with curcumin did not show any cytotoxic effect on normal fibroblasts, while they were able to promote death in colon cancer cells in agreement with the common knowledge of the selective action of curcumin.
... Interestingly, piperine is an inhibitor of various enzymes involved in xenobiotic metabolism and increases the bioavailability of various drugs [5]. Piperine has been shown to inhibit glucuronidation of xenobiotics [30]. Thus, for example, piperine enhanced the bioavailability of epigallocatechin-3-gallate (EGCG) in mice, apparently by inhibiting glucuronidation of EGCG in the small intestine [31]. ...
Article
Recently many studies showed anticancer activities of piperine, a pungent alkaloid found in black pepper and some other Piper species. We attempted to summarize acquired data that support anticancer potential of this natural agent. Piperine has been reported to possess effective chemopreventive activity. It has been studied to affect several mechanisms of action, in brief enhancing antioxidant system, increasing level and activity of detoxifying enzymes and suppressing stem cell self-renewal. Moreover, piperine has been found to inhibit proliferation and survival of various cancerous cell lines via modulating cell cycle progression and exhibiting anti-apoptotic activity, respectively. This compound has been shown to modify activity of various enzymes and transcription factors to inhibit invasion, metastasis and angiogenesis. Interestingly, piperine has exhibited antimutagenic activity and also inhibited activity and expression of multidrug resistance transporters such as P-gp and MRP-1. Besides, about all reviewed studies have reported selective cytotoxic activity of piperine on cancerous cells in compared with normal cells. Altogether, the studies completely underline promising candidacy of piperine for further development. The collected preclinical data we provided in this article can be useful in the design of future researches especially clinical trials with piperine.
... The concept of Yogavahi for enhancing bioavailability is being used in Ayurveda since time immemorial. [4,5] A very common example of Yogavahi in Ayurveda includes Pippali (P. longum) and Maricha (P. ...
... The concept of Yogavahi for enhancing bioavailability is being used in Ayurveda since time immemorial. [4,5] A very common example of Yogavahi in Ayurveda includes Pippali (P. longum) and Maricha (P. ...
Article
Full-text available
The concept of bioavailability enhancer is new to the modern system of medicine. Basically, this concept originated in Ayurveda and being used in this system of medicine since centuries. Bio-enhancers augment the bioavailability or biological activity of drugs when co-administered with principal drug at low doses. Ayurveda is using several drugs such as Piper longum Linn., Zingiber officinale Rosc., and Glycyrhhiza glabra Linn. as bio-enhancers and different methods for bio-enhancing since centuries. The bio-enhancement leads to reduction in therapeutic dose of principal drug, thus reducing the possibilities of toxicity and side effects of drug, potentiating the efficacy, reducing the resistance, decreasing the requirement of raw material for drug manufacture, and ultimately benefitting to the world economy by reducing the treatment cost. This review article attempts to consolidate different drugs as well as methods being used traditionally for enhancing bioavailability in Ayurvedic system of medicine and to discuss their possible mechanism of action. Authentic subject material has been reviewed from different Ayurvedic texts and from different related research and review articles. Thus, it is a humble effort to explore the different aspects of bio-enhancers including therapeutic techniques such as Shodhana, the drugs such as Pippali, and properties such as Yogavahi and Rasayana, which have been described in Ayurveda along with their mechanism of action and uses wherever available.
... Piperine is an alkaloid which constitutes a major active component found in black paper. Different in-vitro and in-vivo experimental models have shown that piperine has the potential to reduce Phase I and Phase II metabolism, in the intestine and in the liver (Shoba et al., 1998;Lambert et al., 2004;Singh et al., 1986). Additionally, several studies have reported that piperine can inhibit major drug-metabolizing enzyme CYP3A4 and P-gp efflux pumps in-vivo and in-vitro (Bhardwaj et al., 2002;Jin and Han, 2004). ...
Article
The lipophilic phytocannabinoids cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL with resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally.
... Piperine, an alkaloid extract from pepper, has been studied in vivo as a bioenhancer of curcumin because of its inhibitory properties on cellular membrane efflux transporters (19)(20)(21) and phase I and phase II metabolizing systems (20,(22)(23)(24)(25)(26)). An early clinical trial of piperine was not certified by peer review) is the author/funder. ...
Preprint
Prior reports have suggested that piperine enhances curcumin anti-carcinogenesis. We tested the hypothesis that piperine increases the intracellular concentrations of curcumin by improving intracellular uptake or reducing curcumin efflux or metabolism in breast cells. We incubated SUM149, MCF10A, primary normal human breast cells, ALDH+, and ALDH-CD44+24- SUM149 cells with curcumin with or without piperine at concentrations 1 uM to 15 uM for time periods of 15 minutes to 24 hours. We assayed cell viability by MTT assay and proliferation by primary mammosphere assay. Curcumin and its metabolites were assayed using liquid chromatography mass spectroscopy. Curcumin, but not piperine, showed significantly higher effects on the viability of breast cancer SUM149 cells than in non-tumorigenic MCF10A cells. Curcumin + piperine synergistically reduced viability of SUM149 cells but had a concentration dependent effect upon MCF10A cell viability. Cellular uptake of curcumin in SUM149 is significantly higher, while the efflux in SUM149 is significantly lower than in MCF10A, which correlated with cell viability. Piperine did not alter curcumin cellular uptake, efflux, or metabolism in any of the cell models. The observed synergism of piperine+curcumin in reducing breast stem cell self renewal is likely due to independent anti-carcinogenesis effects rather than any effects upon intracellular curcumin concentrations.
... Multiple mechanisms have been proposed for the mechanism by which the piperine increases bioavailability. Hence, Piperine promotes gastrointestinal absorption by increasing secretion of bile acids (Sharma et al., 2005), up surging the gastrointestinal blood flow (Johri and Zutshi, 1992), inhibiting efflux pumps (Bhardwaj et al., 2002) and reducing the metabolism by inhibition of multiple enzymes as UDP-glucose dehydrogenase (Singh et al., 1986), cytochrome P450 (Volak et al., 2008) and different oxygenases (Sambaiah and Srinivasan, 1989). Extracts usually consist of mixture of compounds, and it is unreasonable to attribute certain effects or phenomena to one compound only. ...
Article
Full-text available
Chronic inflammation is a key culprit factor in the onset and progression of several diseases. Novel and pharmacologically effective therapeutic approaches are needed for new treatment remedy or improved pharmacokinetics and pharmacodynamics for existing synthetic drugs, in particular natural products. Boswellic acids are well-known natural products, with capacity to effectively retard inflammation without severe adverse effects. However, the therapeutic use of Boswellic acids are greatly hindered by its poor pharmacokinetic properties. Co-administration strategies that facilitate the oral absorption and distribution of Boswellic acids should lead to a safe and more effective use of this product prophylactically and therapeutically in inflammatory disorders. In this study, we examined the effect of Piper longum extract on the absorption and bioavailability of Boswellic acid in rabbits. In addition, we further explored computational pharmacodynamic interactions between Piper longum and Boswellic acid. Piper longum extract at 2.5 and 10 mg/kg, increased the bioavailability of Boswellic acid (p < 0.05). Based on our drug-based computational modeling, cytochrome P450 (CYP450)-mediated mechanism was involved in increased bioavailability. These findings confirmed that Piper longum with Boswellic acid may be administered orally together for effective therapeutic efficacy. Thus, our studies support the application of Piper longum with Boswellic acid as a novel therapeutic avenue in diseases associated with inflammation.
... The most significant from a pharmacological standpoint was piperine (Table 5), the major constituent of black pepper (Piper nigrum) and long pepper (Piper longum). It is well known that this alkaloid is able to inhibit several cytochrome P450-mediated pathways and human P-glycoprotein [135,136], however, several studies reported the efflux inhibitory activity as a primary antibacterial mechanism against S. aureus and MRSA [66,95,137,138]. As previously described, Mothar et al. investigated antibacterial activity of several alkaloids and, except berberine, any inhibition was detected even at 250 µg/mL, suggesting these alkaloids as candidates for an EPI evaluation assay. ...
Article
Full-text available
Antibiotic resistance is now considered a worldwide problem that puts public health at risk. The onset of bacterial strains resistant to conventional antibiotics and the scarcity of new drugs have prompted scientific research to re-evaluate natural products as molecules with high biological and chemical potential. A class of natural compounds of significant importance is represented by alkaloids derived from higher plants. In this review, we have collected data obtained from various research groups on the antimicrobial activities of these alkaloids against conventional antibiotic-resistant strains. In addition, the structure–function relationship was described and commented on, highlighting the high potential of alkaloids as antimicrobials.
... Intra-peritoneal piperine also showed reduction in hepatic cytochrome P-450 [18]. According to the study by Singh et al., piperine decreased the rate of hepatic glucuronidation by inhibiting monooxygenase and UDP-glucuronyl transferase enzymes [19]. In a study by Najar et al., piperine inhibited p-gp ATPase activity at higher concentrations [20]. ...
Article
7-ethyl-10-hydroxy camptothecin (SN38) is poorly soluble in water and pharmaceutical solvents. Oral administration of SN38 was restricted due to poor solubility. Many ways such as encapsulation in carriers are used for solving this restriction. Solid lipid nanoparticles (SLNs) are able to encapsulate lipophilic drugs and improve oral bioavailability. In addition, concomitant use of the efflux pump inhibitors can improve the performance of the encapsulated drug. In the present study, SN38 was loaded in SLNs. Nanoparticle size, zeta potential and drug encapsulation efficacy were investigated. The drug release from nanoparticles was also determined in the simulated intestinal fluid (SIF) and simulated gastric fluid (SGF). Cytotoxicity of nanoparticles after 24 and 48 hours were measured in C26 and Caco-2 cell lines. The cellular uptake of the drug was determined. Tumor growth inhibition and survival were evaluated in animal model. The results showed that the drug-loaded SLNs were about 172.3±3.3 nm in size. The encapsulation efficacy was 61%±7. In cellular studies, higher toxicity of the drug-loaded nanoparticles with the two substances piperine and quercetin were achieved in the Caco-2 cell line. It was observed that drug uptake of nanoparticles containing SN38 with or without piperine and quercetin by C26 and Caco-2 cell line was significantly higher than free SN38 in 2 and 4 hours. According to in vivo studies, the use of piperine and quercetin with SLN containing SN38 has produced a favorable synergistic effect as increasing the survival time in animal model.
Article
Since December 2019, a novel coronavirus known as Severe Acute Respiratory Virus 2 (SARS-CoV-2) has caused an outbreak of a respiratory illness worldwide. Even though SARS-CoV-2 primarily affects the respiratory system, other organs such as the heart and kidneys are implicated. The pathophysiology of Acute Kidney Injury (AKI) in coronavirus 2019 (COVID-19) patients is not clearly defined. Direct kidney injury results from virus entry through angiotensin-converting enzyme-2 (ACE2) receptors which are highly expressed by the podocytes and proximal convoluted tubules, as suggested by "viral-like" particles on electron microscopy. However, the link between the presence of viral particles in kidney tissue and kidney injury has not been fully explained. Furthermore, it is also hypothesized that collapsing focal segmental glomerulosclerosis (FSGS), myoglobin toxicity, sepsis-linked, and glomeruli fibrin thrombi is part of the mechanism for AKI. Reported cases link FSGS and high-risk apolipoprotein 1 (APOL1) alleles in patients of African ancestry. Typically, these patients present with AKI and nephrotic-range proteinuria. The rate of AKI in hospitalized patients is high and associated with a higher mortality rate in older patients with comorbidities. Even higher mortality is now being reported in patients with chronic kidney disease and kidney transplant recipients due to immune system dysfunction. Herein, we review the current literature on kidney disease and pathogenesis in COVID-19 patients.
Article
Effect of piperine which is an alkaloid present in plants such as Piper nigrum and Piper longum on the production of nitric oxide (NO) and tumor necrosis factor‐α (TNF‐α) level was analyzed using in vitro as well as in vivo systems. The level of nitrite in the LPS stimulated Balb/C mice (95.3 µM) was reduced in the piperine treated animals (25 µM) significantly. Nitrite level in the Concanavalin‐A (Con‐A) treated control animals (83.1 µM) was also significantly reduced to 18.5 µM in the piperine treated mice. The drastically elevated levels of TNF‐α in the lipopolysaccharide (LPS) stimulated animals (625.8 pg/mL) was lowered in the piperine treated animals (105.8 pg/mL). Piperine also inhibited the Con‐A induced TNF‐α production. Piperine could inhibit the nitrite production by in vitro activated macrophages (116.25 µM) to the normal level (15.67 µM) at concentration of 5 µg/mL. In vitro L929 bioassay also revealed the inhibition of TNF‐α production by the piperine treatment.
Article
COVID-19 is a pandemic and acute respiratory disease. Every day, all around the world, researchers are endeavoring to find effective or potential adjuvant therapies. Studies illustrate that essential oils from cinnamon and derivatives such as cinnamaldehyde and cinnamic acid possess numerous biological activities. In this paper, we have reviewed the possible mechanisms of cinnamon on the inflammatory cascade as a potential alternative therapy to decrease oxidative stress and inflammation in COVID-19 patients.
Article
Full-text available
Previous research has shown that resveratrol can increase cerebral blood flow (CBF) in the absence of improved cognitive performance in healthy, young human subjects during the performance of cognitively demanding tasks. This lack of cognitive effects may be due to low bioavailability and, in turn, reduced bioefficacy of resveratrol in vivo. Piperine can alter polyphenol pharmacokinetics, but previous studies have not investigated whether this affects the efficacy of the target compound. Therefore, the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol with regard to cognition and CBF. The present study utilised a randomised, double-blind, placebo-controlled, within-subjects design, where twenty-three adults were given placebo, trans-resveratrol (250 mg) and trans-resveratrol with 20 mg piperine on separate days at least a week apart. After a 40 min rest/absorption period, the participants performed a selection of cognitive tasks and CBF was assessed throughout the period, in the frontal cortex, using near-IR spectroscopy. The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography-MS analysis carried out following the administration of the same doses in a separate cohort (n 6). The results indicated that when co-supplemented, piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone. Cognitive function, mood and blood pressure were not affected. The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments, which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects, but not cognitive performance, and does this without altering bioavailability.
Article
COVID-19 is now pandemic throughout the world, and scientists are searching for effective therapies to prevent or treat the disease. The combination of curcumin and piperine is a potential option for the management of COVID-19 based on several mechanisms including antiviral, anti-inflammatory, immunomodulatory, antifibrotic, and antioxidant effects. Here, we describe the probable mechanism of curcumin-piperine against COVID-19. Administration of curcumin-piperine combination appears as a potential strategy to counterbalance the pathophysiological features of COVID-19 including inflammation. The optimal dose and duration of curcumin-piperine supplementation should be determined in the future.
Article
Piperine (1-peperoyl piperidine), a pungent alkaloid, is found in various Pipper species. Piperine produces antioxidant, antiplatelet, anti-inflammatory, antihypertensive, hepatoprotective, antithyroid, antitumor, antiasthmatic activities and also a fertility enhancer. Piperine enhances absorption from gastrointestinal tract by various mechanisms and reduces gut metabolism of drugs. Piperine modulates membrane dynamics and lipid environment and increases permeability at site of absorption Molecular structure of piperine is suitable for enzyme inhibition and it inhibits various metabolizing enzymes like cytochrome bs, NADPH cytochrome, CYP3A4, UDP-glucose dehydrogenase (UDP-GDH), aryl hydrocarbon hydroxylase (AAH) and UDP-glucuronyl transferase. Structural modification of piperine provides selective inhibitors of various cytochrome p450 enzymes. Inhibition of these enzymes by piperine results in enhanced bioavailability of drugs and nutrients like oxytetracyclin, metronidazole, ampicillin, norfloxacin, ciprofloxacin, acefotaxime, amoxicillin trihydrate, curcumin, beta-carotene, carbamazepine, gallic acid, nimesulide, tiferron, nevirapine, pentobarbitone, phenytoin, resveratrol, vasicine and sparteine by different mechanisms. Thus piperine is an absorption enhancer and a potent inhibitor of drug metabolism.
Chapter
Antimicrobial drug resistance occurs when bacteria undergo certain modifications to eliminate the effectiveness of drugs, chemicals, or other agents designed to cure infections. To date, the burden of resistance has remained one of the major clinical concerns as it renders prolonged and complicated treatments, thereby increasing the medical costs with lengthier hospital stays. Of complex causes for bacterial resistance, there has been increasing evidence that proved the significant role of efflux pumps in antibiotic resistance. Coadministration of Efflux Pump Inhibitors (EPIs) with antibiotics has been considered one of the promising ways not only to improve the efficacy but also to extend the clinical utility of existing antibiotics. This chapter begins with outlining current knowledge about bacterial efflux pumps and drug designs applied in identification of their modulating compounds. Following, the chapter addresses and provides a discussion on Quantitative Structure-Activity Relationship (QSAR) analyses in search of novel and potent efflux pump inhibitors.
Chapter
Curcuminoids are biologically active polyphenols present in the spice and coloring agent turmeric. Dietary intake of curcuminoids has been associated a wide range of medicinal properties, including possible beneficial effects in the prevention of many forms of cancer. Studies carried out in vitro on cultured cells show that curcuminoids reduce the rate of cell division and induce apoptosis by affecting signal transduction pathways. However, there is a discrepancy between the curcuminoid dosage required for these in vitro effects and the most optimistic estimates on curcuminoid bioavailability following oral uptake. Therefore, the mechanism by which curcuminoids exert their biological effects through dietary intake remains incompletely understood. Curcuminoid bioavailability is dependent on several factors. These include solubility, chemical stability, efficiency of digestive uptake, metabolic processing, and excretion. This review attempts to illuminate the current state of knowledge on the effect of these factors on curcuminoid bioavailability. In addition, efforts to augment curcuminoid bioavailability through chemical modifications, improved solubilization, increased stability, or alternative routes of administration are addressed. © 2012 Springer Science+Business Media Dordrecht. All rights are reserved.
Article
Curcumin (CUR) is known to exert numerous health-promoting effects in pharmacological studies, but its low-bioavailability hinders the development of CUR as a feasible therapeutic agent. Piperine (PIP) has been reported to enhance the bioavailability of CUR, but the underlying mechanism remains poorly understood. In an attempt to find the mechanism by which PIP enhances the bioavailability of CUR, dosage ratio (CUR: PIP) and PIP pre-treatment are hypothesized as key factors for bioavailability improvement in this combination. Therefore, combining CUR with PIP at various dose ratio (1:1 to 100:1) and pre-dosing PIP (0.5-8 h prior to CUR) were designed to investigate their contributions to the pharmacokinetic parameters of CUR in rats and their effects on the expression of UGT and SULT isoforms. We showed that Cmax and AUC0-t of CUR were slightly increased by 1.29 and 1.67 folds at the ratio of 20:1, while CUR exposure were significantly enhanced in all PIP pre-treatment rats (0.5-8 h), which peaked at 6 h (6.09-fold and 5.97-fold increase in Cmax and AUC0-t, P < 0.01), regardless of unchanged t1/2 and Tmax. We also observed a time-dependent inhibition on the hepatic expression of UGT1A6, 1A8, SULT1A1, 1A3, and the colonic expression of UGT1A6 that occurred within 6 hours PIP pre-treatment but was reversed at 8 h, which was correlated to the changes of CUR exposure. Similarly, the inhibitory effect of PIP on most of UGTs and SULTs are time-dependent in Caco-2 and HepG2. We conclude that PIP pre-treatment time-dependently improves CUR's bioavailability through reversible and selective inhibition of UGTs and SULTs. This article is protected by copyright. All rights reserved.
Article
After oral route of administration, drug absorption is unpredictable and is governed by various factors such as multi drug resistance-1 (MDR1) an efflux transporter and drug metabolizing enzymes (like CYP3A4, CYP3A37, CYP2D6) at intestine and liver. Naturally available phyto chemicals like piperine and quercetin as well as some floroquinolones are known to inhibit MDR1 and CYP3A37 activity and increases bioavailability of co-administered drugs. This study was carried out to investigate the effect of piperine and quercetin alone or in combination with marbofloxacin on CYP3A37 and MDR1 mRNA expression levels in liver and intestine of broiler chicken. After oral administration of piperine and quercetin for 3 consecutive days followed by with or without oral administration of marbofloxacin for 5 days, CYP3A37 and MDR1 mRNA expression levels were determined using quantitative real-time PCR. Total of 36 broiler chickens in seven individual groups were treated with different regimen and the mRNA expression levels at duodenum and liver were analyzed with apt statistical tools. After piperine and quercetin combined treatment with marbofloxacin, CYP3A37 mRNA expression levels were significantly down regulated by 20.57 (p = .034) and 25.95 (p = .003) folds; and MDR1 mRNA expression levels were also significantly down regulated by 11.33 (p = .012) and 33.59 (p = .006) folds in liver and duodenum, respectively. Down regulation of CYP3A37 and MDR1 mRNA in liver and duodenum indicate the combined pretreatment of piperine and quercetin may be useful for improving the pharmacokinetics of orally administered drugs which are substrates for CYP3A37 and MDR1.
Article
A vast range of prescribed drugs suffers from low and variable bioavailability mainly because of metabolism and permeation complications. This issue of bioavailability is a key problem that has been ongoing for many years. Various tactics have been introduced that have been quite beneficial for improving the bioavailability of poorly bioavailable drugs. Some of these tactics are targeted on cytochrome-P450 (CYP) enzymes and the permeability-glycoprotein (P-gp) efflux pump. Strategies include small-molecule inhibitors, novel drug-delivery systems, pharmaceutical synthetic excipients, and natural bioenhancers. This review discusses the role of synthetic excipients and natural bioenhancers in potentiating the activity of poorly bioavailable drugs, including their pharmacological background and their future applicability to health care. The molecules of synthetic origin such as Gelucire (R) and those of natural origin such as quercetin and silibinin can provide noteworthy benefits to patients and the health care system by helping to reduce dosing and drug side effects.
Article
Objectives: Piperine is one of the most promising bioenhancers to date. Methods used for its extraction suffer from drawbacks such as use of organic solvents, poor extraction efficiency, tedious and expensive methodology. These methods are not encouraged with a view to reducing global warming. The objective was therefore to develop an alternative solvent-free extraction method. Methods: An aqueous extract of long pepper fruits was prepared using hydrophilic lipid Gelucire 44/14 as the extracting aid and this was compared with an alcoholic extract. Extracts were characterized using high-performance thin layer chromatography and differential scanning calorimetry. P-glycoprotein (P-gp) inhibitory activity of the aqueous and alcoholic extracts and pure piperine was compared using an in-vitro everted rat intestinal model using ornidazole as the model drug. The study was performed using two oral pretreatment dose levels (10 and 20 mg/kg) and durations (1 and 3 days). Exsorption of ornidazole from serosal to mucosal surface was monitored. Key findings: P-gp inhibitory activity of the aqueous extract was comparable with that of pure piperine (P > 0.05) and was significantly higher than the alcoholic extract (P < 0.05). Pure piperine and the aqueous extract exhibited significant P-gp inhibitory activity compared with control, which was irrespective of oral pretreatment dose and duration levels. No significant effect of oral pretreatment duration of the aqueous extract was observed. The observed enhancement in P-gp inhibitory activity of the aqueous extract may have been attributed to the P-gp inhibitory potential of Gelucire 44/14 and its efficient extraction and solubility enhancement ability. Conclusions: In the field of phytopharmaceuticals efficient and eco-friendly extraction processes are still a goal to be achieved. Extraction with Gelucire 44/14 could be a potential method of extraction for phytopharmaceuticals. Compared with conventional methods of extraction it is more efficient, easier to prepare, eco-friendly and scalable.
Article
Persistent activation of the mechanistic target of rapamycin complex 1 (mTORC1) is linked to sustained inflammation and progression of colorectal cancer. Widely available dietary phenolics, curcumin and piperine, are purported to have anti-inflammatory and anti-carcinogenic activities through yet to be delineated multi-target mechanisms. Piperine is also known to increase the bioavailability of dietary components including curcumin. The objective of the study was to determine whether curcumin and piperine have individual and combined effects in the setting of gut inflammation by regulating mTORC1 in human intestinal epithelial cells. Results show that curcumin repressed (i) mTORC1 activity (measured as changes in the phosphorylation state of p70 ribosomal protein S6 kinase B1 and 40S ribosomal protein S6) in a dose-dependent manner (2.5–20 μM, P<0.007) and (ii) synthesis of nascent proteins. Piperine inhibited mTORC1 activity albeit at comparatively higher concentrations than curcumin. The combination of curcumin + piperine further repressed mTORC1 signaling (P<0.02). Mechanistically, curcumin may repress mTORC1 by preventing TSC2 degradation, the conserved inhibitor of mTORC1. Results also show that a functional mTORC1 was required for the transcription of TNFα as Raptor knockdown abrogated TNFα gene expression. Curcumin, piperine and their combination inhibited TNFα gene expression at baseline but failed to do so under conditions of mTORC1 hyperactivation. Cyclooxygenase-2 expression was repressed by curcumin or curcumin + piperine at baseline and high mTORC1 levels. We conclude that curcumin and piperine, either alone or in combination, have the potential to downregulate mTORC1 signaling in the intestinal epithelium with implications for tumorigenesis and inflammation.
Article
Antimicrobial drug resistance occurs when bacteria undergo certain modifications to eliminate the effectiveness of drugs, chemicals, or other agents designed to cure infections. To date, the burden of resistance has remained one of the major clinical concerns as it renders prolonged and complicated treatments, thereby increasing the medical costs with lengthier hospital stays. Of complex causes for bacterial resistance, there has been increasing evidence that proved the significant role of efflux pumps in antibiotic resistance. Coadministration of Efflux Pump Inhibitors (EPIs) with antibiotics has been considered one of the promising ways not only to improve the efficacy but also to extend the clinical utility of existing antibiotics. This chapter begins with outlining current knowledge about bacterial efflux pumps and drug designs applied in identification of their modulating compounds. Following, the chapter addresses and provides a discussion on Quantitative Structure-Activity Relationship (QSAR) analyses in search of novel and potent efflux pump inhibitors.
Article
Full-text available
In recent years, Phase II metabolism, as a first pass metabolism process occurring to the parent drug, is gaining more and more attention. This is due to its acknowledged significance in drug development as well as drug-drug interactions. However, the predominant role of Phase I metabolism has always overshadowed Phase II metabolism, resulting in insufficient data regarding its mechanisms. In this paper, we investigate the effect of an advanced lipid based drug delivery system on Phase II metabolism at the intestinal level of the enterocytes monolayer. Specifically, we focus on Phase II metabolism of compounds that are cleared primarily by direct glucuronidation without the requirement of P450 enzymes. The investigated formulation is a self-emulsifying drug delivery system, termed pro-nano lipospheres, which contains the natural absorption enhancer piperine. To evaluate the effect of this formulation on direct Phase II metabolism we chose the model molecule raloxifene. First, glucuronidation is the main clearance pathway of this compound without involvement of preceding mechanisms. Secondly, raloxifene's extensive glucuronidation site is primarily at the intestine. Raloxifene's oral bioavailability was determined in a series of pharmacokinetic experiments using the freely moving rat model. In order to test the effect of the formulation directly on the relevant UGT enzymes reported in the clinic, we used the in-vitro method UGT-glo TM assay. Co-administration of raloxifene and piperine-pro-nano lipospheres to rats resulted in a 2-fold increase in the relative oral bioavailability of raloxifene. However, Co-administration of raloxifene with blank pro-nano lipospheres had no effect on its oral bioavailability. In contrast to the difference found in-vivo between the two vehicles, both formulations extended an inhibitory effect on UGT enzymes in-vitro. Ultimately, these findings prove the ability of the formulation to diminish intestinal direct Phase II metabolism. Pro-nano lipospheres is a formulation that serves as a platform for the simultaneous delivery of the absorption enhancer and a required drug. The discrepancy found between the in-vivo and in-vitro models demonstrates that the in-vitro method may not be sensitive enough to distinguish the difference between the formulations.
Article
Full-text available
Cancer is a genetic disease characterized by unregulated growth and dissemination of malignantly transformed neoplastic cells. The process of cancer development goes through several stages of biochemical and genetic alterations in a target cell. Several dietary alkaloids have been found to inhibit the molecular events and signaling pathways associated with various stages of cancer development and therefore are useful in cancer chemoprevention. Cancer chemoprevention has long been recognized as an important prophylactic strategy to reduce the burden of cancer on health care system. Cancer chemoprevention assumes the use of one or more pharmacologically active agents to block, suppress, prevent, or reverse the development of invasive cancer. Piperine is an active alkaloid with an excellent spectrum of therapeutic activities such as anti-oxidant, anti-inflammatory, immunomodulatory, anti-asthmatic, anti-convulsant, anti-mutagenic, antimycobacterial, anti-amoebic, and anti-cancer activities. In this article, we made an attempt to sum up the current knowledge on piperine that supports the chemopreventive potential of this dietary phytochemical. Many mechanisms have been purported to understand the chemopreventive action of piperine. Piperine has been reported to inhibit the proliferation and survival of many types of cancer cells through its influence on activation of apoptotic signaling and inhibition of cell cycle progression. Piperine is known to affect cancer cells in variety of other ways such as influencing the redox homeostasis, inhibiting cancer stem cell (CSC) self-renewal and modulation of ER stress and autophagy. Piperine can modify activity of many enzymes and transcription factors to inhibit invasion, metastasis, and angiogenesis. Piperine is a potent inhibitor of p-glycoprotein (P-gp) and has a significant effect on the drug metabolizing enzyme (DME) system. Because of its inhibitory influence on P-gp activity, piperine can reverse multidrug resistance (MDR) in cancer cells and acts as bioavailability enhancer for many chemotherapeutic agents. In this article, we emphasize the potential of piperine as a promising cancer chemopreventive agent and the knowledge we collected in this review can be applied in the strategic design of future researches particularly human intervention trials with piperine.
Article
We previously reported that piperine, an active alkaloidal principal of black and long peppers, enhances drug bioavailability by inhibiting drug metabolism. Another mechanism influencing drug availability/uptake is its free fraction. Since piperine is highly lipophilic, we hypothesize that it could also interact with drugs through binding displacement and influence their bioavailability. Accordingly, using equilibrium dialysis, we investigated whether piperine alters the binding of model drug ligands, that is flunitrazepam, diazepam, warfarin, salicylic acid, propranolol, lidocaine, and disopyramide to human plasma (n = 4). Since alterations in binding influence drug disposition, we also studied the effects of piperine on the uptake of plasma bound 3H-propranolol and 14C-warfarin by cultured bovine brain microvascular endothelial cells (BMECs). Piperine (1–1000 μM) increased the free fraction (fu) of both albumin and alpha-acid glycoprotein bound drugs in a concentration-dependent manner (p < 0.01). Moreover, piperine (10 μM) increased the uptake of 3H-propranolol and 14C-warfarin by BMECs (p < 0.01). In conclusion, our findings provide the first evidence that piperine displaces plasma bound drugs from both albumin and alpha-acid glycoprotein and facilitates drug uptake across biological membranes (e.g. BMEC). Moreover, it is feasible that piperine may similarly facilitate the transport of drugs into tissues, in vivo, and alter both pharmacokinetics and pharmacodynamics of administered drugs. Copyright
Article
Herbal sources have been explored recently at very high frequency owing to their lower risk benefit ratio as compared to the modern allopathic medicine systems. Herbal bioenhancer is an agent of herbal origin or any phytomolecule, which is capable of enhancing bioavailability and bioefficacy of a particular drug or nutrient with which it is combined, without any typical pharmacological activity of its own at the dose used. The active compound of both Long pepper (Piper longum) and Black pepper (Piper nigrum) is piperine (1-piperoyl piperidine), which is responsible for bioenhancing effect. Piperine enhances absorption from gastrointestinal tract by various mechanisms and reduces gut metabolism of drugs. Piperine modulates membrane dynamics and lipid environment and increases permeability at site of absorption. Thus, piperine acts as absorption enhancer and is a potent inhibitor of drug metabolism as it inhibits various metabolizing enzymes like human p-glycoproteins, CYP3A4, UDP-glucose dehydrogenase (UDP-GDH), aryl hydrocarbon hydroxylase (AAH) and UDP-glucuronyl transferase. The current review also describes the mechanism of action of piperine and bioavailability action of piperine on drugs and nutrients.
Article
This chapter describes the eruption and spread of the SARS-COV-2 virus throughout Brazil. We also describe the governmental measures used to combat the virus, the regional influences impacting viral spreading, and the prevalence of the disease in different Brazilian subpopulations. It is hoped that such information will contribute to the control of the virus and help to prepare the region for future pandemics.
Article
Full-text available
Black pepper (Piper nigrum L.) is a very widely used spice, known for its pungent constituent piperine. However, in addition to its culinary uses, pepper has important medicinal and preservative properties, and, more recently, piperine has been shown to have fundamental effects on p-glycoprotein and many enzyme systems, leading to biotransformative effects including chemoprevention, detoxification, and enhancement of the absorption and bioavailability of herbal and conventional drugs. Based on modern cell, animal, and human studies, piperine has been found to have immunomodulatory, anti-oxidant, anti-asthmatic, anti-carcinogenic, anti-inflammatory, anti-ulcer, and anti-amoebic properties. In this review, the chemical constituents, biological activities, effects of processing, and future potential of black pepper and piperine have been discussed thoroughly. Copyright © 2013 John Wiley & Sons, Ltd.
ResearchGate has not been able to resolve any references for this publication.