Current Drug Metabolism - Volume 9, Issue 10, 2008

Although medicinal herbal products gradually lost importance in the course of chemistry's progress in industrialized countries during the 20th century, the current thriving revival of phytotherapy is followed by an increasing scientific interest in bioactive compounds as lead drugs for semi-synthetic modification. On the other side, it must not be overseen that natural products are still a major resource for drug development and represent a significant segment on the pharmaceutical market as compared to randomly synthesized compounds. About one quarter of all drugs in modern pharmacopeia derives from plants. In the course of this increasing interest both in the public to use natural herbal products as well as in science to understand the modes of action, it is becoming more and more clear that herbal products can interact with standard drugs. These interactions can lead to synergistic or antagonistic effects and might be beneficial or disadvantageous for the human body depending on the specific conditions. It is out of discussion that herbs are not “gentle medicine” without any side effects. The old rule in pharmacology that every active drug has both wanted pharmacological effects and unwanted toxic side effects holds also true for herbal medicines. This is quite logic and meaningful, if one recalls that plants produce chemical compounds in their secondary metabolism as defence weapons towards hervibores and microorganisms. Therefore, the careful investigation of actions in the human body including interaction with other drugs is mandatory. I was fortunate to team up a panel of reputed experts from different fields in pharmacy, biology, and medicine to highlight important aspects of the interaction of natural products with drugs. This Hot Topic Issue of “Current Drug Metabolism” on “Molecular mechanisms and clinical evidence for interactions between natural products and drugs” is organized in two main parts. The first part is molecular pharmacology with contributions of Michael Wink, Adorjan Aszalos, Gert Fricker, Ji Zhang and their co-workers as well as my own group. These topics are more related to basic science. The second part is clinically oriented with contributions of the teams of Sunita Vohra, Peter de Smet and Cathrine Ulbricht......

Plants use complex mixtures of secondary compounds (SM) of different structural classes to protect themselves against herbivores, bacteria, fungi and viruses. These complex mixtures may contain SM, which are specific for a single target (monotarget SM). A majority of SM, however, can interfere with several targets (multitarget SM) in a pleiotropic fashion. The composition of such extracts appears to be optimised, since the components are not only additive but apparently synergistic in their bioactivity. Synergism can be achieved by inhibiting the xenobiotics inactivating activities of animals and microbes (MDR, CYP), by facilitating the uptake of polar SM across biomembranes and/or by affecting several important organs in animals concomitantly. Phytotherapy employs equally complex extracts of medicinal plants. Arguments were put together that the utilisation of complex mixtures with pleiotropic agents presents a unique therapeutic approach with many advantages over monotarget compounds. Mixtures of multitarget SM, used in phytotherapy include phenolics, tannins, mono- and sequiterpenes, saponins, iridoid glucosides and anthraquinones, but only few of them alkaloids or other toxic monotarget SM.Multitarget effects are caused by SM, which can modulate the threedimensional structure of proteins (and thus their function), by interfering with DNA/RNA (especially gene expression) or membrane permeability. In addition, complex extracts may contain synergists, which can inhibit MDR, cytochrome P450 or enhance absorption and thus bioavailability of active metabolites. The molecular modes of action are reviewed for the main groups of secondary metabolites.

Medicinal use of natural products such as extracts of plants has existed for many years in China and in other countries and they are now available worldwide. Citrus fruit juices are consumed on a daily basis around the world. Modern medicine provides well-tested compounds or drugs for most sicknesses. However, the simultaneous consumption of plant extracts, food supplements, and fruit juices with drugs can create metabolic aberrations in humans. Interactions between drugs used simultaneously are regulated by government agencies. Not regulated, but warned against in drug inserts are potential interactions between drugs and food and food-additives containing certain compounds with potential side effects. Summarized here are the results of investigations that point out possible interactions at the level of transporter molecules by drugs and compounds of natural origin. These transporter molecules play important roles in absorption in the intestines, at the blood brain barrier, in the liver, the kidney and in some other parts of the human body. Drugs and metabolites pass through these pumps and may compete with compounds from food supplements. The most studied natural compounds that are potential modulators of these transport molecules are flavonoids, found in fruit juices, vegetables, flowers and tea. Mycotoxins found in cereal grains are also shown to modulate transporter proteins. We detail here how such constituents of natural origin were shown to modulate three types of the major transporter molecules, P-glycoprotein (ABCB1), multidrug resistance proteins (ABCCs) and breast cancer resistance protein (ABCG2). Interference of these natural compounds with drugs at the transporter level is also discussed.

The use of herbal supplements and medicines is rapidly growing as most people consider them as being of natural origin and therefore being safe. However, a significant number of patients combine herbal remedies with prescription medications and there is a growing evidence for interactions of drugs with herbal remedies or single compounds originating from plants. Beside metabolic interactions particularly on the level of barrier tissues being equipped with a multitude of transport proteins such interactions are reason of rising concern. One barrier of particular interest is the blood brain barrier separating blood circulation and central nervous system and protecting the brain from potentially toxic metabolites and xenobiotics. The present review gives a condensed overview about structure and function of the blood-brain barrier and interactions of selected compounds originating from natural products with transport proteins in the barrier.

The phytopharmaceutical agent St. John's wort (SJW) is currently under intense investigation. Studies of drug interactions resulting from concomitant use of SJW and conventional medication are of fundamental importance, since the use of SJW as a complementary and alternative medicine is highly popular. Intake of SJW often remains unrecognized by physicians resulting in clinical relevant alterations of treatment, as this phytopharmaceutical agent is available without prescription. This review elicits molecular explanations for clinical observations in terms of concomitant use of SJW and conventional drugs. Since patients suffering from severe diseases such as cancer are especially at risk, we focus on chemotherapeutic agents. There is strong evidence that SJW extract lowers drug plasma levels of various anti-cancer agents by pregnane X receptor activation resulting in induction of cytochrome P450 isotype 3A4, P-glycoprotein and several other enzymes. New methods such as photophysical diagnosis (PPD) and photodynamic therapy (PDT) seem to be highly promising with respect to their clinical application. Due to its fluorescent activity and an intense accumulation in cancer cells, hypericin could be applied to locate tumorous tissues. Upon excitation by light, hypericin generates cytotoxic products rendering its use attractive as photosensitizing agent. In this review both PPD and PDT are explained in detail, with a particular focus on molecular mechanisms.

Advances in high-throughput technologies to measure genome-scale changes of genes, proteins, and other biomolecular components (‘omics’) in complex biological systems have dramatically revolutionized biomedical research. However, the benefits of utilizing omics information in drug development have not yet been fully realized. Fortunately, the integration of modern systems biology efforts with traditional medicine philosophies, together with integrative bioinformatics, has driven the development of a new drug discovery paradigm. Using leukemia as a disease model, therapeutic synergism between drugs and natural products has been investigated by incorporating transcriptomics and proteomics data into a network-like understanding. Here, these recent advancements will be discussed in detail, along with perspectives in the field of drug synergism.

Increasing numbers of adults and children around the world are using natural health products (NHPs) to promote wellbeing or alleviate illness. Although often considered safe due to their natural origin, NHPs are potentially pharmacologically active and, therefore may cause harm. Limited data suggest that NHPs can interact with other NHPs as well as with prescription medication and foods. Although some common NHP-drug interactions have been identified and studied, in general, the epidemiology of NHP-drug interactions is not well-understood, in part because these harms are often underreported. Users rarely disclose NHP use to their physicians, and physicians rarely enquire about such use. Even if physicians become aware of a potential NHP-drug interaction, passive surveillance systems mean that it is left to the physician's discretion whether or not to report it to the proper authority. It is likely that active surveillance of NHP-drug interactions would result in increased reporting of NHP-related harms as well as better quality reports. Subsequent lab investigation would determine if adulteration, contamination, species misidentification, or misuse was responsible for the harm, or if a pharmacokinetic or pharmacodynamic NHP-drug interaction occurred. This kind of thorough detection and investigation of potential NHP-drug interactions is necessary to ensure the safe use of NHPs.

Clinical risk management offers a systematic approach to minimize healthcare-related risks by paying attention to: (1) risk identification and assessment; (2) development and execution of risk reduction strategies; (3) evaluation of risk reduction strategies. This paper reviews these key areas for the risk of interactions between natural products and drugs (NPDIs) to explore how the impact of these interactions on public health can be minimized. It argues that specific components of clinical risk management need to be evaluated, before adoption, and then actively implemented if proven valuable.

To evaluate the pharmacokinetics and adverse effects of medicinal herbs, as well as clinical evidence of herb-drug interactions. Electronic searches were conducted in multiple databases, including MEDLINE, EMBASE, the Cochrane Library, CINAHL, NAPRALERT, International Pharmaceutical Abstracts, CANCERLIT, CISCOM, and HerbMed. Search terms used included common names, scientific names, and synonyms for the herbs and their primary active constituents. Bibliographies of relevant articles were also searched by hand to obtain additional references. No restrictions were placed on language or quality of publications. All literature collected pertained to adverse effects, pharmacokinetics, and suspected or confirmed cases of herb-drug interactions. Over 80 herbs or botanicals (including plants, fungi, algae, and common constituents) were identified that had clinically significant interactions with prescription and over-the-counter drugs. Interestingly, herbs beginning with the letter “g” (garlic, ginger, ginkgo, and grapefruit) were among the herbs most commonly involved in herb-drug interactions. Drugs with anticoagulant/antiplatelet activity (e.g. warfarin, aspirin) were frequently implicated in herb-drug interactions, with documented interactions with over 30 herbs and herbal products. Because many herbs have demonstrated adverse effects on the liver, the potential for interaction with hepatotoxic agents (such as acetaminophen) is also significant. Clinical outcomes of reported herb-drug interactions ranged from mild to severe. Of note, fatalities (though rare) have occurred with concomitant ephedra and caffeine use. As herbal products (and dietary supplements in general) continue to grow in popularity, patients and health care providers should be vigilant of potential herb-drug interactions.