苯肽胺酸在大鼠体内的毒物动力学及组织分布

采用单次灌胃染毒法,通过高效液相色谱仪测定,研究了苯肽胺酸(N-phenylphthalamicacid,PPA)在大鼠体内的吸收、组织分布及排泄情况,以及其血药浓度经时变化过程和毒物动力学参数。结果表明:苯肽胺酸经消化道吸收速率较快,其半吸收期t1/2ka仅为(0.15±0.11) h,血药浓度的达峰时间(tmax)为(0.68±0.37) h,血药峰浓度(Cmax)值为(141.48±27.87) mg/L;苯肽胺酸在大鼠体内分布快且分布范围广,半分布期(t1/2α)为(0.22±0.18) h,表观分布容积(Vz/F)为(17.54±7.71) L/kg;苯肽胺酸从大鼠体内消除较快,其清除率(CLz/F)为(1.32±0.51) (L/h)/kg,在体内平均驻留时间(MRT(0-∞))为(25.69±2.93) h,消除半减期(t1/2z)为(7.77±1.44) h,约35 h后95%以上的苯肽胺酸可从大鼠体内消除。研究发现:苯肽胺酸的浓度-时间曲线呈现双峰现象,提示其在大鼠体内可能存在肠-肝循环。从大鼠灌胃染毒后至24 h内,被测各组织、脏器中均可检出苯肽胺酸,其浓度由高到低依次为:肾脏> 肺> 肝脏> 心脏> 脾脏> 肌肉> 睾丸> 脂肪> 大脑,肾脏中药物含量达192.7 μg/g,同时仅肾脏组织的靶向分布系数(te)值大于1(4.77),提示苯肽胺酸在大鼠体内分布时对肾脏具有相对较高的选择性。排泄物研究结果显示,苯肽胺酸随粪便排出的总量仅占给药量的1.45%,而尿液中未检出苯肽胺酸。     

2-溴-4-氟乙酰苯胺在雄性大鼠体内的毒物动力学行为

2-溴-4-氟乙酰苯胺 (2-bromo-4-fluoroacetanilide,BFAA) 是多种N-苯基酰胺类化合物合成的中间体,也是合成农药时的主要杂质。本研究建立了一种快速、特异的超高效液相色谱-串联质谱 (UPLC-MS/MS) 检测方法,用于测定大鼠血浆、组织、尿液和粪便中的2-溴-4-氟乙酰苯胺含量,以获得该化合物的吸收、分布及排泄等动力学信息。大鼠经不同剂量的2-溴-4-氟乙酰苯胺灌胃和静脉注射染毒处理后,取血浆及不同组织样品,经蛋白质沉淀法处理后采用所建立的UPLC-MS/MS方法测定,分别计算2-溴-4-氟乙酰苯胺的血药浓度达峰时间 (t_max)、血药峰浓度 (C_max) 和药-时曲线下面积 (AUC_(0-t)) 等血浆毒物动力学参数和绝对生物利用度 (F),考察了药物在组织中的分布和经尿液、粪便排泄的特征。血浆毒物动力学研究表明:大鼠灌胃后药物可被迅速吸收,给予200、500和1000 mg/kg的2-溴-4-氟乙酰苯胺后,其 t_max 值分别为 (0.2 ± 0.1)、(0.4 ± 0.2) 和 (0.5 ± 0.3) h;C_max 和 AUC_(0-t) 值分别为 (32.4±5.0)、(45.2±1.8)、(38.5±3.2) mg/L和(121.2±40.9)、(393.3±51.1)、(321.9±38.0) (mg/L)·h;F 值在 34.1%~83.3% 之间。其血浆药-时曲线具有双峰现象,推测可能存在重吸收或肠-肝循环。组织分布研究表明:2-溴-4-氟乙酰苯胺在组织中分布较广,且主要分布在小肠、胃和脂肪中;此外在脑和睾丸中发现了少量该化合物,表明其可以穿过血脑屏障和睾丸屏障;24 h后大部分组织中已检测不到该化合物,表明其总体不存在蓄积现象;靶向分配系数均小于1.0,提示2-溴-4-氟乙酰苯胺对组织无明显的选择性。排泄研究结果表明:2-溴-4-氟乙酰苯胺经尿液和粪便的排泄主要发生在0~48 h内,分别占总排泄量的93%和92%;经尿液和粪便的总排泄量为 (80.6 ± 29.8) μg,仅占总染毒量的 (0.03 ± 0.01) %,提示经尿液和粪便的排泄并非2-溴-4-氟乙酰苯胺母体化合物主要的体内消除途径。     

QSAR and 3D-QSAR analysis of structurally diverse ALS inhibitors: sulfonylureas and triazolopyrimidine-2-sulfonamides

For the purpose of better understanding the molecular mechanism of action of sulfonylurea and sulfonamide herbicides, the quantitative relationship between their structure and herbicidal activity against rape, Brassica campestris L, was analysed using physicochemical parameters and regression analysis and comparative molecular field analysis (CoMFA). The results showed that the structure–activity relationships of the two sets of compounds were identical, which suggested that the two different sets of compounds affect a common region of the receptor site. The CoMFA results were consistent with those derived from traditional QSAR analysis. Combining the traditional QSAR analysis with the CoMFA results, we can conclude that the variations in the herbicidal activity of the two sets of ALS inhibitors were governed dominantly by the three-dimensional steric and electrostatic field parameters of molecules participating in the interaction with the receptor site and there is apparently an optimum electronic property (Σσ or pKa) for the molecules to fit the receptor. © 1999 Society of Chemical Industry     

The importance of trifluoromethyl pyridines in crop protection

The pyridine ring, substituted by a trifluoromethyl substituent has been successfully incorporated into molecules with useful biological properties. During the period 1990 to September 2017, 14 crop protection products bearing a trifluoromethyl pyridine have been commercialized or proposed for an ISO common name, covering fungicides, herbicides, insecticides and nematicides. Chemical processes have been developed to provide trifluoromethyl pyridine intermediates, from non‐fluorinated pyridine starting materials, at scale and with affordable costs of goods. These attractive starting materials were readily adopted by research chemists, and elaborated through simple chemical modifications into new active ingredients. In a second approach, substituted trifluoromethyl pyridine rings have been constructed from acyclic, trifluoromethyl starting materials, which again has served to identify new active ingredients. Molecular matched pair analysis reveals subtle, yet important differences in physicochemical and agronomic properties of trifluoromethyl pyridines compared with the phenyl analogues. This review focuses on the past 27 years, seeking to identify reasons behind the success of such research programmes, and inspire the search for new crop protection chemicals containing the trifluoromethyl pyridine ring. © 2017 Society of Chemical Industry     

‘Pharmacokinetic’ and ‘pharmacodynamic’ design of lipophilic drugs based on a structural model for drug interactions with biological membranes

The pharmacokinetic profile a drug exhibits will ultimately depend on how the drug molecule interacts with the different cell membranes it encounters en route to its target site of action. Even if the drug molecule targets a soluble protein as its final site of action, there is a reasonable probability that it will interact with some cell membrane on its pathway to this biological target. In some cases, the final protein, lipid or sugar moiety target could be an integral part of the cell membrane architecture whereby the drug's interaction with the cell membrane could influence its pharmacodynamic profile as well, especially if the final site of action is an integral membrane-bound receptor protein. In either case, drug transport across a cell membrane or within the cell membrane lipid bilayer compartment can dictate partial or dominant control of the drug's bioavailability. A molecular understanding of the equilibrium membrane partition coefficient, the rates of drug partitioning into and out of a cell membrane and the equilibrium location of the drug within the cell membrane can provide critical chemical design strategies for altering overall drug bioavailability and optimal pharmacokinetics.     

Physicochemical structure-activity relationship of DDT congeners and the inhibition of mitochondrial ATPase

Structure-activity relationships were used to determine the physicochemical properties of DDT that are important in the inhibition of oligomycin-sensitive mitochondrial ATPase activity of red coxal muscle tissue homogenates of the American cockroach (Periplaneta americana). The results were compared with structure-activity relationships derived from toxicity values for houseflies (Musca domestica) and blowflies (Phormia regina), reported in the literature. Toxicity was found to be promoted by hydrophobicity and electron donation. Toxicity was concluded to be a route of action process involving the distribution and partitioning of insecticide to active sites and apart from them. Enzyme inhibition, in contrast to factors contributing to toxicity, was determined to be a mode of action process predicted by the lipophilic parameter (π) and the steric constant, van der Waals radii (VWR), and represents action upon a sterically sensitive, hydrophobic site in the membrane sector of mitochondrial ATPase.     

高效液相色谱-串联质谱法研究哌虫啶在大鼠体内的吸收、分布及排泄

为阐明杀虫剂哌虫啶在SD大鼠体内的代谢动力学过程,以期为进一步的毒理学研究提供依据,采用所建立的高效液相色谱-串联质谱(HPLC-MS/MS)分析方法,测定了单次灌胃给药后大鼠血浆、组织(心、肝、脾、肺、肾、脑、骨骼肌、脂肪)、粪便和尿液样品中哌虫啶的含量,对该药在大鼠体内的吸收、分布和排泄进行了研究。结果表明:哌虫啶750 mg/kg单次经口灌胃给药,雌性大鼠血药浓度-时间曲线下面积(AUC)高于雄性大鼠,且达到峰值时间(T_(max))明显长于雄性大鼠,具有统计学差异,提示在此剂量下,哌虫啶在代谢及毒性效应上可能存在性别差异;在100~750 mg/kg受试剂量范围内,哌虫啶的平均半衰期为4~8 h,表观分布容积为10~30 L/kg,给药剂量与血药浓度-时间曲线下总面积(AUC_(0-inf))呈线性相关性(雄:r=0.996 4,雌:r=0.991 3)。组织分布试验表明,哌虫啶经口给药后,能迅速、广泛地分布到各组织中,并可有效地透过血脑屏障,其中肝、肾中哌虫啶的含量最高,提示其可能主要经肝、肾代谢。排泄试验显示,经尿液及粪便排出的原形哌虫啶含量极低,提示哌虫啶在大鼠体内可能发生广泛的代谢后再排出体外。     

Herbicide safety relative to common targets in plants and mammals

Most modern herbicides have low mammalian toxicity. One of the reasons for this safety is that the target site for the herbicides is not often present in mammals. There are approximately 20 mechanisms of action that have been elucidated for herbicides. Of these, some do share common target sites with mammals. The mechanisms include formation of free radicals, protoporphyrinogen oxidase (PROTOX), glutamine synthetase (GS) and 4-hydroxyphenylpyruvate dioxygenase (HPPD). PROTOX, HPPD and GS inhibitors have been shown to inhibit these enzymes in both plants and mammals and there are measurable effects in mammalian systems. However, the consequences of inhibiting a common target site in plants can be quite different than in animals. What may be a lethal event in plants, eg inhibition of HPPD, can have a beneficial effect in mammals, eg treatment for tyrosinemia type I. These chemicals also have low mammalian toxicity due to rapid metabolism and/or excretion of the herbicide from mammalian systems.     

The application of granular pesticides

Three basic processes are involved in the application of granular pesticides—metering, transporting and distributing. Metering may be simply dependent upon flow through an orifice under gravity but preferably force-feed mechanisms, usually driven in relation to forward speed are used. Transport may be effected merely under gravity, but pneumatics is also an accepted method particularly for large swath widths. Kinetic energy is also an agency in transporting granules as in “throwing” type distributors and this also achieves the distribution element. With gravity and pneumatic transport the final distribution is usually by spreaders or by nozzles at each outlet. Assessment of performance is rendered difficult by the very small size of the particles to be detected and the very low rates of application usually employed. Data are required on the appropriate sampling areas which should be used in assessing uniformity of distribution and the significance of the variations measured. Cooperation between all the disciplines of workers in the field is necessary for further development of the technique and in particular in the field of formulation a valuable contribution would be in the reduction in the diversity of physical properties of all the granular materials in use or projected.     

A review of the correlation between physicochemical properties and bioaccumulation

Bioaccumulation, describing selective transfer of a chemical from compartments into organisms, and biomagnification, describing such a transfer from organisms of lower trophic levels to organisms of higher trophic levels in food chains, are environmental partitioning processes that have received special attention because of their potential toxicological significance. Both phenomena are determined by certain physicochemical properties of a given chemical and by the environmental systems concerned, as well as by the chemical and metabolic degradability of the chemical in these systems. A number of correlations between the physicochemical properties and the bioaccumulation potential of a chemical have been established of which the relationship between the n-octanol/water partition coefficient and the bioaccumulation factor is the most relevant. The predictive value and the limitations of these correlations have been discussed. Included in this discussion is the question as to what extent degradability allows the predicted bioaccumulation potential of a chemical to come into effect in different species. A pragmatic use of the established relationships and bioaccumulation test results in a stepwise approach is recommended to provide a realistic estimate of the bioaccumulation potential of a chemical for the assessment of its environmental risk.     

Vectorizing agrochemicals: enhancing bioavailability via carrier‐mediated transport

Systemicity of agrochemicals is an advantageous property for controlling phloem sucking insects, as well as pathogens and pests not accessible to contact products. After the penetration of the cuticle, the plasma membrane constitutes the main barrier to the entry of an agrochemical into the sap flow. The current strategy for developing systemic agrochemicals is to optimize the physicochemical properties of the molecules so that they can cross the plasma membrane by simple diffusion or ion trapping mechanisms. The main problem with current systemic compounds is that they move everywhere within the plant, and this non‐controlled mobility results in the contamination of the plant parts consumed by vertebrates and pollinators. To achieve the site‐targeted distribution of agrochemicals, a carrier‐mediated propesticide strategy is proposed in this review. After conjugating a non‐systemic agrochemical with a nutrient (α‐amino acids or sugars), the resulting conjugate may be actively transported across the plasma membrane by nutrient‐specific carriers. By applying this strategy, non‐systemic active ingredients are expected to be delivered into the target organs of young plants, thus avoiding or minimizing subsequent undesirable redistribution. The development of this innovative strategy presents many challenges, but opens up a wide range of exciting possibilities. © 2018 Society of Chemical Industry     

Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical

The pioneering work of Gerry Brooks on cyclodiene insecticides led to the discovery of a class of enzymes known as epoxide hydrolases. The results from four decades of work confirm Brooks' first observations that the microsomal epoxide hydrolase is important in foreign compound metabolism. Brooks and associates went on to be the first to carry out a systematic study of the inhibition of this enzyme. A second role for this enzyme family was in the degradation of insect juvenile hormone (JH). JH epoxide hydrolases have now been cloned and expressed from several species, and there is interest in developing inhibitors for them. Interestingly, the distantly related mammalian soluble epoxide hydrolase has emerged as a promising pharmacological target for treating hypertension, inflammatory disease and pain. Tight-binding transition-state inhibitors were developed with good ADME (absorption, distribution, metabolism and excretion). These compounds stabilize endogenous epoxides of fatty acids, including arachidonic acid, which have profound therapeutic effects. Now EHs from microorganisms and plants are used in green chemistry. From his seminal work, Dr Brooks opened the field of epoxide hydrolase research in many directions including xenobiotic metabolism, insect physiology and human health, as well as asymmetric organic synthesis.     

Long-Term Ecological Monitoring

The intent of long-term ecological monitoring is to document changes in important properties of biological communities. At the least, a long-term monitoring system should be designed to detect long-term trends in three key attributes: soil and site stability, hydrologic function, and the biotic integrity of the system. There are four basic guidelines for developing integrated soil-vegetation monitoring systems for rangelands. These are: (1) identifying a suite of indicators which are consistently correlated with the functional status of one or more critical ecosystem processes and/or properties; (2) selecting base indicators on site specific objectives and resource concerns, and inherent soil and site characteristics; (3) using spatial variability in developing and interpreting indicators to make them more representative of ecological processes; and (4) interpreting indicators in the context of an understanding of dynamic, nonlinear ecological processes. To the extent possible, indicators should reflect early changes in ecological processes and indicate that a more significant change is likely to occur. In addition to these guidelines, measurements included in long-term monitoring systems should be rapidly applied, simple to understand, inexpensive to use, and quantitatively repeatable.     

The role of translocation in selectivity of herbicides with reference to MCPA and MCPB

The distribution of 2.5 mM-[¹⁴C]MCPA

1 MCPA = (2-methyl-4-chlorophenoxyacetic acid).

and [¹⁴C]MCPB

2 MCPB = (4-(2-methyI-4-chlorophenoxy) butyric acid).

formulated as sodium salts with 0.05% tergitol, have been investigated when applied to an isolated leaf/agar block sink system of Vicia faba L. Results are presented which show the effect on absorption and translocation of method of application, age of treatment leaf, treatment period, pretreatment with 5 μM ATP and removal of cuticle wax by chloroform wipe treatment. Significant negative correlations between cuticle wax fixation/translocation and leaf tissue content/translocation were recorded for both compounds, particularly MCPB, suggesting the involvement of both physicochemical and metabolic components in the process of absorption and translocation. The nature of the mechanisms involved was further investigated using isolated cuticle/epidermal systems and tightly-coupled mitochondria isolated from roots of V. faba L. The results suggest that non-movement of MCPB in this species is largely due to its enhanced retention within the cuticle and to the fact that it is a more effective uncoupler of oxidative phosphorylation than MCPA. The importance of these findings in terms of the relative efficiency of translocation of MCPA and MCPB when applied in vivo is discussed.     

新疆杨对盐分离子吸收选择性和运输选择性的研究

本文研究两组同龄新疆杨(Populus alba L.var.pyramidalis)(一组土壤含盐量较低,树木长势良好,另一组土壤盐分高,树木长势差)对盐分离子的吸收选择性系数和从根至边材,从边材至叶的运输选择性系数,结合盐分离子在树体各部位的分布状况,探讨新疆杨对长期盐胁迫的生理反应。主要结论为:盐胁迫下新疆杨通过选择性吸收K+,抑制过多Na+进入根系,新疆杨对盐分离子的运输选择性主要体现在根向边材的运输中,新疆杨根系对Na+具有较强的截留作用,对Cl-和SO42-也有一定截留作用。     

Interaction of pesticides with p-glycoprotein and other ABC proteins: A survey of the possible importance to insecticide, herbicide and fungicide resistance

P-glycoproteins (p-gps) are ubiquitous membrane proteins from the ABC (ATP-binding cassette) family. They have been found in many animals, bacteria, plants and fungi and are extremely important in regulating a wide range of xenobiotics including pesticides. P-gps have been linked to xenobiotic resistance, most famously in resistance to cancer drug treatments. Their wide substrate range has led to what is known as “multidrug resistance”, where resistance developed to one type of xenobiotic gives resistance to a different classes of xenobiotic. P-gps are a major contributor to drug resistance in mammalian tumours and infections of protozoan parasites such as Plasmodium and Leishmania. There is a growing body of literature suggesting that p-gps, and other ABC proteins, are important in regulating pesticide toxicity and represent potential control failure through the development of pesticide resistance, in both agricultural and medical pests. At the same time, aspects of their biochemistry offer new hope in pest control, in particular in furthering our understanding of toxicity and offering insights into how we can improve control without recourse to new chemical discovery.     

Selecting the right compounds for screening: does Lipinski's Rule of 5 for pharmaceuticals apply to agrochemicals?

Large numbers of compounds are now available through combinatorial chemistry and from compound vendors to screen for lead‐level agrochemical activity. The likelihood that compounds with whole‐organism activity will be discovered can be increased if compounds with physicochemical parameters consistent with transport to the target site are selected for screening. Certain ranges of simple parameters (molecular mass, log P, hydrogen‐bond donors and acceptors, rotatable bonds) have been correlated with oral bioavailability of drugs. The distribution of these parameters for commercial insecticides and post‐emergence herbicides was examined and ranges consistent with whole‐organism activity are proposed for the two classes of agrochemical. The most significant difference identified between drugs and these two classes of agrochemicals was the lower numbers of hydrogen‐bond donors allowed in the latter cases. The frequency with which certain functional groups occur in drugs and agrochemicals was also compared. © 2001 Society of Chemical Industry     

Knockdown by pyrethroids: Its role in the intoxication process

Using techniques for treating the insects unanaesthetised, knockdown of aduit Musca domestica by pyrethrin I applied topically to or injected into the thorax was assessed by measuring the ED₅₀s on 13 occasions 1 min-48 h after treatment. From 1 min to approximately 1 h after treatment, ED₅₀s for topical application decreased quickly with increasing time. During this “knockdown phase” ED₅₀ values were probably determined mainly by rate of penetration of the insecticide into the insect, but the rate of elimination of the insecticide probably determined the increasing ED₅₀ values during the “recovery phase” which followed. ED₅₀s for injected pyrethrin I were initially much smaller than after topical application but increased continuously until 24 h after treatment. From 100 min onwards ED₅₀s by topical application and injection were similar. These results indicate (1) that the site affected during knockdown is within the insect rather than superficial, and (2) that detoxication and excretion processes determine the ultimate toxicity of the insecticide apparently independently of the method of treatment. Additional tests with a strain of flies having the penetration delaying factor and with the cockroach Periplaneta americana L. supported these conclusions. Speed of knockdown after topical treatment was also affected by the site of application and the solvent in which pyrethrin I was applied. Bioresmethrin was about as effective as pyrethrin I in knocking down flies when applied topically or when injected, but because the ED₅₀ increased very little during the recovery phase it was ultimately much more toxic.     

Foliar uptake of pesticides—Present status and future challenge

Uptake of pesticides into plant foliage varies with plants and chemicals, and can be greatly influenced by adjuvants and environmental conditions. It is known that the penetration of pesticides into plant leaves is related to the physicochemical properties of the active ingredients, especially molecular size and lipophilicity. However, the uptake rate of a compound cannot be predicted by either of them or even combination of them. For a specific chemical, uptake varies greatly with plant species and there is no simple method at the moment to quickly evaluate the leaf surface permeability of a plant. Various adjuvants are being used to increase the penetration of pesticides into target plant foliage, but their effects vary with chemicals and plant species. The mechanisms of action of adjuvants in enhancing pesticide uptake remain unclear despite the effort made during the last three decades. Modern analytical and microscopic techniques provide powerful tools to deepen our understanding in this field. However, a more multidisciplinary approach is urgently needed to elucidate the transcuticular diffusion behaviour of pesticides and the mode of action of adjuvants. A better understanding of the foliar uptake process should lead to a more rational use of pesticides and minimize their negative impact on the environment.