Introkjljduction
Plants have always provided an important source of medicines. The use of herbs to treat disease emanates from the ancient Greek, Egyptian and Chinese civilizations (Ioannides, 2002). They generally were used by natives in folk medicine and later adopted by conventional western medicine as their efficacy was confirmed. The progress of pharmacology in the 20th century created the misconception that there is a pill for every ill, while at the same time faith in science was undermined by disasters such as the thalidomide tragedy (Angell, 2003). Consequently, a mistaken belief emerged that all that is natural is superior to all that is synthetic. The recent increase in the popularity of herbal medicine, especially during the preceding several years has flooded the world's pharmaceutical markets with over 20,000 herbal and other natural products (De Smet, 1995).
In 2005 studies estimated that 42% of Americans use some type of complementary and alternative medicine (CAM) and herbal therapy is among the most prevalent types (Eisenberg et al, 2001). On the other hand an estimated one third of adults in developed nations and more than 80% of the population in many developing countries use herbal medicines in the hope of promoting health and to manage common maladies such as colds, inflammation, heart disease, diabetes and central nervous system diseases (Braun, 2000). Furthermore, as Western medicines become more expensive and fewer people carry health insurance, the use of herbal supplements with their promise of wonderful results can only increase (Philip, 2004). Large variety of herbal preparations and products is used by people all over the world, and the selection of a particular herb reflects the diverse ethnic backgrounds of the users (Bush et al, 2007).
Problems Associated with the Use of Herbal Remedies
I. Problems associated with the use of herbal remedies
While the public perception is that herbal remedies are safe, many published reports and scientific researches have been presented about the potential problems associated with the use of herbal remedies. Some of these problems will be presented, briefly, in the following points
I.1. Scarcity of established regulatory standards and safety concerns for herbal drugs
In both the United States and Canada, herbs are currently classified as dietary supplements. The law, declared by the Dietary Supplements Health and Education Act (DSHEA) in 1994, defines a dietary supplement as a vitamin, mineral, amino acid, herb or other botanical combination (Noonana and Noonan, 2006). Dietary supplements do not require premarket approval and, therefore, are sold without undergoing extensive testing for safety and efficacy. To be removed from the market, a herb must be proven unsafe and the proof submitted to the Secretary of Health and Human Services. The Food and Drug Administration (FDA) has no authority to test dietary supplements, but can stop the sale of supplements that pose a “significant unreasonable risk of illness or injury” or that make unsubstantiated claims (Soller, 2000). In contrast, Germany appears to be the only developed country to have established a comprehensive legislative body to deal with herbal remedies, Commission E, a committee of doctors, pharmacists, scientists and herbalists to evaluate data regarding the efficacy and safety of herbal remedies and publishes monographs on these judgments (Valli and Giardina, 2002). Products on Germany, can only be registered if based on approximately 300 monographs on herbs with concise information on dose, indications, contraindications, interactions and mechanisms (De Smet, 2002). In Saudi Arabia, survey of available literature revealed the lack of quality control and product standardization of the majority of the used herbal preparations which makes it difficult to establish safe administration of herbal products.
I.2. The complex nature of herbal drugs
Herbal products, as taken by the general population, are usually complex mixtures of many molecular entities and often a complete characterization of all the chemical constituents from a natural product is not possible (Pal and Mitra, 2006). Additionally, chemical constituents of natural product may vary depending on the part of the plant processed (stems, leaves, roots), seasonality, growing conditions and finally the manufacturing process. What complicate matters further is the fact that many marketed herbal drugs are combination products composed of multiple natural extracts and a single herbal preparation may contain more than 100 components (Hu, 2005).
Because herbal products are not regulated by the FDA, as previously mentioned, there are no standards for herbal products (Mary et al, 2005). Indeed, some products have been found to be misidentified, substituted and/or adulterated with other natural products or unwanted substances including microbes, microbial toxins, environmental pollutants, or heavy metals (Seth and Sharma, 2004). Testing the quality of more than 1200 dietary supplement products by the independent laboratory Consumerlab.com found that 1 in 4 dietary supplement products lacked the labeled ingredients or had other serious problems such as unlisted ingredients or contaminants (Con, 2005).
I.3. The lack of accurate information sources
Although the safety concern and the awareness regarding allopathic drugs are increasing rapidly, up to day it is hard for the consumer to find trustworthy and reliable sources for balanced information about this emerging field regarding their safety profile, the exact constituents of the conventional herbal formulations, adulteration in the drug formulations, manufacturing standards, etc. (Percival, 2000).
1.4. Toxicity and adverse effects of herbal drugs
As herbs are considered natural products, evaluation of the toxicity and adverse reaction of the herbal preparation has been a neglected area for a long time. This lack of information makes it difficult to compare the benefit-risk profile of herbal medicines.
Even with the increased awareness regarding the adverse herb reaction reporting and evaluation, the long term toxicity, mutagenicity and genotoxicty studies are still deficient (Seth and Sharma, 2004).
1.5. The interaction between complementary herbal drugs and conventional medicines
The interaction of drugs with herbal medicines is a significant safety concern, as the consequence of some of these interactions may be severe and even life threatening (Fugh-Berman, 2001).
The focus of this review article will be on the interactions of some herbal phytochemicals with conventional drugs. It is important to recognize herbs with high potential to interact with conventional medications through detailed investigation of the mechanisms involved in this process.
Mechanisms for Herbal Interactions with Prescription Drugs
II. Mechanisms for herbal interactions with prescription drugs
There are numerous ways in which pharmacologically active agents can interact, regardless of whether they are prescription medications, proprietary medicines or herbal preparation (Goldman, 2001).
A herb-drug interaction is defined as any pharmacological modification caused by a herbal substance(s) to another exogenous-chemical (e.g. a prescription medication) in the diagnostic, therapeutic or other action of a drug in or on the body (Brazier and Levine, 2003). This relates to drug-drug interactions, herb-herb interaction or drug-food interaction. A herb can potentially mimic, increase, or reduce the effects of co-administered drugs and the consequences of these interactions can be beneficial, undesirable or harmful effects (Fugh-Berman, 2000). It should be pointed out that both the putative active ingredient(s) and other constituents present in that herbal mixture have the potential to interact with various classes of drugs (Venkataramanan et al, 2003)
The underlying mechanisms for most reported drug interactions with herbal medicines have not been fully elucidated. However, as with drug-drug interactions, both pharmacokinetic and pharmacodynamic mechanisms are implicated in these interactions.
II.1. Pharmacokinetic (PK) herb-drug interactions
PK interactions result from alteration of absorption, distribution, metabolism or elimination of a conventional drug by a herbal product or a dietary supplement (Zhou et al, 2007). As known herbal components are chemicals and, like drugs, they are metabolized by phase I and phase II pathways (Woolf, 1999).
II.1.A. Phase I pathway
Phase I processes include oxidation, reduction, hydrolysis and hydration resulting in the formation of functional groups (OH, SH, NH2 or COOH) that impart the metabolite with increased polarity compared to the parent compound (Gibson and Skett, 2001). In phase I processes, the cytochrome P450 (CYP) super family is responsible for the metabolism of a variety of xenobiotics and endobiotics (Venkataramanan et al, 2003). The effect of phase I enzymes on the drug’s activity depends on the nature of the drug. Some drugs (e.g., cyclophosphamide, ifosfamide) are introduced into the body as prodrugs, whose structure must be altered by phase I enzymes to become active. Drugs that are introduced into the body in their active forms, on the other hand, are de-activated by phase I enzymes as a part of the process of their clearance or removal from the body (Block and Gyllenhaal, 2002).
II.1.B. Phase II pathway
Phase II processes include sulfation, methylation, acetylation, glucuronidation glutathione conjugation and fatty acid conjugation (Gibson and Skett, 2001). In conjugation, a new chemical entity is attached to a drug’s functional group to make the drug more polar, facilitating its removal from the body (Block and Gyllenhaal, 2002). Glucuronidation is catalyzed by uridine diphosphoglucuronosyltransferases (UGTs) and involves the transfer of the glucuronic acid residue from uridine 5--diphosphoglucuronic acid to a hydroxyl or a carboxylic acid group on the compound (Meech and Mackenzie, 1997). As the case with CYPs, UGTs metabolize a broad range of endogenous and exogenous substances (Radominska-Pandya et al, 1999). Phase II enzymes are also considered to have a significant role in disabling and exporting chemical carcinogens (Kensler et al, 2000).
It is important to note that not all drugs go through the phase II metabolizing enzymes; many are removed after metabolism by phase I cytochrome P450 enzymes. The activities of phase I and phase II enzymes on active drugs and prodrugs are summarized in Table 1.
Table 1. Functions of phase I and phase II enzymes on prodrugs and drugs administered in active form
Drug Type / Phase I Enzymes / Phase II EnzymesActive drugs / Deactivation, clearance / Conjugation, clearance
Prodrugs / Activation, clearance / Conjugation, clearance
II.2. Role of drug metabolizing enzymes and transporters in herbal-drug interaction
Herbal or even dietary phytochemicals can cause induction of drug metabolizing enzymes (DME’s: phase I and phase II) and transporters via nuclear hormone receptors, as well as non-hormonal receptors (Mandlekar et al, 2006). In the following section the role of DME’s and efflex proteins and transporters in the mechanism of drug-herbal interactions will be discussed.
II.2.A. Role of CYP450 in herbal-drug interaction
A recent study showed that 82% of the drugs that were reported to interact with herbs are substrates for various cytochrome P450s (CYPs) (Rendic, 2002). The CYPs are a group of enzymes found primarily in the liver and the gut mucosa; and lower levels may be found in the lungs, the kidneys and brain. The enzymes catalyze phase I biotransformation of a variety of compounds including most drugs (Wong et al, 1991). CYP3A is the most abundant isozyme in the human liver; representing approximately 30% of total hepatic CYP and more than 70% of intestinal CYP activity. Moreover CYP3A is responsible for the metabolism of more than 50-70% of all prescribed drugs (Kaminsky and Zhang, 1997). A congener of CYP family is CYP3A4, the most abundant form that account with the isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A3 for the metabolism of almost half of all clinically used drugs (Figure 1)
Fig. 1. Relative levels of P450 isozymes in human liver
Xenobiotics, drugs and a variety of naturally occurring dietary or herbal constituents can interact in several ways with the CYP450 system (Lehmann, 1998) resulting in altered drug clearance and effect (Rendic, 2002).
• A compound may be a substrate of one or several CYP isoforms. If the main isoform is saturated, it becomes a substrate for the secondary enzyme(s).
• A compound can be an inducer of a CYP isoform, either of the one it is a substrate for, or may induce several different enzymes at the same time. The process of induction increases the rate of metabolism of substrates of that enzyme.
• A compound may also be an inhibitor of CYP450 enzymes. There are several mechanisms of inhibition, and a compound may inhibit several isoforms including others than those for which it is a substrate (Zhou, 2003).
In humans, there is a wide range of variation in expression of CYP450 enzymes. This accounts for the inter-individual variability in responses to drugs, as well as in the occurrence and severity of adverse effects and drug interactions. Some of the underlying factors affecting individual variation in CYP450 expression are age; genetics including gender and race; disease, including both general infection as well as specific hepatic conditions (Bourian et al, 1999).
Importantly, the expression of CYP3A4, CYP3A5, CYP2B6 and CYP2C8 is tightly regulated by the nuclear factor pregnane x receptor (PXR/NR112), which is activated by a number of structurally distinct ligands, including certain herbal components such as hyperforin from St John’s wort (Matic, 2007).
A funded research, performed in Germany, identified the following herbal remedies as, in vitro, inhibitors of the various CYP isozymes with IC50 values between 20 and 1000mg/mL The herbs identified were: devil's claw root (Harpagophytum procumbens), feverfew herb (Tanacetum parthenium), fo-ti root (Polygonum multiflorum), kava-kava root (Piper methysticum), peppermint oil (Mentha piperita), eucalyptus oil (Eucalyptus globulus) and red clover blossom (Trifolium pratense) (Frank and Unger, 2004).
II.2.B. Role of efflex proteins and transporters in drug-herbal interaction
On the other hand, 29.4% of the drugs that interact with herbs have been identified as substrates for P-glycoprotein (P-gp) and multiple resistance proteins (MRPs) (Evans, 2000; Pal and Mitra, 2006). P-gp and MRPs are members of the ATP binding cassette family (ABC), responsible of transporting compounds against a steep concentration gradient (efflux) (Pizzagalli et al, 2001). A well-known drug transporter, P-gp, is found in the intestines, liver and kidneys. It plays important roles in the absorption, distribution or elimination of drugs from various tissues (Gerloff et al, 1998). The multidrug resistance-associated protein (MRP) is another famous ATP-binding cassette transporter involved in biliary, renal, and intestinal secretion of numerous organic anions, including endogenous compounds such as bilirubin and exogenous compounds such as drugs and toxic chemicals (Faber et al, 2003).