OPEM www.opem.org Oriental Pharmacy and Experimental Medicine 2009 9(4), 269-276 DOI 10.3742/OPEM.2009.9.4.269 Molecular targets of pepper as bioavailability enhancer Priyanshee Gohil and Anita Mehta* Department of Pharmacology, LM College of Pharmacy, Navrangpura, Ahmedabad–380009, Gujarat, India Received for publication January 21, 2008; accepted March 20, 2009 SUMMARY 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. Key words: Piperine; Bioavailability enhancer INTRODUCTION and 3 - 5% (on dry weight basis) in P. nigrum Linn (black pepper) and P. longum Linn (long pepper) Pepper species present as one of the key component respectively. It is isolated from fruits and it is in many preparations and formulations in traditional absent in the leaves and stem of plants. Other Ayurvedic medicine used for various ailments pungent alkaloids which occur in pepper species in particularly neurological, broncho-pulmonary and small amount are chavicine, piperidine and gastrointestinal disorders (Raj et al., 1978; Johri et piperrettin. The sharp flavor of freshly ground al., 1992). Black pepper is known as king of spices pepper is attributed to the compound chavicine, a because it is one of the oldest spices and alone geometric isomer of piperine. The loss of flavor of accounts for about 35% of the world’s total spice pepper on storage is associated with slow trans- trade (Majeed et al., 2000). Piperine (a pungent formation of chavicine into piperine (Anonymous, alkaloid) belongs to family Piperaceae, is the major 1989). Pepper has been reported to have various constituent of these plants and its content is 5 - 9% pharmacological actions like immunomodulatory, antitumor (Sunila et al., 2004), analgesic, anti- *Correspondence: Anita Mehta, Department of inflammatory (Annamalai et al., 1990), antiulcer Pharmacology, LM College of Pharmacy, Navrangpura, (Raffaele et al., 2002), antidiarrheal (Bajad et al., 2001) Ahmedabad–380009, Gujarat, India. Tel: +91 796302746; Fax: +91 796304865; E-mail: [email protected], etc. but recently, it is highlighted as a bioavailability [email protected] enhancer and this property of pepper results in 2009 Kyung Hee University Press 269 270 Priyanshee Gohil and Anita Mehta higher plasma concentration of drugs, nutrients, ions etc., rendering them more bioavailable for physiological as well as pharmacological actions in the body. In Ayurveda, black pepper, long pepper and ginger often used together in equal proportions in a formulation known as ‘trikatu’. Trikatu is a Sanskrit word meaning three acrids. According to Ayurveda, the three acrids collectively act as “kaphavatta-pitta-haratwam” which means “correctors of the three humors (doshas) of the human organism” (Johri et al., 1992). The use of Trikatu or its ingredients is traditionally well-known in the treatment of a variety of gastrointestinal disorders, and all three acts to improve digestion. Out of 370 compound formulations listed in the Handbook of Domestic Medicines and Common Ayurvedic Fig. 1. Schematic diagram of molecular targets of Remedies, 210 contain either trikatu or its individual Piperine as bioavailability enhancer. ingredients like long pepper or black pepper. Experimental evidence shows that the main purpose of the use of trikatu, and/or its constituents natural compounds. Extensive research was carried individually as well as collectively into numerous out to find out mechanisms of pepper in Ayurvedic formulations was most probably to bioavailability enhancement. Our body has several enhance the efficacy of pharmacologically active mechanisms to control the exposure of its cells to ingredients (Johri et al., 1992). The first scientific nutrients & other substances. Four of these study carried out at the Regional Research mechanisms are important with regard to pepper: Laboratory, Jammu-Tawi in India by Atal et al. assisted absorption, metabolic conversion, assisted (1981) to confirm the bioavailability enhancing exclusion and solubilizer attachment (Russell, 2003). property of pepper. They found that there was Piperine has remarkable ability to manipulate all increase in blood levels of vasicine by 232% and four of these mechanisms to act as bioavailability sparteine by more than 100% in Pepper longum enhancer (Fig. 1). treated group as compare to control animals. Based on studies carried out in animals as well as human Assisted absorption volunteers, it was noted that the bioavailability This involves the use of transporter proteins in the enhancing property of pepper was attributed to its digestive tract. These proteins actively transport principle alkaloid, piperine. the substances into the intestinal lining; from there they can be transferred further into the blood stream. MATERIALS AND METHODS Assisted absorption is particularly important to the amino acids in adequate amount in the body. Mechanism of bioavailability enhancement by Piperine stimulates amino acid transporters (Leucine the pepper amino peptidase and glycyl-glycine dipeptidase) Pepper has been shown to increase the bioavailability activity due to alteration in enzyme kinetics in and efficacy of large number of synthetic as well as intestinal wall. A recent study using human intestinal 2009 Oriental Pharmacy and Experimental Medicine 9(4), 269-276 Molecular targets of pepper as bioavailability enhancer 271 cells as an experimental model, showed that piperine administration in rats resulted in 50% piperine by inducing alteration in membrane decrease of total Cytochrome P450 content indicating a dynamics and permeation characteristics, along suicide inhibition by piperine (Dalvi, 1991). Thus, with induction in the synthesis of proteins associated by inhibiting the microsomal enzyme system, with cytoskeletal function, resulting an increase in piperine protects the drug from being metabolized/ microvilli length (small intestine absorptive surface), oxidized in its first pass passage through the liver thereby assisting efficient permeation through the after being absorbed. Moreover, the prolongation of epithelial barrier. The results also suggested that bioavailability duration depends on the duration of piperine is absorbed very fast across the intestinal inhibition of Cytochrome P3A4 in liver by piperine barrier and it may modulate membrane dynamics (Bhardwaj et al., 2002). due to its easy partitioning thus helping an efficient permeability across the intestinal wall (Khajuria et Assisted exclusion al., 1998; Khajuria et al., 2002). In conclusion, it was This involves the use of transporter proteins that suggested that piperine by acting as an apolar pump certain substances out of the cells, whereupon molecule and forming apolar complex with drugs they can be taken away from the cells by the blood. and solutes, alter the membrane lipid dynamics On one hand, the activities of these pumps protect and change in confirmation of intestinal enzymes. cells from toxic overloads of many poisonous Besides these specific mechanisms, some non-specific substances, on other hand; they can also decrease mechanisms are also reported to be involved in the efficacy of many beneficial drugs and supplements promoting rapid absorption of drugs and nutrients by pumping out these substances from the cells by the piperine, e.g. increased gastrointestinal blood before they can act. One of the most important supply, decreased hydrochloric acid secretion, such pump proteins is p-glycoprotein (Pgp), which is increased emulsifying content of the gut, increased found in the membrane of the cells in the intestine, enzymes like gamma-glutamyl transpeptidase which brain, liver, pancreas, kidneys and other tissues. participate in active and passive transport of Piperine inhibits this Pgp and thereby preventing nutrients to the intestinal cells (Annamalai et al., elimination of drugs, making them more bioavailable 1990; Johri et al., 1992). to the tissue (Johri et al., 1992). Metabolic conversion Solubilizer attachment This mechanism involves the use of enzymes to This prevents substances from entering cells by convert substances (substrates) into different linking them chemically to a highly water-soluble substances (metabolites) that may be biologically substance. This not only alters the biological activity of less active and/or, are more easily carried in the the substance but also make the hydrophilic blood to kidneys for easy excretion. Piperine inhibits complex unable to diffuse through the cell number of enzymes responsible for