Nanoparticulate drug delivery in pregnancy: placental passage and fetal exposure

During the past decade there has been an explosion in the number of nanoparticulate drugs or drug delivery systems being explored, developed and marketed for the treatment and prevention of human diseases. While the potential dangers of drug administration in pregnancy are well known, there are circumstances where the benefits of maternal drug administration are perceived to outweigh the risks to the fetus. Hence, the administration of potentially harmful drugs in pregnancy is surprisingly common. Nanoparticulate delivery systems offer a potential avenue for delivering therapeutics to maternal tissues with minimal risk of incidental fetal exposure, depending on the ability of the nanoparticle in question to cross the placenta. As the conduit to the fetus, the placenta is both a drug target and a drug barrier, as well as a potential target of any toxicity. Limited studies on this topic show considerable uncertainty regarding the transplacental passage of nanoparticles, and our understanding of the criteria that determine transferability is poor. Despite the fact that the toxicity caused by environmental and man-made nanoparticulates has been widely studied in various organ systems, data on the effects of maternal nanoparticle exposure on human fetal tissues are lacking, although studies in rodents indicate that caution is justified. In this review, we examine the evidence relating to the potential toxicity of nanoparticles in pregnancy, the ability of the placenta to take up and transfer nanoparticles to the fetus, and the theoretical benefits and risks of administration of nanoparticle-based therapeutics in pregnancy.     

Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical implications

There is a growing epidemic of type 2 diabetes (T2DM), and it is associated with various comorbidities. Patients with T2DM are usually treated with multiple drugs, and are therefore at an increased risk of harmful drug-drug interactions (DDIs). Several potentially life-threatening DDIs concerning oral antidiabetic drugs have been identified. This has mostly been initiated by case reports but, more recently, the understanding of their mechanisms has greatly increased. In this article, we review the pharmacokinetic DDIs concerning oral antidiabetics, including metformin, sulfonylureas, meglitinide analogs, thiazolidinediones and dipeptidyl peptidase-4 inhibitors, and the underlying mechanistic basis that can help to predict and prevent DDIs. In particular, the roles of membrane transporters and cytochrome P450 (CYP) enzymes in these DDIs are discussed.     

Interindividual variability in oral antidiabetic drug disposition and response: the role of drug transporter polymorphisms

BACKGROUND: Numerous effective oral pharmacologic therapies are available to treat type 2 diabetes. However, a substantial number of patients do not achieve the expected glucose-lowering response, or may be predisposed to adverse effects, from these agents. The application of pharmacogenetics to the field of type 2 diabetes is one step towards the goal of improved pharmacotherapeutic management of this progressive disease. METHODS: A PubMed literature search was conducted to identify clinical studies that have examined the extent to which drug-transporter gene polymorphisms influence interindividual variability in oral antidiabetic drug disposition and response in humans. RESULTS/CONCLUSION: Available data suggest that drug transporters play an important role in the disposition of some oral antidiabetic drugs in the body, particularly the meglitinides and metformin. Moreover, polymorphisms in genes encoding drug transport proteins may alter the pharmacodynamic profile of these agents. Drug transporters, drug-metabolizing enzymes, and drug targets each play a distinct and important role in the disposition and action of many oral antidiabetic agents. Thus, future studies may need to take a pharmacogenomic (i.e., multiple gene) approach in order to comprehensively understand the extent to which genetic variation contributes to interindividual differences in oral antidiabetic drug clinical pharmacology.     

Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy

There has been increasing appreciation of the role of drug transporters in pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. The clinical relevance of drug transporters depends on the localisation in human tissues (i.e., vectorial movement), the therapeutic index of the substrates and inherent interindividual variability. With regard to variability, polymorphisms of drug transporter genes have recently been reported to be associated with alterations in the pharmacokinetics and pharmacodynamics of clinically useful drugs. A growing number of preclinical and clinical studies have demonstrated that the application of genetic information may be useful in individualised pharmacotherapy for numerous diseases. However, the reported effects of variants in certain drug transporter genes have been inconsistent and, in some cases, conflicting among studies. Furthermore, the incidence of almost all known variants in transporter genes tends to be racially dependent. These observations suggest the necessity of considering interethnic variability before extrapolating pharmacokinetic data obtained in one ethic group to another, especially in the early phase of drug development. This review focuses on the impact of genetic variations in the function of drug transporters (ABC, organic anion and cation transporters) and the implications of these variations for pharmacotherapy from pharmacokinetic and pharmacodynamic viewpoints.     

二甲双胍——治疗糖尿病的经典用药

甲双胍于1957年首次用于临床,以其卓越的降糖作用及相对安全性被医学界认可,成为最常用的口服降糖药之一.为了增进大家对二甲双胍的认识,我们邀请了国内几位著名专家(石福彦、袁群.陈丽.杨晓晖等)对该药进行了评述与综述.     

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.     

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.     

Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer

There is wide variability in the response of individuals to standard doses of drug therapy. This is an important problem in clinical practice, where it can lead to therapeutic failures or adverse drug reactions. Polymorphisms in genes coding for metabolising enzymes and drug transporters can affect drug efficacy and toxicity. Pharmacogenetics aims to identify individuals predisposed to a high risk of toxicity and low response from standard doses of anti-cancer drugs. This review focuses on the clinical significance of polymorphisms in drug-metabolising enzymes (cytochrome P450 [CYP] 2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase [UGT] 1A1, glutathione S-transferase, sulfotransferase [SULT] 1A1, N-acetyltransferase [NAT], thiopurine methyltransferase [TPMT]) and drug transporters (P-glycoprotein [multidrug resistance 1], multidrug resistance protein 2 [MRP2], breast cancer resistance protein [BCRP]) in influencing efficacy and toxicity of chemotherapy.The most important example to demonstrate the influence of pharmacogenetics on anti-cancer therapy is TPMT. A decreased activity of TPMT, caused by genetic polymorphisms in the TPMT gene, causes severe toxicity with mercaptopurine. Dosage reduction is necessary for patients with heterozygous or homozygous mutation in this gene.Other polymorphisms showing the influence of pharmacogenetics in the chemotherapeutic treatment of cancer are discussed, such as UGT1A1*28. This polymorphism is associated with an increase in toxicity with irinotecan. Also, polymorphisms in the DPYD gene show a relation with fluorouracil-related toxicity; however, in most cases no clear association has been found for polymorphisms in drug-metabolising enzymes and drug transporters, and pharmacokinetics or pharmacodynamics of anti-cancer drugs. The studies discussed evaluate different regimens and tumour types and show that polymorphisms can have different, sometimes even contradictory, pharmacokinetic and pharmacodynamic effects in different tumours in response to different drugs.The clinical application of pharmacogenetics in cancer treatment will therefore require more detailed information of the different polymorphisms in drug-metabolising enzymes and drug transporters. Larger studies, in different ethnic populations, and extended with haplotype and linkage disequilibrium analysis, will be necessary for each anti-cancer drug separately.     

Genetic polymorphisms of human flavin-containing monooxygenase 3: implications for drug metabolism and clinical perspectives

Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases.     

Targeting intestinal transporters for optimizing oral drug absorption

While the oral exposure continues to be the major focus, the chemical space of recent drug discovery is apparently trending towards more hydrophilic libraries, due to toxicity and drug-interactions issues usually reported with lipophilic drugs. This trend may bring in challenges in optimizing the membrane permeability and thus the oral absorption of new chemical entities. It is now apparent that the influx transporters such as peptide transporter 1 (PepT1), organic-anion transporting polypeptides (OATPs), monocarboxylate transporters (MCT1) facilitate, while efflux pumps (e.g. P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) limit oral absorption of drugs. This review will focus on intestinal transporters that may be targeted to achieve optimal clinical oral plasma exposure for hydrophilic and polar drugs. The structure, mechanism, structure-activity relationships and the clinical examples on the functional role of these transporters in the drug absorption was discussed. Physicochemical properties, lipophilicity and hydrogen-bonding ability, show good correlation with transport activity for efflux pumps. Although several attempts were made to describe the structural requirements based on pharmacophore modeling, lack of crystal structure of transporters impeded identification of definite properties for transporter affinity and favorable transport activity. Furthermore, very few substrate drug datasets are currently available for the influx transporters to derive any clear relationships. Unfortunately, gaps also exist in the translation of in vitro end points to the clinical relevance of the transporter(s) involved. However, it may be qualitatively generalized that targeting intestinal transporters are relevant for drugs with high solubility and/or low passive permeability i.e. a class of compounds identified as Class III and Class IV according to the Biopharmaceutic Classification System (BCS) and the Biopharmaceutic Drug Disposition Classification System (BDDCS). A careful considerations to oral dose based on the transporter clearance (V(max)/K(m)) capacity is needed in targeting a particular transporter. For example, low affinity and high capacity uptake transporters such as PEPT1 and MCT1 may be targeted for high oral dose drugs.     

我院口服降糖药物应用分析

目的对我院口服降糖药物的应用情况进行分析评估,为临床合理用药提供参考依据.方法对我院2007年度口服降糖药的用药频度、销售金额等进行统计、分析.结果磺酰脲类药物使用频率较高,占30.90%,其次是葡萄糖苷酶抑制剂,占29.32%.结论磺酰脲类降糖药物仍是Ⅱ型糖尿病的首选药物,其降糖效果显著、安全、价格适中,易为患者接受.     

我院2006-2009年口服抗糖尿病药物应用分析

目的了解该院口服抗糖尿病药物的应用现状和发展趋势。方法对该院口服抗糖尿病药物的主要品种、用药金额、用药频度、限定日费用等进行统计和分析。结果该院口服抗糖尿病药物2009年用药金额是2006年的1.21倍,呈上升趋势。磺酰脲类药物在几年中的构成比居首位。最常用的口服降糖药是二甲双胍、格列吡嗪和瑞格列奈。瑞格列奈、阿卡波糖、吡格列酮用药频度上升较大。结论口服抗糖尿病药物在2型糖尿病治疗中应用合理,需求量逐年增加。安全、有效、依从性好、价格适中是糖尿病治疗药物发展的必然趋势。     

Genetic polymorphisms of SLCO1B1 for drug pharmacokinetics and its clinical implications

Various drug transporters are selectively expressed in single or multiple tissues, such as the intestine, liver and kidney, where these transporters play various roles in drug absorption, distribution and excretion. Genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy and toxicity. Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). Some single nucleotide polymorphisms or haplotypes of the SLCO1B1 gene have been identified and demonstrated to have functional significance for transporter activity. For examples, the SLCO1B1*15 haplotype (or 521T>C genotype) results in decreased uptake activity of SN-38 from systemic circulation, leading to increased plasma concentration of SN-38 and an enhanced risk of neutropenia. This review focuses on the impact of genetic polymorphisms of the SLCO1B1 gene on transport activity, and implications for the clinical efficacy and toxicity of clinically useful drugs.     

上海市社区口服降糖药的可负担性评价

目的：评价上海市社区口服降糖药的可负担性。方法：采用世界卫生组织/国际健康行动组织（WHO/HAI）的标准化调查方法进行价格调查,采用WHO/HAI标准化可负担性评价方法、贫化法和灾化法3种方法对口服降糖药物的可负担性进行评价。结果：在社区医疗机构,大部分口服降糖药的可负担性较差,仿制药的负担性均优于原研药;城镇居民与农村居民相比负担较重,不同种类的口服降糖药在上海市居民中致贫作用差异较大,约20倍;5种口服降糖药会导致上海市10多万居民陷入灾难性支出。医保政策可以大幅降低口服降糖药带来的负担,缩小高价药品与低价药品之间的致贫差距。结论：上海市口服降糖药的可负担性较差,建议相关部门做好原研药品价格调整与监管,鼓励和引导仿制药品的研发,推进异地医保对接,以提高糖尿病患者的可负担性。     

Pioglitazone: update on an oral antidiabetic drug with antiatherosclerotic effects

Pioglitazone, a member of the PPAR-gamma agonist drug family, has been demonstrated to improve both metabolic and vascular insulin resistance when applied to patients with Type 2 diabetes mellitus. The drug is well tolerated with fluid retention and weight gain being the most frequently described side effects. The observed effects (e.g., improvements in glucose and lipid metabolism, improvements of endothelial function and microcirculation, reduction of surrogate markers of atherosclerosis and inflammation and an improvement in hypertension) have made pioglitazone one of the frequently prescribed antidiabetic drugs in the US and Europe. Several trials have shown its potency to reduce carotid intima-media thickness, and outcome studies with pioglitazone have shown its potential to delay the progression of Type 2 diabetes and atherosclerosis and even reduce cardiovascular mortality. The purpose of this review is to provide an overview about recently published clinical results with pioglitazone. They underline the value of this drug when used alone or in combination with other antidiabetic drugs for a successful management of Type 2 diabetes mellitus.     

Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug–drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.     

Interactions of pesticides with membrane drug transporters: implications for toxicokinetics and toxicity

Introduction: Drug transporters are now recognized as major actors of pharmacokinetics. They are also likely implicated in toxicokinetics and toxicology of environmental pollutants, notably pesticides, to which humans are widely exposed and which are known to exert various deleterious effects toward health. Interactions of pesticides with drug transporters are therefore important to consider.

Areas covered: This review provides an overview of the interactions of pesticides with membrane drug transporters, i.e. inhibition of their activity, regulation of their expression, and handling of pesticides. Consequences for toxicokinetics and toxicity of pesticides are additionally summarized and discussed.

Expert opinion: Some pesticides belonging to several chemical classes, such as organochlorine, pyrethroid, and organophosphorus pesticides, have been demonstrated to interact with various uptake and efflux drug transporters, including the efflux pump P-glycoprotein (P-gp) and the uptake organic cation transporters (OCTs). This provides proof of the concept that pesticide–transporter relationships merit attention. More extensive and systematic characterization of pesticide–transporter relationships, possibly through the use of in silico methods, is however likely required. In addition, consideration of transporter polymorphisms, pesticide mixture effects, and realistic pesticide concentrations reached in humans may help better define the in vivo relevance of pesticide–transporter interactions in terms of toxicokinetics and toxicity.     

药物基因多态性与口服降糖药物效应多样性关系的研究进展

2型糖尿病是一种高发的基础疾病,以药物治疗为主,饮食、运动为辅。在降糖药物的治疗中,由于个体差异,导致疗效及不良反应多样性。药物基因组学是导致这一差异的重要原因,其研究目的是明确遗传因素对药物效应的影响,是近年来一大研究热点。并为临床合理用药提供理论依据,这也势必将成为未来医药学的一个重要发展方向。