TEPP Research Articles

Phosphorus fluoride exchange: Multidimensional catalytic click chemistry from phosphorus connective hubs

Phosphorus Fluoride Exchange (PFEx) represents a cutting-edge advancement in catalytic click-reaction technology. Drawing inspiration from Nature's phosphate connectors, PFEx facilitates the reliable coupling of P(V)-F loaded hubs with aryl alcohols, alkyl alcohols, and amines to produce stable, multidimensional P(V)-O and P(V)-N linked products. The rate of P-F exchange is significantly enhanced by Lewis amine base catalysis, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). PFEx substrates containing multiple P-F bonds are capable of selective, serial exchange reactions via judicious catalyst selection. In fewer than four synthetic steps, controlled projections can be deliberately incorporated along three of the four tetrahedral axes departing from the P(V) central hub, thus taking full advantage of the potential for generating three-dimensional diversity. Furthermore, late-stage functionalization of drugs and drug fragments can be achieved with the polyvalent PFEx hub, hexafluorocyclotriphosphazene (HFP), as has been demonstrated in prior research.

Dilution or enrichment: the effects of flood on pollutants in urban rivers

BackgroundFlood events increase the risk of sediment erosion and hence the release of particle-bound pollutants besides other processes that can be observed during such events like transportation, lateral distribution and other. Macropollutants, such as acids, salts, nutrients, and natural organic matter, are usually diluted by flooding, while the effect of floods on micropollutants is still unclear. To fill this gap, Qingshui Stream, a tributary of the Jialing River in the city of Chongqing that suffered 75,000 m3·s−1 flood in August 2020 was selected in the current study to clarify effects of flood-induced pollution transportation. 14 surface water samples and 14 sediment samples were collected to analyze the occurrence of micropollutants (including 21 organochlorine pesticides (OCPs), 34 organophosphorus pesticides (OPPs) and 3 estrogenic compounds) before, during and after the flood. Finally, the environmental risks were evaluated by risk quotient (RQ).ResultsThe concentrations of total phosphorus (TP), total nitrogen (TN), chemical oxygen demand (COD) in the surface water decreased from upstream to downstream, and the amounts were diluted by flooding from 0.08 to 0.05 mg·L−1 for TP, from 0.06 to 0.02 mg·L−1 for TN and from 132 to 27 mg·L−1 for COD, respectively. The concentration of estrogenic compound was up to 90 ng·g−1, which was reduced to be lower than the limit of detection during flood. Alpha-endosulfan, delta-BHC, mirex, dichlorvos, phosdrin, thionazine, tetraethyl pyrophosphate, diazinon, methyl parathion, malathion, chlorpyrifos, famphur, and EPN were diluted by flooding, i.e., the concentration of delta-BHC reduced from 6.67 to 0.09 ng·g−1; whereas, pp'-DDD, heptachlor epoxide, o,o,o-triethylphosphorothioate, dimethoate, rabon and fensulfothion were enriched after the flood. The environmental risk was observed to be mainly arise from the presence of OPPs, which increased after flooding. The RQ values of OPPs and OCPs increased after the flood, and the potential environmental risk of OPPs accounted for the majority portion of the risk.ConclusionsThe concentrations of macropollutants in surface water and sediments, and 14 micropollutants in sediments were diluted, while pesticides such as pp′-DDD, heptachlor epoxide, o,o,o-triethylphosphorothioate, dimethoate, rabon and fensulfothion were enriched after the flood. These results suggested management on urban river should focus on potential risk of OPPs. The current study therefore could provide scientific evidence and regulatory reference for urban river ecosystem protection.

Efficiency of the removal of tetraethyl pyrophosphate (TEPP) pesticide in water: use of cork granules as a natural adsorbent on acetylcholinesterase activity in neuronal PC12 cell

Tetraethyl pyrophosphate (TEPP) is an organophosphate pesticide that irreversibly inhibits acetylcholinesterase (AChE). Cork powder or granules have been recommended as a sustainable sorbent to remove pesticides from water. In the present study, we evaluated the effectiveness of removing TEPP from water using wine corks to obtain cork granules as natural adsorbent, analyzing the TEPP effects on AChE activity in commercial enzyme from Electrophorus electricus and secreted by neuronal PC12 cells. TEPP inhibited AChE activity in a concentration-dependent manner. For the first time, we showed that different concentrations of TEPP diluted in water after adsorption experiments using cork granules decreased TEPP's inhibitory effects on AChE activity in commercial enzyme and neuronal PC12 cell culture medium. Our results suggest that the optimum removal of TEPP from water by corks was 91.4 ± 4.0%. Overall, the findings support the hypothesis that cork granules can be used to remediate pesticide-contaminated environments, such as those contaminated by organophosphate pesticides, and demonstrate a new application of a biochemical assay on AChE activity using a commercial enzyme or secreted by neuronal PC12 cells in culture as a possible methodologic strategy for evaluating the success of TEPP removal from water.

Spectroscopic investigation on molecular aspects and structural and functional effects of tetraethyl pyrophosphate organophosphorus insecticide interaction with adult human hemoglobin

Organophosphates are extremely toxic compounds that use extensively in agriculture and household as insecticides. However, their binding mechanism to bio-macromolecules especially blood proteins is not clearly understood. In this research, various spectroscopic techniques utilized to analyze the effect of Tetraethyl Pyrophosphate (TEPP), as an organophosphorus insecticide, on the structure, function, stability, and aggregation of adult human hemoglobin and also hemolysis potential of the TEPP on red blood cells (RBCs) examined. Molecular docking was used for TEPP binding to human Hemoglobin (Hb), too. The results demonstrated that the TEPP insecticide has the potential for lysing RBCs. UV-Vis experiment indicated that globin part and heme group influenced by TEPP. Oxygen affinity measurements revealed the formation of deoxy-Hb and met-Hb, also decreased in oxygen affinity of Hb upon interaction with TEPP that is due to heme destruction. Fluorescence spectroscopy confirmed the production of heme degradation species after interaction of Hb with TEPP, which is inconsistent with oxygen affinity measurements. Thermal and aggregation studies indicated that TEPP induced aggregation of Hb in a concentration manner and Tm of protein reduced to lower temperatures. Docking's study also showed that TEPP interacts with Hb through hydrophobic interactions, which confirms UV-Vis results. ATR-FTIR study also revealed that TEPP can induce changes in the alpha helix element of Hb’s secondary structure. Totally, Experimental and theoretical results indicate that tetraethyl pyrophosphate has unfavorable effects on hemoglobin structure and function. Communicated by Ramaswamy H. Sarma

TEPP in 2021: Welcoming opportunities and rising to challenges.

The past year has held many challenges that have impacted health service psychology education and training, including the COVID-19 pandemic, the U S 's racial reckoning, and the impact of these events on virtually every aspect of life, work, and training As Training and Education in Professional Psychology (TEPP) moves into 2021, its articles illustrate the training community's ability to advance the science and practice of education and training, both in spite of and because of challenges In addition to outstanding articles on topics of interest to the training community, including articles that address innovations and diversity, a new recurring special section will feature articles addressing education and training in the context of COVID-19 Together, these articles demonstrate the training community's commitment to continually strengthening health service psychology education and training (PsycInfo Database Record (c) 2021 APA, all rights reserved) Impact Statement Public Significance Statement-TEPP's 2021 articles demonstrate the training community's strong commitment to rising to challenges and using them as opportunities to strengthen education and training in health service psychology In addition to articles on the science and practice of training, training innovations, and inclusion, diversity, and equity, TEPP will publish articles on how the COVID-19 pandemic impacted training (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Molecular docking analyses of CYP450 monooxygenases of Tribolium castaneum (Herbst) reveal synergism of quercetin with paraoxon and tetraethyl pyrophosphate: in vivo and in silico studies.

Pest management in stored grain industry is a global issue due to the development of insecticide resistance in stored grain insect pests. Excessive use of insecticides at higher doses poses a serious threat of food contamination and residual toxicity for grain consumers. Since the development of new pesticide incurs heavy costs, identifying an effective synergist can provide a ready and economical tool for controlling resistant pest populations. Therefore, the synergistic property of quercetin with paraoxon and tetraethyl pyrophosphate has been evaluated against the larvae and adults of Tribolium castaneum (Herbst). Comparative molecular docking analyses were carried out to further identify the possible mechanism of synergism. It was observed that quercetin has no insecticidal when applied at the rate of 1.5 and 3.0mg/g; however, a considerable synergism was observed when applied in combination with paraoxon. The comparative molecular docking analyses of CYP450 monooxygenase (CYP15A1, CYP6BR1, CYP6BK2, CYP6BK3) family were performed with quercetin, paraoxon and tetraethyl pyrophosphate which revealed considerable molecular interactions, predicting the inhibition of CYP450 isoenzyme by all three ligands. The study concludes that quercetin may be an effective synergist for organophosphate pesticides depending upon the dose and type of the compound. In addition, in silico analyses of the structurally diversified organophosphates can effectively differentiate the organophosphates which are synergistic with quercetin.

Evaluation of an acute oral gavage method for assessment of pesticide toxicity in terrestrial amphibians.

Development of an acute oral toxicity test with a terrestrial-phase amphibian was considered necessary to remove the uncertainty within the field of agrochemical risk assessments. The bullfrog (Lithobates catesbeianus) was selected for use as it is a representative of the family Ranidae and historically this species has been used as an amphibian test model species. Prior to definitive study, oral gavage methods were developed with fenthion and tetraethyl pyrophosphate. Dimethoate and malathion were subsequently tested with both male and female juvenile bullfrogs in comprehensive acute oral median lethal dose (LD50) studies. Juvenile bullfrogs were administered a single dose of the test article via oral gavage of a single gelatin capsule of dimethoate technical (dimethoate) or neat liquid Fyfanon® Technical (synonym malathion), returned to their respective aquaria, and monitored for survival for 14 d. The primary endpoint was mortality, whereas behavioral responses, food consumption, body weight, and snout-vent length (SVL) were used to evaluate indications of sublethal toxicity (secondary endpoints). Acute oral LD50 values (95% fiducial interval) for dimethoate were 1459 (1176-1810, males) and 1528 (1275-1831, females), and for malathion they were 1829 (1480-2259, males) and 1672 (1280-2183, females) mg active substance/kg body weight, respectively. Based on the results of these studies, the methodology for the acute oral gavage administration of test items to terrestrial-phase amphibians was demonstrated as being a practical method of providing data for risk assessments. Environ Toxicol Chem 2018;37:436-450. © 2017 SETAC.

Kinetic and physicochemical properties of brain acetylcholinesterase from the peacock bass (Cichla ocellaris) and in vitro effect of pesticides and metal ions

Brain acetylcholinesterase (AChE; EC 3.1.1.7) from peacock bass (Cichla ocellaris) was characterized and the effect of organophosphorus and carbamate pesticides as well as ions and heavy metals was evaluated. The kinetic parameters Km and Vmax were determined as 0.769mM and 0.189U/mg of protein respectively. Optimal pH and temperature were found to be 8.0 and 45°C. The enzyme retained approximately half of the activity after incubation at 50°C for 30min. Total cholinesterase activity on brain of this species can be ascribed to AChE according to selective inhibitors analysis (neostigmine, eserine and BW284c5 reduced its activity whereas no effect was noticed for Iso-OMPA). Seven pesticides (five organophosphates: dichlorvos, diazinon, chlorpyrifos, temephos, tetraethyl pyrophosphate – TEPP and two carbamates: carbaryl and carbofuran) showed inhibitory effects on C. ocellaris AChE. However, the strongest effect was observed with carbofuran (IC50=0.21μM and Ki=2.57×10−3μM). The following ions (1mM) showed to inhibit its activity (decrescent order): Hg2+>As3+>Cu2+>Zn2+. EDTA2− did not affect enzyme activity. The present study provides assay conditions and data to suggest this enzyme as in vitro biomarker of organophosphorus and carbamate pesticides in routine environmental screening programs.

Comparative effect of pesticides on brain acetylcholinesterase in tropical fish

Monitoring of pesticides based on acetylcholinesterase (AChE; EC 3.1.1.7) inhibition in vitro avoids interference of detoxification defenses and bioactivation of some of those compounds in non-target tissues. Moreover, environmental temperature, age and stress are able to affect specific enzyme activities when performing in vivo studies. Few comparative studies have investigated the inter-specific differences in AChE activity in fish. Screening studies allow choosing the suitable species as source of AChE to detect pesticides in a given situation. Brain AChE from the tropical fish: pirarucu (Arapaima gigas), cobia (Rachycentron canadum) and Nile tilapia (Oreochromis niloticus) were characterized and their activities were assayed in the presence of pesticides (the organophosphates: dichlorvos, diazinon, chlorpyrifos, temephos, tetraethyl pyrophosphate— TEPP and the carbamates: carbaryl and carbofuran). Inhibition parameters (IC50 and Ki) for each species were found and compared with commercial AChE from electric eel (Electrophorus electricus). Optimal pH and temperature were found to be 8.0 and 35–45°C, respectively. A. gigas AChE retained 81% of the activity after incubation at 50°C for 30min. The electric eel enzyme was more sensitive to the compounds (mainly carbofuran, IC50 of 5nM), excepting the one from A. gigas (IC50 of 9nM) under TEPP inhibition. These results show comparable sensitivity between purified and non-purified enzymes suggesting them as biomarkers for organophosphorus and carbamate detection in routine environmental and food monitoring programs for pesticides.

Characterization of acetylcholinesterase from the brain of the Amazonian tambaqui (Colossoma macropomum) and in vitro effect of organophosphorus and carbamate pesticides

In the present study, acetylcholinesterase (AChE) from the brain of the Amazonian fish tambaqui (Colossoma macropomum) was partially characterized and its activity was assayed in the presence of five organophosphates (dichlorvos, diazinon, chlorpyrifos, and tetraethyl pyrophosphate [TEPP]) and two carbamates (carbaryl and carbofuran) insecticides. Optimal pH and temperature were 7.0 to 8.0 and 45°C, respectively. The enzyme retained approximately 70% of activity after incubation at 50°C for 30 min. The insecticide concentration capable of inhibiting half of the enzyme activity (IC50) for dichlorvos, chlorpyrifos, and TEPP were calculated as 0.04 µmol/L, 7.6 µmol/L, and 3.7 µmol/L, respectively. Diazinon and temephos did not inhibit the enzyme. The IC50 values for carbaryl and carbofuran were estimated as 33.8 µmol/L and 0.92 µmol/L, respectively. These results suggest that AChE from the juvenile C. macropomum brain could be used as an alternative biocomponent of organophosphorus and carbamate biosensors in routine pesticide screening in the environment.

Simultaneous modulation of transport and metabolism of acyclovir prodrugs across rabbit cornea: An approach involving enzyme inhibitors

The aim of this study is to identify the class of enzymes responsible for the hydrolysis of amino acid and dipeptide prodrugs of acyclovir (ACV) and to modulate transport and metabolism of amino acid and dipeptide prodrugs of acyclovir by enzyme inhibitors across rabbit cornea. l-Valine ester of acyclovir, valacyclovir (VACV) and l-glycine-valine ester of acyclovir, gly-val-acyclovir (GVACV) were used as model compounds. Hydrolysis studies of VACV and GVACV in corneal homogenate were conducted in presence of various enzyme inhibitors. IC 50 values were determined for the enzyme inhibitors. Transport studies were conducted with isolated rabbit corneas at 34 °C. Complete inhibition of VACV hydrolysis was observed in the presence of Pefabloc SC (4-(2-aminoethyl)-benzenesulfonyl-fluoride) and PCMB ( p-chloromercuribenzoic acid). Similar trend was also observed with GVACV in the presence of bestatin. IC 50 values of PCMB and bestatin for VACV and GVACV were found to be 3.81 ± 0.94 and 0.34 ± 0.08 μM respectively. Eserine, tetraethyl pyrophosphate (TEPP) and diisopropyl fluorophosphate (DFP) also produced significant inhibition of VACV hydrolysis. Transport of VACV and GVACV across cornea showed decreased metabolic rate and modulation of transport in presence of PCMB and bestain respectively. The principle enzyme classes responsible for the hydrolysis of VACV and GVACV were carboxylesterases and aminopeptidases respectively. Enzyme inhibitors modulated the transport and metabolism of prodrugs simultaneously even though their affinity towards prodrugs was distinct. In conclusion, utility of enzyme inhibitors to modulate transport and metabolism of prodrugs appears to be promising strategy for enhancing drug transport across cornea.

Quaternary salts of 4,3′ and 4,4′ bis-pyridinium monooximes. Part 2: Synthesis and biological activity

In continuation of our investigations of unsymmetrical bisquaternary monooximes, we synthesized four new series of compounds bridged by hexyl, heptyl, octyl and nonyl groups. All eight monooximes viz., dibromides of 1-(4-hydroxyiminomethylpyridinium)6-(3/4-carbamoylpyridinium)hexane, 1-(4-hydroxyiminomethylpyridinium)-7-(3/4-carbamoylpyridinium)heptane, 1-(4-hydroxyiminomethylpyridinium)-8-(3/4-carbamoylpyridinium)octane, 1-(4-hydroxyiminomethylpyridinium)-9-(3/4-carbamoylpyridinium)nonane as well as the corresponding bis-oximes were synthesized and characterized by spectral data. Their ability to reactivate tetraethylpyrophosphate (TEPP) inhibited mouse total brain cholinesterase was investigated and compared with the conventional oxime 2-pyridinealdoxime chloride (2-PAM). Mouse brain homogenate was used as the source of acetylcholinesterase. Among all the compounds, tested the compound with the hexylene bridge ( 6b) and a 3-carbamoyl group on the second pyridine ring was found to be the most active acetylcholinesterase reactivator (72%) which is greater than that of 2-PAM (56%). However, the activity was reversed; as the chain length increased from a heptylene to a nonylene bridge, they potentiated the inhibitory effect of TEPP rather than reactivation. It is interesting to note that compound 6b with a carbamoyl group at the 3rd position of the pyridine ring showed dose dependent reactivation whereas the corresponding compound 6a with the carbamoyl group present at the 4th position of the pyridine ring showed reactivation at lower concentration (30 μM) and potentiation of TEPP inhibition at higher concentrations (100 and 300 μM).

Quaternary salts of 4,3′ and 4,4′ bis-pyridinium monooximes: Synthesis and biological activity

Six unsymmetrical bis-quaternary monooximes viz. dibromides of 1-(4-hydroxyiminomethyl pyridinium)-3-(3/4-carbamoyl pyridinium)propane, 1-(4-hydroxyiminomethyl pyridinium)-4-(3/4-carbamoyl pyridinium) butane, 1-(4-hydroxyiminomethyl pyridinium)-5-(3/4-carbamoyl pyridinium)pentane were synthesized and characterized by spectral data. Their ability to reactivate tetraethyl pyrophosphate inhibited mouse total brain cholinesterase was investigated and compared with 2-pyridine aldoxime chloride (2-PAM). All the compounds were found to be more effective acetylcholinesterase reactivators when compared with the conventional oxime, 2-PAM, except the compound ( 5a) with pentylene bridge and carbamoyl group present at fourth position. The bis-pyridinium monooximes with 3-carbamoyl group were more potent reactivators than the corresponding 4-carbamoyl compounds and bis-oximes tested.

Removal of organophosphorus pesticides from water by electrogenerated Fenton's reagent

Aqueous solutions of organophosphorus pesticides were completely mineralized via in-situ generated hydroxyl radicals (HO·) by the Electro-Fenton process. Formation of Fenton's reagent (H2O2, Fe2+) was carried out by simultaneous reduction of O2 and Fe3+ on carbon cathode in acidic medium. The electrochemistry combined with Fenton's reagent provides an excellent way to continuously produce the hydroxyl radical, a powerful oxidant. We demonstrate the efficiency of the Electro-Fenton process to degrade three organophosphorus insecticides: malathion, parathion ethyl and tetra-ethyl-pyrophosphate (TEPP). Degradation kinetics and removals of chemical oxygen demand (COD) have been investigated. Here we show that the mineralization efficiency was over 80% for three organophosphorus pesticides.

Synthesis of Phosphorocyanidates via Phosphorochloridates

Dialkyl phosphorocyanidates ( 2 ) were obtained from dialkyl phosphorochloridates ( 1 ) in high yield (80-86%) at room temperature in methyl cyanide. Reaction between diethyl phosphorochloridate and potassium cyanide was greatly influenced by the solvents used. Tetraethyl pyrophosphate also was found to react with potassium cyanide to give diethyl phosphorocyanidate in methyl cyanide.

Crucial Role of TCRγ Chain Junctional Region in Prenyl Pyrophosphate Antigen Recognition by γδ T Cells

AbstractHuman γδ T cells recognize prenyl pyrophosphate Ags and their analogues in a Vγ2Vδ2 TCR-dependent manner. Few data are available regarding the TCR structural requirements for recognition of such prenyl pyrophosphate Ags by γδ T cells. Presently, we made chain pair switch, chimeric, and site mutant γδ TCRs and transfected them into TCR− mutant Jurkat T cells to examine the effects of changing the TCRγ junctional region sequences on reactivity to prenyl pyrophosphate Ags. Substitution of the TCRγ junctional region (N and J) sequences from an Ag-reactive TCR with TCRγ junctional region sequences from an Ag-nonreactive TCR abrogated reactivity to the prenyl pyrophosphate Ag isopentenyl pyrophosphate and to its synthetic analogue ethyl pyrophosphate but not to a mycobacterial supernatant containing a mixture of prenyl pyrophosphate Ags. Substitution of only the TCRγ N nucleotide region with that from this Ag-nonreactive TCR destroyed reactivity to isopentenyl pyrophosphate and to the mycobacterial supernatant. Substitution of the entire Vδ2 chain from the Ag-reactive TCR with a Vδ1 chain from an Ag-nonreactive TCR yielded a prenyl pyrophosphate Ag-nonreactive TCR. Thus, using TCR mutagenesis and TCR transfectants, we show that γδ TCR reactivity to prenyl pyrophosphate Ags is dependent upon the junctional region of the TCRγ chain and upon pairing of Vγ2 and Vδ2 TCR chains. These structural requirements of TCRγδ recognition of prenyl pyrophosphates distinguish this reactivity from that of protein superantigens and emphasize the importance of the TCRγ CDR3 loop and adjacent residues.

The Pharmacology of Physostigmine

The Pharmacology of Physostigmine

Single-cell cytokine analysis of gamma delta T cell responses to nonpeptide mycobacterial antigens.

TCR gamma delta T cells are considered important in the rapid immune response to intracellular infection. We investigated the early response of peripheral blood gamma delta T cells to the nonpeptide Ag isopentenyl pyrophosphate and to its synthetic analogue ethyl pyrophosphate. In healthy donors, an increase in the number of gamma delta T cells was detected as soon as 4 days after stimulation with the nonpeptide Ags. Single-cell analysis of cytokine production was performed by intracellular staining of IFN-gamma and IL-4. gamma delta T cells were found to rapidly expand and produce IFN-gamma in response to nonpeptide Ags. Furthermore, IL-12 augmented the IFN-gamma response. In contrast, gamma delta T cells from the majority of HIV+ donors did not expand or express IFN-gamma in response to nonpeptide Ags, even in the presence of IL-12. These findings indicate a role for nonpeptide-reactive gamma delta T cells in effective cell-mediated immunity for intracellular pathogens.

A Prodrug Approach to Increasing the Oral Potency of a Phenolic Drug. 1. Synthesis, Characterization, and Stability of an O-(lmidomethyl) Derivative of 17β-estradiol

AnO-(saccharinylmethyl) prodrug was synthesized to improve the poor oral potency of the phenolic drug 17β-estradiol. ThisO-(imidomethyl) type of prodrug was designed to undergo chemical hydrolysis and to be a poor substrate for enzymatic hydrolysis. At 37 °C, it was found to exhibit half-lives of about 13 min in 50% methanol:pH 7.0 (v/v) phosphate buffer, about 3 min in rat plasma, about 15 min in human plasma, and about 50 min in 20% rat liver homogenate. Introduction of the enzyme poison tetraethyl pyrophosphate or the protein denaturant sodium fluoride into rat plasma had no significant effect on the half-life. Thus, the observed increased rate of hydrolysis in biological media is not due to enzymatic catalysis but to a nonspecific solventlike effect. The fact that the rate of hydrolysis in the methanol:buffer exhibited a first-order dependence on the hydroxide ion concentration and that the rate of hydrolysis increased with increasing methanol concentrations up to 70% supported an SN2 mechanism of hydrolysis for the prodrug. These results suggest that anO-(imidomethyl) type prodrug is insensitive to enzymatic catalysis of hydrolysis yet may hydrolyze quickly enough to release 17β-estradiol faster than 17β-estradiol is conjugated and excreted.

Kinetics of hydrolysis of meclofenoxate hydrochloride in human plasma

The kinetics of hydrolysis of meclofenoxate hydrochloride in human plasma have been compared with those of clofibrate. The hydrolysis rate in fractionated plasma was determined in the presence and absence of a plasma esterase inhibitor, tetraethyl pyrophosphate. The kinetic data indicated that clofibrate decomposed only by esterase-induced hydrolysis, which was inhibited by binding of clofibrate to plasma proteins. In contrast to clofibrate, meclofenoxate decomposed rapidly in human plasma via spontaneous hydrolysis as well as esterase-induced hydrolysis. The spontaneous hydrolysis appeared to be inhibited by some components present in the esterase fraction isolated from plasma, while no significant inhibition of the hydrolysis by protein binding was observed.