Current Drug Metabolism - Volume 12, Issue 9, 2011

With the ever-increasing acceptance of combination therapy and the prevalence of chronic diseases in the world, the development of multi-component drug therapies including the use of herbs has become an emerging trend. Herbal medicines (HMs), generally prepared with a specific combination of different herbs, are becoming increasingly popular as a multi-component drug therapy. In addition, drug combination, as another multi-component therapeutics, also can be used to treat complex disease. Recently, clinical results demonstrated that multi-component therapeutics had achieved numerous successes in treating complex diseases. However, the use of multi-component drug may mimic, increase or reduce the effects of either component in drug, resulting in clinically important metabolic drug interactions. Metabolic drug interactions are as a result of altered absorption, distribution, metabolism, excretion and toxicity (ADME/T) of components. So, the study on multi-component drug ADME/T and metabolic interactions plays a major role in current drug metabolism study. It will be the aim of this special issue on Multi-component Drug ADME/T and Metabolic Interactions to illustrate the recent advances and to highlight new trends in ADME/T and metabolic interactions of multi-component drugs. It is hoped that the scientists involved in drug metabolism and the related research fields will find the selection of these reviews beneficial and informative. In the metabolism studies of multi-component drug, one requirement that is common for many stages is the need for bioanalytical methodologies or strategies. The review by G.Z. Xin et al., from State Key Laboratory of Natural Medicines, China Pharmaceutical University, illustrates the new improvement in strategies for integral metabolism profile of multiple compounds in HMs: pharmacokinetics, metabolites characterization, and metabolic interactions. HMs have played an important role in human history for preventing and treating diseases. Ginseng is an HM used worldwide. Recently, the metabolism and pharmacokinetic studies of ginseng have become an important issue.The article by C.S. Yuan et al, from the Tang Center for Herbal Medicine Research, University of Chicago, reviews the known metabolism and pharmacokinetic data on ginseng. While the use of herbal products in many cases causes adverse effects, to date, safety issues of herbal products have not been adequately addressed. It is rarely determined whether the non-purported bioactive constituents in the herbs and the metabolites of the bioactive components can lead to adverse effects. In the third review, written by G. Lin, from School of Biomedical Sciences, the Chinese University of Hong Kong, they discuss, using pyrrolizidine alkaloids as an example, the hepatotoxicity and tumorigenicity induced by metabolic activation of herbal components and by herb-herb and herb-drug interactions with other herbal ingredients and synthetic drugs. The combined use of herbs and drugs has increased the possibility of pharmacokinetic and pharmacodynamic interactions. The paper by C.X. Liu et al., from the State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, highlights recent knowledge to discuss herb-drug interactions involving metabolizing enzymes and drug transporters. Translational research is an emerging discipline that aims to fill the gap through the whole pipeline from bench to bedside. This review by G.J. Wang, from Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, highlights the importance and urgency of incorporating translational research into the study of pharmacokinetic herb drug interactions (PHDI), based on an intensive discussion on the controversial and inconsistent reports from preclinical to clinical, in vitro to in vivo, and across different studies concerning PHDI......

Herbal medicines (HMs) are gaining more and more attention all over the world, because of their significant curative effect in treating multi-factorial diseases. Recently, the in vivo and in vitro metabolism study of HMs has become an important issue because these data can help us to better understand the efficacies and toxicities of HMs. However, the integral metabolism profile of HMs is confronted with many challenges: 1) HM is a multi-component system; 2) most components are unknown (nontarget); 3) trace of components in HM. Given the challenges described above, the demand for more powerful bioanalytical tools and strategies that are adequate for integral metabolism profile of HMs' multi-components has increased. In the past few years, newer methods, or adaptations to methods, have been published, and this review will attempt to discuss new improvements in strategies and methodologies for HMs' multi-component ADME evaluation. In particular, improvements have been reported for experimental approaches to pharmacokinetics study of HMs, as well as strategies applied to metabolites characterization of HMs' multi-components, and the metabolic interactions between ingredients in HMs, including advance and proposed strategy: “chemical fishing” based strategy for metabolic interactions of HMs.

Ginseng is an herbal medicine used worldwide. It is reported to have a wide range of pharmacological activities because of a diversified group of steroidal saponins called ginsenosides. Compared to extensive pharmacological studies of ginseng, the pharmacokinetics, especially the metabolism of this herb, has received less attention. In this article we review the known pharmacokinetic data on ginseng. Understanding ginseng's pharmacokinetics may reduce the potential for interactions in patients who use both ginseng and prescription medications. In addition, bioavailability after taking ginseng orally is low, and the metabolites of ginsenosides produced by gut microbiota may be biologically active. One ginseng metabolite, Compound K, and its potential for cancer chemoprevention is also discussed. An active ginseng metabolite may differ in distribution and clearance from its parent compound, and the parent compound and its metabolite may be bioactive by similar or different mechanisms. Thus, further investigation of ginseng metabolites is needed for predicting the therapeutic outcome with ginseng.

In the recent decades, the use of herbal products has been rapidly growing in the Western countries. While their use in many cases causes adverse effects, to date, safety issues of herbal products have not been adequately addressed. It is rarely determined whether the non-purported bioactive constituents in the herbs and the metabolites of the bioactive components can lead to adverse effects. In this review, we discuss, using pyrrolizidine alkaloids (PAs) as an example, the hepatotoxicity and tumorigenicity induced by metabolic activation of herbal components and by herb-herb and herb-drug interactions with other herbal ingredients and synthetic drugs. PAs are constitutively produced by plants as the secondary metabolites. There are more than 600 PAs and PA N-oxides identified in over 6000 plants, and more than half of them exhibit hepatotoxicity. Toxic PA-containing plants grow in many geographical regions worldwide, rendering it highly possible that PA-containing plants are the most common poisonous plants affecting livestock and humans. PAs require metabolic activation mediated by cytochrome P450 enzymes to generate reactive pyrrolic metabolites that react with cellular proteins and DNA leading to hepatotoxicity and genotoxicity. PAs can also modulate both phase I and phase II metabolizing enzymes, which may alter the metabolic fate of endogenous and exogenous chemicals. Alteration and/or competition of the metabolizing enzymes by PAs upon the co-administered herbal medicines or drugs can potentially result in serious clinical and toxicological consequences through decreased pharmacological activities or increased toxic effects.

Herbal medicines and their active ingredients are widely used worldwide, and they have become an important part of clinical medicine. The combined use of herbs and drugs has increased the possibility of pharmacokinetic and pharmacodynamic interactions. Clinical studies have demonstrated that the combined use of herbs and drugs can enhance or attenuate the drug efficacy and toxicity. The herb-drug combinations may reduce a drug efficacy and lead to treatment failure when long-term administration. Case reports detailing serious clinical adverse reactions have promoted studies on the interactions between herbs and drugs. This review highlights recent knowledge to discuss herb-drug interactions involving metabolizing enzymes and drug transporters. Drug transporters are widely present in body and play an important role in the absorption, distribution, excretion and metabolism, efficacy, and toxicity of drugs. Investigation of transporters has developed rapidly since 1990s, the effects of many transporters on the pharmacokinetics of drugs and herb-drug interactions have been reported. Some concepts on drug transporters issued experimentally and clinically drug-drug and herb-drug interactions have applied in many studies. Methodology studies are very important for understanding the mechanism, considerations and evaluation of experiments and clinical studies on drug metabolizing enzymes and transporters in drug-drug interactions.

Translational research is an emerging discipline that aims to fill the gap through the whole pipeline from bench to bedside. This review highlights the importance and urgency of incorporating translational research into the study of pharmacokinetic herb drug interactions (PHDI), based on an intensive discussion on the controversial and inconsistent reports from preclinical to clinical, in vitro to in vivo, and across different studies concerning PHDI. Current controversial and dispersed reports confer poor translational capacity of experimental research data to guiding the clinical practices. We propose that the herbal complexities in their chemical compositions, biphasic and tissue-specific effects of enzymes, and the present incomplete understanding of the disposition properties of herbal medicines themselves; and the enzymatic complexities in the species differences, individual genotype and phenotype, differential regulation during healthy and pathological conditions, substrate dependent modulations, and their interplay with transporters, collectively constitute the major translational blocks in PHDI from experimental research to daily clinical practice. In clinical considerations, this review indicates that PHDI are far from clear based on the isolated preclinical findings, and that the intestine is a much more susceptible site than liver when subjected to herbal regulations, and that enzymatic induction could be more predominant than inhibition upon chronic ingestion of herbal medicines. Hopefully, this review would be helpful for better understanding the nature of hurdles in PHDI research, and for igniting the future translational research initiatives.

As the prevalence of polypharmacy increases with our aging population, the propensity for adverse drug-drug interactions arising from the altered metabolism of co-administered medicines remains an important consideration for drug development. Mechanismbased inactivation (MBI) of the cytochrome P450 enzyme system is responsible for many clinically relevant drug-drug interactions (DDIs) due to the irreversible and long-lasting effects of the enzyme inactivation. Unlike competitive inhibition, MBI persists after the inactivator has been cleared from the system, since de novo enzyme synthesis is required to restore metabolic activity. Recognizing the potential severity of DDIs arising from MBI, there is increasing need for predictive methodologies that can enable prospective risk assessment for the likelihood of a clinical DDI. Steady-state models, which simplify the system to a single inactivator concentration and assume static, equilibrium conditions, are important tools for assessing the potential for DDIs. More sophisticated, physiologically-based models offer advantages over the static models by taking into account changing inactivator concentration over time, in addition to incorporating population variability into the prediction. Despite the differences between the static and dynamic approaches, a key consideration for both is the sensitivity of the models to the input parameters. These inputs include inactivator-specific kinetic parameters describing MBI in terms of potency (KI) and inactivation rate (kinact), the unbound inactivator concentration (Iu), and the enzyme degradation rate, (kdeg). This commentary investigates the impact of the selection of input parameters, and the uncertainty in their assessment, on the prediction for DDIs arising from MBI and the relevance to risk-assessment.

Nitric oxide, a unique signalling molecule, is synthesized from L-arginine by a family of isoenzymes called nitric oxide synthase. Function of nitric oxide largely depends on the concentrations of surrounding free radicals and redox state. The local concentration of the nitric oxide defines its anti- or protumorigenic function by interacting with DNA or DNA repair enzymes and tumor suppressor gene, p53, as well. Indoleamine 2,3-dioxygenase activity is induced by interferon-gamma in many human cell types or cancer cells. Indoleamine 2,3- dioxygenase depletes locally available L- tryptophan producing cytotoxic metabolite kynurenine. Nitric oxide regulates the indoleamine 2,3-dioxygenase activity in a dose dependent-manner leading to either enhanced immune response or immune tolerance against tumor tissue. Additionally, the overproduction of nitric oxide may also trigger the cyclooxygenase-lipooxygenase pathways. Nitric oxide synthase expression correlates with cyclooxygenase-2 expression in cancer cells. On the other hand, tetrahydrobiopterin acts as the cofactor for nitric oxide synthase and stabilizes nitric oxide synthase dimers. However, tetrahydrobiopterin acts biphasically; under limited concentrations of tetrahydrobiopterin, nitric oxide generates superoxide radicals. Thus the dual action of nitric oxide and its interaction with the related compounds are of concern for their contribution in the development of carcinogenesis. In this review critical links between the nitric oxide and chronic inflammation associated carcinogenesis are summarized.

The phase II metabolism sulfation and glucuronidation, mediated by sulfotransferases (SULTs) and UDP-glucuronosyltransferases (UGTs) respectively, are significant metabolic pathways for numerous endo-and xenobiotics. Understanding of SULT/UGT substrate specificity including regioselectivity (i.e., position preference) is of great importance in predicting contribution of sulfation/ glucuronidation to drug and metabolite disposition in vivo. This review summarizes regioselective sulfation and glucuronidation of phenolic compounds with multiple hydroxyl (OH) groups as the potential conjugation sites. The strict regioselective patterns are highlighted for several SULT and UGT isoforms towards flavonoids, a large class of natural polyphenols. To seek for a molecular-level explanation, the enzyme structures (i.e., SULT crystal structures and a homology-modeled UGT structure) combined with molecular docking are employed. In particular, the structural basis for regioselective metabolism of flavonoids by SULT1A3 and UGT1A1 is discussed. It is concluded that the regioselective nature of these phase II enzymes is determined by the size and shape of the binding pocket. While the molecular structures of the enzymes can be used to explain regioselective metabolism regarding the binding property, predicting the turnover at different positions remains a particularly difficult task.