Drug Interaction Potential of Tinospora cordifolia: A Review
Rajanikanta Sahu, Tapas Kumar Mohapatra, Bharat Bhusan Subudhi*
Drug Development and Analysis Laboratory, School of Pharmaceutical Sciences, Siksha O Anusandhan (Deemed to be University), Bhubaneswar-751029
*Corresponding Author E-mail: bharatbhusans@gmail.com
ABSTRACT:
Natural products mainly herbs are regularly administered in combination with conventional drugs, hoisting the potential of herb-drug interactions. When the constituents of herb regulate absorption, distribution, metabolism, and excretion of other co-administered drugs, then there will be an onset of pharmacokinetic drug interaction. On the other hand when the constituents alter the activity of receptors involved in the mechanism of action of the co-administered drug, then there will be an onset of a pharmacodynamic interaction. Tinospora cordifolia (TC) is widely used in Ayurvedic medicine as a tonic vitalizer, antipyretic and as a remedy for diabetes and other metabolic disorders. Hence TC is considered as a Complementary and Alternative Medicine (CAM) in the form of herbal supplement. Overall it is observed that people suffering from various diseases are using herbal medicines in the form of a single herb or a polyherbal preparation, besides the prescribed medicines. These herbal formulations are considered to function as a nutritive supplement. Even though herbal supplements are claimed to be free from side effects but needs to be assessed for the HDI potential with the co-administered prescription drug. Hence, an intense effort has been made here to review and analyze the affirmative as well as negative impact of TC with commonly co-administered contemporary medicine.
KEYWORDS: Tinospora cordifolia, Herb drug interaction, Complementary and alternative medicine, Cytochrome P450, Drug interaction.
INTRODUCTION:
As per National centre for complementary and integrative health "complementary and alternative medicine (CAM)" is the term used for medical products and practices that are not part of standard medical care. CAM is used to enhance the therapeutic benefits of standard medical treatment. Difficulties in finding new drugs and issues related to toxicities have encouraged the use of CAM either to maximize efficacy or minimize toxicity. Accordingly, around 80% of the present day global populations rely on CAM as per a recent estimate1. However, growing acceptance has also led to improper use as in many instances these measures are used without discussion with the physician2.
A general lack of knowledge of the interaction potentials of concurrent use of CAM/herbs with prescription or over-the-counter medicines, posses a great challenge for health care professionals and a safety concern for consumers. Most people, especially in developing countries consider herbs as harmless plants. They have growing acceptance also in developed countries. That natural products are largely unregulated contributes to the misconception that they are safe, with the effect that patients don’t feel the need to tell their physicians that they are using them, and physicians don’t routinely ask patients if they are taking them3. Since herbs contain multiple components in variable quantity they may affect body functions leading to drug interactions which may impact the clinical effects of the standard drugs.
Broadly, three pathways account for herb-drug interaction. These include variation in metabolic system, modulation of the transporter proteins and agonistic/antagonistic effect of herbs with the co-administered drug (Fig. 1). The oxidative actions of cytochrome P450 (CYP) mono-oxygenase has a major role in regulating pharmacokinetic of xenobiotics. Herbal drugs have been known to stimulate or suppress the activities of this enzymes thus leading to altered metabolism of conventional drugs4.
Fig. 1: Schematic presentation of variation in metabolic system, modulation of the transporter Proteins and agonistic/antagonistic effect of herbs with co-administered drug
Humans, CYPs are the major enzymes involved in drug metabolism and bioactivation, accounting for almost 75% of the total drug metabolism. The variability in drug metabolisms that are mainly induced by the CYP polymorphisms is reflected by the differences of the maximal plasma concentrations, half-lives of some drugs and their clearance. Besides, it can also lead to adverse drug reactions that are considered as a major factor in drug toxicity5.
Numerous
mechanisms have been proposed to influence the fate of drug availability, such
as passive diffusion, carrier-mediated transport, endocytosis and efflux system
(Fig 2). Modulation of carrier-mediated transport system mainly by
P-glycoproteins (pgp) contributes to the drug-herb interaction to a great
extent6. Transporter proteins are responsible for the clearance of
xenobiotic compounds out of the cell. However, natural compounds like herbal
drugs inhibit the actions of these transporter proteins most importantly,
ATP-binding cassette (ABC) transporter and P-glycoprotein leading to poor
transport across membranes7. Besides many drugs are eliminated as
such without bio-transformation by utilizing cellular transport mechanism at
renal tubular cells like organic cation transporters (OCTs) and human
multi-antimicrobial extrusion (hMATE) transporters8. Many herbal
constituents can alter the activity of such transporters and modulate the
pharmacokinetics of co-administered drugs. Further, the multiple components of
herbal drugs/CAM may have multiple pharmacodynamics which may either promote or
retard the effectiveness of drugs. Hence validation of
pharmacokinetic/pharmacodynamic interaction is desirable before the use of CAM.
Fig
2: Factors influencing drug availability at the site of action.
Tinospora cordifolia (TC), commonly known as Guduchi is a large, glabrous, deciduous climbing shrub belonging to the family Menispermaceae. The shrub is known as Guduchi/Giloy in Hindi and Amrita in Sanskrit. It is widely used in Ayurvedic medicine for treating diabetes mellitus9. TC is also widely used in traditional therapy for various diseases. TC (Amrita) is mentioned in the various classical text of Ayurveda, viz Charak, Sushurut, Ashtanga, Hridaya, Bhaba Prakash, and Dhanvantri Nighantu, under various name viz Amara, Amritvalli, Chinnarrhuha, Chinnodebha, and Vatsadani etc. Sushruta Samhita claims the use of TC to treat Kustha (leprosy), Maha Jvara (a kind of fever), Asthma and Anorexia under "Tikta-Saka Varga"10. It is mentioned in Ayurvedic literature as a constituent of several compound formulations used in general debility, dyspepsia, fever and urinary diseases. Some of the important formulations are Guduchyadi churna, Guduchi taila, Dashmoolarishtha, Sanjivani vati, Kantakari avaleha, Chyavanaprasha, Guduchi sattva, Brihat guduchi taila, Stanyashodhana kashaya churana, Punchnimba churana, Guduchi ghrita, Amritaguggulu, Amritashtaka churna, etc11. In Unani System, mostly "Sat Giloe" is incorporated in the preparations. "Arq Giloe" prepared from the fresh plant is considered a febrifuge, while "Arq Maul Laham Mako-kashiwala" is a general tonic"12. A variety of chemical constituents such as alkaloids, glycosides, steroids, diterpenoid lactones, aliphatic compounds, polysaccharides and essential oils have been reported from different parts of Tinospora cordifolia. Various natural products (active compounds) isolated from different plant parts along with their biological activities. Leaves of TC are loaded with protein (11.2%) and are quite rich in calcium and phosphorus13. Stem and root part of TC contain alkaloids like Berberine, Choline, Tembetarine, Magnoflorine, Tinosporin, Palmetine, Isocolumbin, Aporphine, Jatrorrhizine and Tetrahydropalmatine14-18. Diterpenoid, Lactones like Furanolactone, Clerodane derivatives [(5R, 10R)-4R-8Rdihydroxy-2S-3R:15, 16- diepoxy-cleroda-13 (16), 14-dieno-17, 12S:18,1S-dilactone], Tinosporon, Tinosporides, Jateorine, Columbin are distributed in all parts of the plant19. Stem extract contains Glycosides like 18-norclerodane glucoside (Tinosporaside), Furanoid diterpene glucoside, Tinocordiside, Tinocordifolioside, Cordioside, Cordifolioside, Syringin, Syringinapiosylglycoside, Pregnane glycoside, Palmatosides, Cordifolioside A, B, C, D and E20-22. Tinocordifolin a Sesquiterpenoid isolated in stem extract23. Aliphatic compounds like Octacosanol, Heptacosanol Nonacosan-15-one dichloromethane are distributed all over the plant24. Many other compounds like 3,(a,4-di hydroxy-3methoxy-benzyl)-4-(4-hydroxy-3-methoxy-benzyl) tetrahydrofuran, Jatrorrhizine, Tinosporidine, Cordifol, Cordifelone, Giloinin, Giloin, N-trans-feruloyltyramine as diacetate and Tinosporic acid are found in different parts of the plant25.
Considering the wide use of TC as CAM, its potential for drug interaction must be considered. Since it is rich in a variety of chemical constituents; it can modulate the metabolic enzymes, transporters and can affect the mechanism of action of other drug substances. Keeping the above facts in mind a serious effort was put to make this review article.
PHARMACOKINETIC INTERACTION POTENTIAL:
In silico analysis done by our group has shown the components of TC as a substrate of CYP enzymes26. This may inhibit these enzymes leading to modulation of the pharmacokinetics of co-administered drugs. This was in agreement with previous reports where the hydro-alcoholic extract of TC has been shown to inhibit CYP3A4 and 2D6 with the IC50 value below 0.2 mg/mL27. Berberine, the major active constituent of TC is reported to inhibit 50 % of CYP 2C9 activity at a concentration of 500 µM28. It has also been shown to induce drug metabolism in mice29. Although previous reports had concluded about the low potential of TC for herb-drug interaction, our group has found some contrasting results 26. TC was found to decrease the activity of CYP2C9 with an IC50 of less than 0.1 mg/mL, whereas the activity of 2D6 and 2C19 were inhibited with an IC50 of 0.170 mg/mL and 0.866 mg/mL extract respectively. This was further validated by the fact TC aqua-alcoholic extract at 400 mg/kg dose enhanced the bioavailability of Glibenclamide due to a reduction in its metabolism by CYP enzymes30. This suggests the fact that TC should be contraindicated as CAM with glibenclamide, in spite of its potent antidiabetic effects. In another report, TC at 500 mg/kg/day significantly decreased the plasma concentration of warfarin, furosemide and diazepam in rats31. Although the exact mode of interaction is not known TC should be used with caution while administering these drugs. Other than metabolic enzyme modulation, interference in active transportation during absorption and elimination is a probable medium for drug interaction of TC. This is evident from the higher bioavailability of dexamethasone by use of TC as CAM32. Due to its ability to inhibit the efflux enzymes (PgP) chronic use of TC was shown to significantly enhance the permeability of dexamethasone across intestine32. However, the exact mode of Pgp inhibition is not known. Constituents of TC including berberine, palmatine, and jatrorrhizine are substrates of Pgp but had no inhibitory effects on P-gp33. Nevertheless, as substrates, a competitive inhibition can be expected to reduce the drug efflux leading to higher drug availability when co-administered with TC.
Organic cationic transporters are responsible for active transport of drugs during absorption. Besides, during elimination also these transporters may account for elimination of drug and metabolite. As these active transporters are saturable, their transportation ability can be influence by cationic molecules. Since, TC contains many cationic components including Berberine, Choline, Tembetarine, Magnoflorine, Tinosporin, Palmetine, Isocolumbin, Aporphine, Jatrorrhizine and Tetrahydropalmatine it can be expected to influence the absorption and elimination of cationic drugs including metformin34- 36.
PHARMACODYNAMIC INTERACTION POTENTIAL:
Concurrent
administration of TC with metformin has shown beneficial pharmacodynamic
interaction leading to enhanced antihyperglycemic and antihyperlipidemic
activity37, 38. This can be attributed to the pharmacodynamic
principles of TC. Many animal experimental studies have demonstrated
that extracts of TC could change lipid metabolism39. Its
phytoconstituents including berberine, palmatine, jatrorrhizine and
mangnoflorine have been reported with insulin mimicking and insulin-releasing
effect both in vitro as well as in vivo40, 41.
Tinosporin, isocolumbin, palmatine, tinocordiside, cordioside and ß-sitostrol
compounds present in TC are also reported to possess antidiabetic,
antihyperlipidemic and antioxidant properties42. Further, it is
shown to inhibit glucose 6-phosphatase and fructose 1, 6-diphosphatase, and
restore glycogen content in liver43, 44. It also is known to improve
the insulin and C-peptide levels which may contribute to its effectiveness
against diabetes45. The positive interaction can also be partly
explained by the fact that, berberine the principal alkaloid from TC is
reported to boost the effects of metformin and 2, 4-thiazolidinedione against
diabetes46. TC is also known to possesses antipyretic,
antispasmodic, anti-inflammatory, anti-arthritic, antioxidant, anti-allergic,
anti-stress, anti-leprotic, antimalarial, hepato-protective, immuno-modulatory
and anti-neoplastic activities47. However, there is very little
progress in its validation as a CAM against these indications. With wide
acceptability and low toxicity, TC has huge potential for use as CAM48.
However, this must be justified based on its pharmacokinetic and
pharmacodynamic interaction.
CONCLUSION:
There is a huge potential of TC for use as CAM. However, the information available regarding its herb-drug interactions with co-administered drugs is not adequate. Although most of its use as CAM have focused on antidiabetics, more drug interaction studies with other antidiabetic drugs are necessary to validate its use. As the drug properties may even vary for drugs from the same class, drug interaction cannot be generalized and needs to be experimentally tested for each drug. To widen the use of TC against other indications similar drug interaction studies must be conducted to justify its use. Besides clinical correlation should be established. Thus clinicians are recommended to trace the information regarding usage of TC supplement along with prescribed medication by their patients. Awareness needs to be generated to document the adverse events, if any, with all the relevant information. This review can be a document for the researches those who are interested in studying drug-herb interaction.
ACKNOWLEDGEMENT:
Authors are thankful to School of Pharmaceutical Sciences, Siksha O Anusandhan (deemed to be University), Bhubaneswar for providing essential facilities to make this work successfully.
LIST OF ABBREVIATION:
TC: Tinospora cordifolia
CAM: Complementary and alternative medicine
ASBT: Apical Sodium Dependent Bile Acid Transporter
CYP: Cytochrome P450
Pgp: P-glycoproteins
ABC: ATP-binding cassette
OCTs: Organic cation transporters
hMATE: human multi-antimicrobial extrusion
IC: Inhibitory Concentration
MRP: Multi drug resistance-associated protein
BCRP: Breast cancer resistance protein
OAT: Organic anion transporter
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Received on 03.07.2018 Modified on 09.09.2018
Accepted on 24.10.2018 © RJPT All right reserved
Research J. Pharm. and Tech 2018; 11(11): 5179-5183.
DOI: 10.5958/0974-360X.2018.00946.0