Absorption, disposition, and pharmacokinetics of saponins from Chinese medicinal herbs: what do we know and what do we need to know more?

Saponins are a group of amphiphilic glycosides containing one or more sugar chains linked to a nonpolar triterpene or steroid aglycone skeleton, which are believed to be responsible for the pharmacological activities of many Chinese medicinal herbs. The purpose of this paper is to summarize the contemporary knowledge of the absorption, disposition, and pharmacokinetics of some important saponins, including ginsenosides, licorice saponins, dioscorea saponins, astragalosides, and saikosaponins. Poor intestinal absorption of saponins is mainly due to their unfavorable physicochemical traits, such as large molecular mass ( > 500 Da), high hydrogen-bonding capacity ( > 12), and high molecular flexibility ( > 10), that underlie poor membrane permeability. Rapid and extensive biliary excretion is another primary factor that limits the oral bioavailability of most saponins. However, several saponins, including ginsenosides Ra3, Rb1, Rc, and Rd, and dioscin, are excreted slowly into the bile and in turn have significantly long elimination half lives (7-25 h in rats). These longcirculating saponins may be used as pharmacokinetic markers to substantiate systemic exposure to the ingested herb extracts. In addition to biliary excretion for elimination of most saponins unchanged, renal excretion may also be important for certain saponins. Saponins can be hydrolyzed by the colonic microflora. After absorption, the deglycosylated aglycones undergo phase I and/or II metabolism by the host. In line with the poor permeability, saponin concentrations in most rat tissues are lower than the concurrent plasma level and the brain level is usually very low. However, the liver concentrations of many saponins, as well as the kidney levels of certain saponins, can be quite high, which involves transporter-mediated uptake mechanisms. Repeated p.o. ingestion of glycyrrhizin appears to be able to induce CYP3A in rodents and humans, while several deglycosylated products of ginsenosides can moderately inhibit CYP activities in vitro with IC50 values of 10-50 μM. More research is required for elucidation of the absorption, disposition, and pharmacokinetics of multiple saponins to enhance understanding which saponins are most likely to exert pharmacological effects in vivo, as well as influence of complex herb matrix. In addition, research is also needed to characterize the microbiotal deglycosylation and the subsequent aglycone metabolism by the host for a broader range of saponins, as well as the hepatobiliary transporter phenotyping for and the interaction with saponins. Furthermore, in vitro and in vivo studies of saponin-based herb-drug interactions are also warranted.     

Are herbal medicines effective?

Herbal medicine is again popular and its widespread use demands that we assess its effectiveness objectively. The evidence in this area has grown considerably in recent years, not least due to the endeavors of the Cochrane Collaboration. They show amongst other things that it is possible to evaluate herbal medicines in much the same way as conventional drugs. By far the biggest hindrance to research into herbal medicine is the lack of funds available for this line of scientific investigation. In view of the present popularity of herbal medicine it seems necessary to overcome obstacles to rigorous research and establish which herbal medicines do more good than harm for which conditions.     

Evidence-based treatment: Why,what, where,when, and how?

Research and clinical perspectives are blended in this commentary on the rapidly emerging requirement for evidence-based treatment (EBT) in substance abuse programs. Although, historically, it has not been a standard of care in behavioral health, there are sound scientific, ethical, and compassionate reasons to learn and deliver an EBT as it becomes available. This article explores a series of issues, including the following: (1) Why should EBTs be used in substance abuse treatment? (2) What kinds of treatment are EBTs, and how are they determined? (3) Where can EBTs be implemented—at what levels of service delivery? (4) When should EBTs be used? and (5) How do clinicians learn EBTs? Potential pitfalls in implementing EBTs are also considered.     

Consumers’ attitude towards the use and safety of herbal medicines and herbal dietary supplements in Serbia

Background The use of herbal medicines and herbal dietary supplements in Serbia is very common and many patients consume herbal preparations with conventional drug therapy. Objective The aim of this survey was to evaluate the consumers’ awareness of herbal remedies and the safety of herbal dietary supplements, their attitude towards combining herbals and drugs, and the source of recommendations for their use. Setting The study included all consumers who bought herbal remedies and herbal dietary supplements in 15 pharmacies on the territory of Novi Sad during 2011 and who accepted to be interviewed. Methods Structured interviews using questionnaire, conducted by pharmacists. The questionnaire included 4 parts: socio-demographic characteristics of consumers, source of recommendations for the use of herbal products, attitude towards safety of herbal remedies and herbal dietary supplements use and their combination with regular drugs, as well as the question of purchased herbal products. Main outcome measure Consumers’ attitude towards the safety and use of herbal medicines and herbal dietary supplements measured by 9 items. Results The majority of interviewed participants were highly educated, aged 41–60 and they consumed herbal remedies on their own initiative or on recommendation of nonmedically educated person, without previous consultation with medical doctor or pharmacist. Out of all participants: 88.9 % did not consider it important to inform their physician or pharmacist about use of herbal remedies and herbal dietary supplements; 73.3 % found the use of herbal remedies harmless (where 9.4 % did not have any attitude towards that issue), while 40.3 % of participants regarded the combining of herbal and regular drugs unsafe. Conclusion There is a need for consumers’ education on reliable use of herbal medicines and herbal dietary supplements, in order to improve their awareness of the limits of herbal remedies safety and potential risks of their combination with drugs.     

The pharmacokinetics of levosalbutamol: what are the clinical implications?

Salbutamol (albuterol) is a beta2-adrenoceptor agonist used as a bronchodilator for the treatment of asthma and as a uterine relaxant for the suspension of premature labour. Salbutamol has been marketed as a racemic mixture, although beta2-agonist activity resides almost exclusively in the (R)-enantiomer. The enantioselective disposition of salbutamol and the possibility that (S)-salbutamol has adverse effects have led to the development of an enantiomerically pure (R)-salbutamol formulation known as levosalbutamol (levalbuterol). Salbutamol is metabolised almost exclusively by sulphotransferase (SULT) 1A3 to an inactive metabolite. (R)-Salbutamol is metabolised up to 12 times faster than (S)-salbutamol. This leads to relatively higher plasma concentrations of (S)- salbutamol following all routes of administration, but particularly following oral administration because of extensive metabolism by the intestine. Enantiomer concentrations are similar for the first hour following an inhaled dose, reflecting the fact that salbutamol in the lung probably undergoes little metabolism. Subsequently, (S)-salbutamol predominates due to absorption and metabolism of the swallowed portion of the inhaled dose. Following oral or inhaled administration of enantiomerically pure salbutamol, a small amount (6%) is converted to the other enantiomer, probably by acid-catalysed racemisation in the stomach. Tissue binding of salbutamol is not enantioselective and plasma protein binding is relatively low. Both enantiomers are actively excreted into the urine. Compared with healthy individuals, patients with asthma do not have substantially different pharmacokinetics of the salbutamol enantiomers, but they do appear to have less drug delivered to the lung following inhaled administration because of their narrowed airways. Levosalbutamol elicits an equal or slightly larger response than an equivalent dose of the racemic mixture. This is probably due to competitive inhibition between the enantiomers at beta-adrenoceptors. Pharmacokinetic-pharmacodynamic relationships for levosalbutamol show relatively large interindividual variations. Functionally significant genetic polymorphisms have been identified for beta2-adrenoceptors, SULT1A3 and organic action transporters, all of which affect the disposition or action of levosalbutamol. Animal, in vitro and some clinical studies have reported deleterious effects of (S)-salbutamol on smooth muscle contractility or lung function. However, well-designed clinical studies in patients with asthma have failed to find evidence of significant toxicity associated with (S)-salbutamol. The clinical consequences of relatively higher plasma concentrations of (S)-salbutamol following administration of racemate remain unclear, but in the absence of clear evidence of toxicity the clinical superiority of levosalbutamol over racemic salbutamol appears to be small.     

Heart regeneration: what cells to use and how?

Coronary artery disease (CAD) is the leading cause of death in modern societies. Recent achievements in the treatment of CAD including statins, ACE inhibitors, beta blockers, and interventional procedure improved the outcome of patients with CAD, but this conventional approach failed to control cardiovascular mortality. Nowadays, cells (stem cells) and their potential role in managing patients with heart disease is a field of intensive research. Various types of cells have been used for transplantation targeting heart regeneration, including bone marrow cells (BMCs), cardiac stem cells (CSCs), endothelial progenitor cells (EPCs), skeletal myoblasts (SMs), adipose stroma tissue cells (ATSCs), mesenchymal cells (MCs), and embryonic stem cells (ESCs). Several routes have been used to deliver these cells to human myocardium or to the coronary circulation such as, intracoronary injection, intravenous infusion, direct injection into the ventricular wall, or transepicardial/transendocardial infusions. Although the results of the recent clinical trials in this area are rather conflicting, these therapeutic approaches seem to be promising for the treatment of ischemic heart disease.     

Metabolism and transport of drugs and Chinese herbal medicines： from molecule to malady

Detailed ADME （absorption, distribution, metabolism and excretion） evaluation is required in the preclinical stage of drug development. The preclinical ADME data may be extrapolated to humans and some predictions may be made with the application of proper pharmacokinetic and pharmacodynamic principles. Novel drugs with validated drug targets and favorable ADME properties are being sought by drug scientists, and oral administration is becoming a major delivery approach for many drugs due to its great safety, reduced cost, improved quality of life, and the potential for improved efficacy. The incorporation of herbal therapy into the main stream medical-care system has been encouraged by World Health Organization （WHO）. Chinese herbal medicines may represent an important group of multi-component therapeutics suitable for the management of diseases with networked abnormalities such as cancer and diabetes. However, the disposition pathways, pharmacological targets and safety profiles of most Chinese herbal medicines are unknown or not well characterized. The evidence for the use of Chinese herbal medicines as effective and safe multi-component therapeutics is not established. The quality control and standardization of these natural products still constitute a major chal-lenge in their evidence-based clinical application. Recently, there is an increased interest in the incorporation of systems biology approaches and combined use of preclinical and clinical models in understanding the complex disposition pathways, multiple targets and toxicities of Chinese herbal medicines.[第一段]     

A review of phthalate pharmacokinetics in human and rat: what factors drive phthalate distribution and partitioning?

Abstract

Phthalates are a class of compounds that have been extensively used as plasticizers in different applications. Several phthalates have been recognized as substances of very high concern (SVHCs) in the EU, because of their toxicity for reproduction. However, high amounts of other phthalates are still produced and imported in the European Economic Area. In China and the US, recent studies show increasing concentrations of several phthalates in the air and in human urine, respectively. The understanding of phthalate absorption, distribution, metabolism, and elimination (‘pharmacokinetics’) in the organism is still limited. Specifically, phthalate partitioning among tissues is insufficiently understood. Here, we estimate partition coefficient (PC) values for different phthalates by using five algorithms and compare them to experimental (in-vivo and in-vitro) PC values. In addition, we review all pharmacokinetic steps for phthalates in human and rat, based on data from 133 peer-reviewed publications. We analyze the factors that determine phthalate partitioning and pharmacokinetics. Four processes are particularly relevant to phthalate distribution: protein binding, ionization, passive partitioning, and metabolism in different tissues. The interplay of these processes needs to be better represented in methods for determining the PC values of phthalates. The hydrophobicity of phthalates affects all pharmacokinetic steps. The exposure route has an influence on specific steps of phthalate pharmacokinetics but generally does not affect the pattern of metabolites in urine. The age of the organism has an influence on phthalate metabolism. More studies on the protein-bound fraction of phthalates in plasma and pharmacokinetic studies following inhalation and dermal exposure are desirable.     

Chirality and pharmacokinetics: an area of neglected dimensionality?

Drug stereochemistry has, until relatively recently, been an area of neglected dimensionality with the development of the majority of synthetic chiral drugs as racemates. This situation has changed in recent years as a result of advances in the chemical technologies associated with the synthesis, analysis and preparative scale resolution of the enantiomers of chiral molecules. As a result of the application of these technologies the potential significance of the differential pharmacodynamic and pharmacokinetic properties of the enantiomers present in a racemate have become appreciated. Many of the processes involved in drug disposition, i.e. absorption, distribution, metabolism and excretion, involve a direct interaction with chiral biological macromolecules, e.g. transporters, membrane lipids and enzymes, and following administration of a racemate the individual enantiomers frequently exhibit different pharmacokinetic profiles and rarely exist in a 1:1 ratio in biological fluids. The magnitude of the differences between a pair of enantiomers observed in their pharmacokinetic parameters tends to be relatively modest in comparison to their pharmacodynamic properties. However, the observed stereoselectivity may be either amplified or attenuated depending on the organisational level, e.g. whole body, organ or macromolecular, the particular parameter represents. Differences in parameters involving a direct interaction between a drug enantiomer and a biological macromolecule, e.g. intrinsic metabolite formation clearance and fraction unbound, tend to be largest, and comparison of parameters reflecting the whole body level of organisation, e.g. half-life, clearance, volume of distribution, may well mask significant stereoselectivity at the macromolecular level. In spite of the recent interest in drug chirality relatively limited pharmacokinetic data are available for the enantiomers of a number of commonly used racemic drugs. Factors influencing the stereo-selectivity of drug disposition include: formulation and route of administration; in vivo stereochemical stability, both chemical and enzymatic; drug interactions, both enantiomeric and with a second drug; disease state; age; gender; race; and pharmacogenetics. As a result of such factors estimation of pharmacokinetic parameters, development of complex pharmacokinetic models and plasma-concentration-effect relationships based on 'total' drug concentrations following administration of a racemate are of limited value and potentially useless.     

Prediction of warfarin dose: why, when and how?

Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.     

Effect of different durations and formulations of diltiazem on the single-dose pharmacokinetics of midazolam: how long do we go?

Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compound's sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional release [CR]) had on the single-dose pharmacokinetics of midazolam. The geometric mean ratio (GMR; midazolam + diltiazem(XR × 5 days)/midazolam + diltiazem(XR × 2 days)) for midazolam AUC(0-∞) was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazem(XR × 2 days)/midazolam + diltiazem(CR × 2 days)) for midazolam AUC(0-∞) was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (k(deg)) different from that provided by the software was used. The data suggest that dosing diltiazem XR for 2 days predicts the change in midazolam AUC as reliably as 5 days of XR dosing and 2 days of CR dosing. In addition, the authors believe that a hepatic CYP3A kdeg of 0.03 h(-1) should be considered for future Simcyp studies.     

Variability in susceptibility - how big, how often, for what responses to what agents?

This paper surveys some recent available observations in humans on interindividual variability in exposure-related parameters, pharmacokinetics, and pharmacodynamics. Overall, I think two inferences are warranted. First, the drug and epidemiological literatures do contain information that can shed new light on the extent of variability in the doses associated with different non-cancer responses. These data are waiting to be systematically extracted and analyzed. Second, I think it is likely that with more systematic measurement and analysis of interindividual variability we are likely to find that there are systematic tendencies for some kinds of responses to some categories of agents to occur at more variable exposures/doses than others. If we gather and analyze additional data of this type, we may be able to recommend adaptive modifications to the ten-fold safety factor tuned to these differences.     

Methylene blue and vasoplegia: who, when, and how?

Systemic inflammatory response can be associated with clinically significant and, at times, refractory hypotension. Despite the lack of uniform definitions, this condition is frequently called vasoplegia or vasoplegic syndrome (VS), and is thought to be due to dysregulation of endothelial homeostasis and subsequent endothelial dysfunction secondary to direct and indirect effects of multiple inflammatory mediators. Vasoplegia has been observed in all age groups and in various clinical settings, such as anaphylaxis (including protamine reaction), sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. Among mechanisms thought to be contributory to VS, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway appears to play a prominent role. In search of effective treatment for vasoplegia, methylene blue (MB), an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase (GC), has been found to improve the refractory hypotension associated with endothelial dysfunction of VS. There is evidence that MB may indeed be effective in improving systemic hemodynamics in the setting of vasoplegia, with reportedly few side effects. This review describes the current state of clinical and experimental knowledge relating to MB use in the setting of VS, highlighting the potential risks and benefits of therapeutic MB administration in refractory hypotensive states.     

Do herbal medicines have potential for managing snake bite envenomation?

Snake envenomation is a global public health problem, with highest incidence in Southeast Asia. Inadequate health services, difficult transportation and consequent delay in antisnake venom administration are the main reasons for high mortality. Adverse drug reactions and inadequate storage conditions limit the use of antisnake venom. The medicinal plants, available locally and used widely by traditional healers, therefore need attention. A wide array of plants and their active principles have been evaluated for pharmacological properties. However, numerous unexplored plants claimed to be antidotes in folklore medicine need to be studied. The present article reviews the current status of various medicinal plants for the management of snake bite.