Multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines

Traditional medicine has provided a basis for health care and disease treatment to Chinese people for millennia, and herbal medicines are regulated as drug products in China. Chinese herbal medicines have two features. They normally possess very complex chemical composition. This makes the identification of the constituents that are together responsible for the therapeutic action of an herbal medicine challenging, because how to select compounds from an herbal medicine for pharmacodynamic study has been a big hurdle in such identification efforts. To this end, a multi-compound pharmacokinetic approach was established to identify potentially important compounds (bioavailable at the action loci with significant exposure levels after dosing an herbal medicine) and to characterize their pharmacokinetics and disposition. Another feature of Chinese herbal medicines is their typical use as or in combination therapies. Coadministration of complex natural products and conventional synthetic drugs is prevalent worldwide, even though it remains very controversial. Natural product–drug interactions have raised wide concerns about reduced drug efficacy or safety. However, growing evidence shows that incorporating Chinese herbal medicines into synthetic drug-based therapies delivers benefits in the treatment of many multifactorial diseases. To address this issue, a drug-combination pharmacokinetic approach was established to assess drug–drug interaction potential of herbal medicines and degree of pharmacokinetic compatibility for multi-herb combination and herbal medicine–synthetic drug combination therapies. In this review we describe the methodology, techniques, requirements, and applications of multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines and to discuss further development for these two types of pharmacokinetic research.     

Pharmacokinetic profiles of anticancer herbal medicines in humans and the clinical implications

A number of herbal medicines are increasingly used by cancer patients worldwide, despite the fact that the clinical evidence that supports their use to fight cancer is weak or lacking. Pharmacokinetic studies have been integrated into modern drug development, but they are generally not needed for herbal remedies. To update our knowledge in this field, this paper highlights the pharmacokinetic properties of anticancer herbal medicines and the clinical relevance. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase ((all from inception to May 2011). An extensive literature search indicatesthat there are limited data on the pharmacokinetic properties of anticancer herbal medicines in humans. There are increasing pharmacokinetic studies of anticancer herbal remedies, but these studies are mainly focused on a small number of herbal medicines including curcumin, ginseng, ginkgo, ginger and milk thistle. For an anticancer herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and pharmacokinetic processes of active herbal components in the body determine their target-site concentrations and thus the anticancer effect. In this regard, a safe and optimal use of anticancer herbal medicines requires a full understanding of their pharmacokinetic profiles. To optimize the use of anticancer herbal remedies, further studies to explore their pharmacokinetic properties and the relevance to pharmacodynamics and toxicity in humans are certainly warranted.     

Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections

INTRODUCTION: Invasive fungal infections remain a leading cause of infectious morbidity and mortality in immunocompromised patients. There are relatively few effective antifungal agents, and currently available agents all have significant limitations. Isavuconazole is a novel second-generation triazole with broad-spectrum antifungal activity, and a favorable pharmacokinetic-pharmacodynamic profile. Isavuconazole is available as an oral and intravenous formulation. Phase III studies that are examining the efficacy of isavuconazole for invasive candidiasis and invasive aspergillosis are currently in progress. AREAS COVERED: This review provides a summary of the pharmacological characteristics of isavuconazole and the potential future use of this agent. The preclinical and clinical pharmacokinetics and pharmacodynamics are discussed. This review was constructed by searching isavuconazole, triazole, pharmacokinetics and pharmacodynamics in PubMed. References and abstracts that were not identified by this method were retrieved from the respective publications. EXPERT OPINION: Isavuconazole has the potential to become an important agent for the treatment of invasive fungal infections, principally because of its relatively broad and potent in vitro antifungal activity, and its favorable pharmacokinetic profile. Further preclinical and clinical studies are required to define the clinical utility of this agent, especially for invasive candidiasis and invasive aspergillosis. Further information is required on the likely drug interactions, and in vitro susceptibility breakpoints for medically important invasive fungal pathogens. Further pharmacokinetic studies are also required in a range of patient populations to quantify the extent and sources of pharmacokinetic variability.     

Chronopharmacology and antimicrobial therapeutics

Chronobiology studies the phenomenon of rhythmicity in living organisms. Circadian rhythms are genetically determined and are regulated by external synchronizers (i.e. light/day cycle). Several biological processes involved in the pharmacokinetics and pharmacodynamics of drugs are subject to circadian variations. Chronopharmacology studies how biological rhythms impact on drug pharmacokinetic (chronokinetics), pharmacodynamics (chronoesthesy) and toxicity and determines whether time of day administration modifies drug's pharmacological characteristics. Chronotherapy applies chronopharmacological studies to clinical treatments, determining the best biological time for its dosing, i.e. when beneficial effects are maximal and incidence and/or intensity of related side-effects and toxicity are minimal. Significant variations in the pharmacokinetics and toxicity of antibiotics (aminoglycosides, beta-lactams and fluoroquinolones) related to administration time are well known. The aims of this review are to discuss, briefly, the currently accepted model of the circadian system that substantiates endogenous rhythmicity and to provide an update on the knowledge of circadian rhythms applied to drugs used as medicines, with a special mention to the possible impact on antimicrobial treatments. It is concluded that the dosing time of an antimicrobial agent might be clinically relevant in some treatments, thus, clinicians should be aware that the dosing time might affect the clinical response of a drug.     

液相色谱-质谱联用技术在中药药代动力学研究中的应用进展

液相色谱-质谱法在中药药代动力学研究中的应用,包括中草药单一有效成分体内药物浓度测定及多组分同时测定、中草药体内代谢产物的鉴定与分析等。中草药特别是中药方剂,成分较复杂,较化学药物的药代动力学研究更困难;而液相色谱-质谱法结合了液相色谱的高分离能力和质谱的高灵敏度和极强的定性专属性,适于中药药代动力学研究。     

ADME properties of herbal medicines in humans: evidence, challenges and strategies

Herbal medicines, an important group of multicomponent therapeutics, are widely and increasignly used worldwide. Despite the popularitiy of herbal medicines, the clinical evidence that support the use of most herbal medicines is weak. Pharmacokinetic and absorption, distribution, metabolism and excretion (ADME) studies have been integrated into modern drug development, but ADME studies are generally not needed for herbal remedy discovery and development. For the majority of herbal medicines, data on their ADME and pharmacokinetic properties in humans are lacking or scant. An extensive literature search indicates that there are limited data on ADME properties of herbal medicines in humans. Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp/MDR1/ABCB1) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are critical determining factors for the in vivo ADME processes of herbal remedies. There are increasing ADME studies of herbal remedies, but these studies are mainly focused on a small number of herbal medicines including St John's wort, milk thistle, curcumin, echinacea, ginseng, ginkgo, and ginger. For an herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and ADME processes of active herbal components in the body govern their target-site concentrations and thus the therapeutic responses. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their ADME profiles. To optimize the use of herbal remedies, further studies to explore their ADME properties in humans are certainly warranted.     

Optimisation of DMPK by the inhaled route: challenges and approaches

The renewed interest in inhalation delivery over recent years has led to an expansion in the understanding of lung pharmacokinetics. Historically optimisation of inhaled drugs focused largely on development of material properties, consistent with achieving a good lung deposition, alongside demonstrating appropriate in vivo efficacy with little understanding of the relationship to pharmacokinetics in the lung. Recent efforts have led to an increased understanding of lung concentrations and how to maximise exposure in order to achieve the desired pharmacological response at a dose consistent with development of an inhaled product. Although there is a prerequisite for excellent potency in inhalation delivery, it is essential that this be combined with pharmacokinetic properties that allow sufficient free concentration at the effect site in lung to exert the pharmacological response for an appropriate dosing interval. Increases in basicity, polarity and/or decreases in aqueous solubility can extend pharmacokinetic duration and assist in finding the right balance between lung and systemic exposure. Current evidence suggests there are similarities in lung retention in rat and dog and that animal lung concentration data can enable pharmacokinetic-pharmacodynamic relationships to be derived thus providing more confidence in the requirements for man. Although inhaled delivery is challenging from a pharmacokinetic point of view, direct evaluation of exposure in the target organ has enabled further understanding of the drivers for drug disposition and highlighted the need for further development of predictive lung pharmacokinetic tools in the future.     

Toward a better understanding of metabolic and pharmacokinetic characteristics of low-solubility,low-permeability natural medicines

Abstract

Today, it is very challenging to develop new active pharmaceutical ingredients. Developing good preparations of well-recognized natural medicines is certainly a practical and economic strategy. Low-solubility, low-permeability natural medicines (LLNMs) possess valuable advantages such as effectiveness, relative low cost and low toxicity, which is shown by the presence of popular products on the market. Understanding the in vivo metabolic and pharmacokinetic characteristics of LLNMs contributes to overcoming their associated problems, such as low absorption and low bioavailability. In this review, the structure-based metabolic reactions of LLNMs and related enzymatic systems, cellular and bodily pharmacological effects and metabolic influences, drug–drug interactions involved in metabolism and microenvironmental changes, and pharmacokinetics and dose-dependent/linear pharmacokinetic models are comprehensively evaluated. This review suggests that better pharmacological activity and pharmacokinetic behaviors may be achieved by modifying the metabolism through using nanotechnology and nanosystem in combination with the suitable administration route and dosage. It is noteworthy that novel nanosystems, such as triggered-release liposomes, nucleic acid polymer nanosystems and PEGylated dendrimers, in addition to prodrug and intestinal penetration enhancer, demonstrate encouraging performance. Insights into the metabolic and pharmacokinetic characteristics of LLNMs may help pharmacists to identify new LLNM formulations with high bioavailability and amazing efficacy and help physicians carry out LLNM-based precision medicine and individualized therapies.     

Identification of molecular mechanism for actions of existing medicines and its application for drug development

As a new strategy for drug discovery and development, we propose here the establishment of drug re-profiling strategy. In this strategy, the actions of existing medicines, whose safety and pharmacokinetic effects in humans have been confirmed already, are examined comprehensively at the molecular level and the results are used for the development of new medicines. For example, identification of the mechanisms underlying the side effects of medicines enables us to develop safer drugs. The results can also be used for developing existing drugs for use as medicines in treatment of other diseases. Promoting this research strategy could provide breakthroughs in drug discovery and development by pharmaceutical companies.     

药动学研究常用软件介绍

药动学是一门研究药物体内动态变化规律及其影响因素的学科。药动学模型研究从经典的房室模型,统计矩理论的应用,到复杂的群体药动学、生理药动学以及药动-药效学建模,都需要可靠的软件工具来完成复杂的数学计算过程。一些商业公司开发的药动学模型专业软件,已在药物研发和科学研究中广为应用;另一方面,开源工具正得到大力推广。本文总结目前用于药动学模型研究的主流软件工具,对其功能应用做简要介绍,以期为国内相关研究者提供有价值的信息。     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.     

Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. EXPERIMENTAL APPROACH: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines. KEY RESULTS: Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation. CONCLUSIONS AND IMPLICATIONS: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.     

Combination therapy of Western drugs and herbal medicines: recent advances in understanding interactions involving metabolism and efflux

INTRODUCTION: While complementary and alternative medicine markets prosper with an increasing number of consumers of herbal medicines, there is an associated likelihood for herb-drug interactions to occur. Modulation of the activity of metabolic enzymes and/or active transporters by chemical constituents of herbal medicines may influence the therapeutic outcomes of coadministered allopathic medicines due to changes in their pharmacokinetic profiles. Although valuable information on herb-drug interactions is obtained by in vitro studies, such as the mechanisms of interaction, clinical significance of interactions is ultimately demonstrated by in vivo data. AREAS COVERED: The authors outline the mechanisms of herb-drug pharmacokinetic interactions briefly and discuss pharmacokinetic interactions between different therapeutic classes of Western drugs and herbal medicines. Furthermore, the authors also discuss herb-drug interactions from both in vitro and in vivo studies with specific focus on recent findings. EXPERT OPINION: Basic and clinical researches have contributed to the comprehension of the underlying mechanisms involved as well as the practical implications of herb-drug interactions. This provides a foundation for development of guidelines to inform patients about herb-drug interactions that can affect their health.     

Adaptive control methods for the dose individualisation of anticancer agents

Numerous studies have found a clear relationship between systemic exposure and the toxicity or (more rarely) the efficacy of anticancer agents. Moreover, the clearance of most of these drugs differs widely between patients. These findings, combined with the narrow therapeutic index of anticancer drugs, suggest that patient outcome would be improved if doses were individualised to achieve a target systemic exposure. Bayesian maximum a posteriori probability (MAP) forecasting is an efficient and robust method for the optimisation of drug therapy, but its use for anticancer drugs is not yet extensive. The aim of this paper is to review the application of population pharmacokinetics and MAP to anticancer drugs and to evaluate whether and when MAP Bayesian estimation improves the clinical benefit of anticancer chemotherapy. For each drug, the relationships between pharmacokinetic variables [e.g. plasma concentration or the area under the concentration-time curve] and pharmacodynamic effects are described. Secondly, the methodologies employed are considered and, finally, the results are analysed in terms of predictive performance as well as, where possible, the impact on clinical end-points. Some studies were retrospective and intended only to evaluate individual pharmacokinetic parameter values using very few blood samples. Among the prospective trials, a few studied the pharmacokinetic/pharmacodynamic relationships which provided the basis for routine pharmacokinetic monitoring. Others were performed in clinical context where MAP Bayesian estimation was used to determine maximum tolerated systemic exposure (e.g. for carboplatin, topotecan, teniposide) or for pharmacokinetic monitoring (e.g. for methotrexate or platinum compounds). Indeed, its flexibility in blood sampling times makes this technique much more applicable than other limited sampling strategies. These examples demonstrate that individual dose adjustment helps manage toxicity. The performance of pharmacokinetic monitoring is linked to the methodology used at each step of its design and application. Moreover, a limitation to the use of pharmacokinetic monitoring for certain anticancer drugs has been the difficulty in obtaining pharmacokinetic or pharmacodynamic data. Recent progress in analytical methods, as well as the development of noninvasive methods (such as positron emission tomography) for evaluating the effects of chemotherapy, will help to define pharmacokinetic-pharmacodynamic relationships. Bayesian estimation is the strategy of choice for performing pharmacokinetic studies, as well as ensuring that a given patient benefits from the desired systemic exposure. Together, these methods could contribute to improving cancer chemotherapy in terms of patient outcome and survival.     

蝙蝠葛苏林碱和蝙蝠葛碱在犬体内的药动学-药效学模型

目的：研究蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的药动学-药效学结合模型,并比较两种药物对其心电、血压和血流动力学的作用。方法：利用反相高效液相色谱法测定其血药浓度,生理记录仪观察药理效应,并计算药动学和药动学-药效学结合模型参数．结果：血药浓度-时间数据符合二房室开放模型．药效与效应室药物浓度之间的关系符合sigmoid-Emax模型．主要药动学和药动学-药效学结合模型参数在两种药物间差异无显著性．结论：蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的处置规律和对心血管系统的抑制作用基本-致。     

Drug interactions with herbal medicines

In recent years, the issue of herbal medicine-drug interactions has generated significant concern. Such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e.g. warfarin, ciclosporin and digoxin). The present article summarizes herbal medicine-drug interactions involving mainly inhibition or induction of cytochrome P450 enzymes and/or drug transporters. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and the majority of the interactions may be difficult to predict. Potential pharmacodynamic and/or pharmacokinetic interactions of commonly used herbal medicines (black cohosh, garlic, Ginkgo, goldenseal, kava, milk thistle, Panax ginseng, Panax quinquefolius, saw palmetto and St John's wort) with conventional drugs are presented, and sometimes the results are contradictory. Clinical implications of herbal medicine-drug interactions depend on a variety of factors, such as the co-administered drugs, the patient characteristics, the origin of the herbal medicines, the composition of their constituents and the applied dosage regimens. To optimize the use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and to delineate the underlying mechanisms.     

Disposition pathways and pharmacokinetics of herbal medicines in humans

Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their pharmacokinetic profiles. To optimize the use of herbal remedies, further clinical studies to explore their biological fate including the disposition pathways and kinetics in the human body are certainly needed.